Langerhans cell histiocytosis
Proliferative disorder of monocytes
Variants include:
Hand-Schuller-Christian disease
-Skull lesions
-Exophthalmos
-Diabetes insipidus
-Mostly in patients older than 2
Letterer-Siwe syndrome
-Hepatosplenomegaly
-Anemia/hemorrhage
-Patients usually under 2
Histiocytosis X
-solitary eosinophilic granuloma
-bone lesions
-older children (over 2)
-may be observed if asymptomatic
-RT given for lesions recurrent after surgery or refractory to steroids/chemo
-10Gy gives good local control, over 80%
Saturday, September 4, 2010
Retinoblastoma
Epidemiology
300 cases/year
Almost all patients are under 5
60 - 70% sporadic
30 - 40% hereditary (younger patients, more likely to be bilateral, 5 - 10% develop osteosarcoma later in life)
Trilateral RB (Bilateral RB with pineal PNET)
5 to 10% of hereditary RB cases
Biology
Two-hit hypothesis
Rb is tumor suppressor gene located on chromosome 13
If a mutated copy of Rb is inherited, patients are at higher risk of losing the second copy and developing RB
Clinical
Leukocoria, strabismus, decreased visual acuity
Biopsy is contraindicated as it can seed the rest of the eye
Treatment
Primarily laser/surgical
Plaque brachy can be performed
300 cases/year
Almost all patients are under 5
60 - 70% sporadic
30 - 40% hereditary (younger patients, more likely to be bilateral, 5 - 10% develop osteosarcoma later in life)
Trilateral RB (Bilateral RB with pineal PNET)
5 to 10% of hereditary RB cases
Biology
Two-hit hypothesis
Rb is tumor suppressor gene located on chromosome 13
If a mutated copy of Rb is inherited, patients are at higher risk of losing the second copy and developing RB
Clinical
Leukocoria, strabismus, decreased visual acuity
Biopsy is contraindicated as it can seed the rest of the eye
Treatment
Primarily laser/surgical
Plaque brachy can be performed
Neuroblastoma
Epidemiology
Most common cancer in infants
700 cases per year
Median age at diagnosis is 2 years
Screening programs have been tested (famously in Japan) without affecting the mortality rate
No screening is currently offered
Prognostic factors
Unfavorable
-n-myc amplification
-unfavorable Shimada classification
-diploid DNA
-LOH at 1p
-Age older than one year
-Higher stage
Clinical
Most common site adrenal glands, then paraspinal
70% have mets at diagnosis
Skin mets: "Blueberry muffin" sign; blanch when pressed
85% of masses are calcified
Tumor markers: urinary and serum catecholamines (VMA, HVA)
Paraneoplastic syndromes: opsoclonus/myoclonus syndrome, fever, weight loss, hyper-VIP-ism
Staging: should include MIBG scan, bone marrow biopsy
Therapy
Low risk = stage I - II or IVS with favorable histology, normal n-myc, aneuploid
-Surgery only for stage I (gross total resection)
-Surgery + chemo for stage IIA (subtotal resection, node negative)
-Observation for IVS patients
Intermediate risk = stage IIA - IIB with any histology; III (unresectable) with favorable histology, infants with stage IV
-Induction chemo
-Surgery
-RT (24Gy) for residual disease)
High risk = Older than one year with mets; any age or stage with unfavorable pathology
-High intensity chemo with BMT
-Adjuvant cis-retinoic acid
-RT to primary and sites of bulky disease (24-30Gy)
Most common cancer in infants
700 cases per year
Median age at diagnosis is 2 years
Screening programs have been tested (famously in Japan) without affecting the mortality rate
No screening is currently offered
Prognostic factors
Unfavorable
-n-myc amplification
-unfavorable Shimada classification
-diploid DNA
-LOH at 1p
-Age older than one year
-Higher stage
Clinical
Most common site adrenal glands, then paraspinal
70% have mets at diagnosis
Skin mets: "Blueberry muffin" sign; blanch when pressed
85% of masses are calcified
Tumor markers: urinary and serum catecholamines (VMA, HVA)
Paraneoplastic syndromes: opsoclonus/myoclonus syndrome, fever, weight loss, hyper-VIP-ism
Staging: should include MIBG scan, bone marrow biopsy
Therapy
Low risk = stage I - II or IVS with favorable histology, normal n-myc, aneuploid
-Surgery only for stage I (gross total resection)
-Surgery + chemo for stage IIA (subtotal resection, node negative)
-Observation for IVS patients
Intermediate risk = stage IIA - IIB with any histology; III (unresectable) with favorable histology, infants with stage IV
-Induction chemo
-Surgery
-RT (24Gy) for residual disease)
High risk = Older than one year with mets; any age or stage with unfavorable pathology
-High intensity chemo with BMT
-Adjuvant cis-retinoic acid
-RT to primary and sites of bulky disease (24-30Gy)
Wilms tumor
Epidemiology
Most common pediatric renal tumor
450 cases per year
Age: 3 to 4 years
Risk factors
WAGR syndrome (Wilms tumor, aniridia, GU abnormalities, mental retardation)
Denys-Drash syndrome (Wilms tumor, pseudohermaphroditism, renal failure)
Beckwith-Wiedemann syndrome (hemihyperptrophy)
Pathology
WT1: tumor suppressor gene (located at 11p13)
-abnormal in 82% of Wilms patients with a congenital syndrome
-WT1 mutations are more rare in sporadic cases
WT2: mutated in Beckwith-Wiedemann syndrome
Clear cell sarcoma and rhabdoid tumor of the kidney are pediatric tumors that do not represent true Wilm's: rhabdoid tumor of the kidney may be related to ATRT
Prognostic factors
Stage
Histology: anaplastic Wilms (diffuse anaplasia is worse than focal)
LOH @ 1p or 16q
Clinical
Flank mass, hypertension, hematuria
Only 5-10% of tumors are calcified (calcified flank masses are much more likely to be neuroblastoma)
Therapy
Surgery only if:
-Patient less than 2 years old
-Stage I (confined to kidney and completely resected without spillage or biopsy)
-Tumor weighs less than 550g
-Favorable histology
Surgery + chemo if:
-Stage I, any of above criteria not fulfilled
-Any Stage II (extends beyond kidney with complete resection)
Surgery + chemo + RT if:
-Stage II, unfavorable histology (flank gets 10.8Gy)
-Stage III (residual disease), favorable histology (flank gets 10.8Gy)
-Stage III with diffuse anaplasia/RTK (flank gets 19.8Gy)
-Spillage or intra-abdominal tumor implants (whole abdomen gets 19.8Gy)
-Lung mets (12Gy whole lung irradiation, current COG protocol eliminates WLI if pt obtains a rapid complete response to chemo)
-Liver mets (19.8Gy to whole liver)
-Bone mets (25.2Gy)
Bilateral (stage V):
Induction chemo
Nephron sparing surgery if at all possible
Most common pediatric renal tumor
450 cases per year
Age: 3 to 4 years
Risk factors
WAGR syndrome (Wilms tumor, aniridia, GU abnormalities, mental retardation)
Denys-Drash syndrome (Wilms tumor, pseudohermaphroditism, renal failure)
Beckwith-Wiedemann syndrome (hemihyperptrophy)
Pathology
WT1: tumor suppressor gene (located at 11p13)
-abnormal in 82% of Wilms patients with a congenital syndrome
-WT1 mutations are more rare in sporadic cases
WT2: mutated in Beckwith-Wiedemann syndrome
Clear cell sarcoma and rhabdoid tumor of the kidney are pediatric tumors that do not represent true Wilm's: rhabdoid tumor of the kidney may be related to ATRT
Prognostic factors
Stage
Histology: anaplastic Wilms (diffuse anaplasia is worse than focal)
LOH @ 1p or 16q
Clinical
Flank mass, hypertension, hematuria
Only 5-10% of tumors are calcified (calcified flank masses are much more likely to be neuroblastoma)
Therapy
Surgery only if:
-Patient less than 2 years old
-Stage I (confined to kidney and completely resected without spillage or biopsy)
-Tumor weighs less than 550g
-Favorable histology
Surgery + chemo if:
-Stage I, any of above criteria not fulfilled
-Any Stage II (extends beyond kidney with complete resection)
Surgery + chemo + RT if:
-Stage II, unfavorable histology (flank gets 10.8Gy)
-Stage III (residual disease), favorable histology (flank gets 10.8Gy)
-Stage III with diffuse anaplasia/RTK (flank gets 19.8Gy)
-Spillage or intra-abdominal tumor implants (whole abdomen gets 19.8Gy)
-Lung mets (12Gy whole lung irradiation, current COG protocol eliminates WLI if pt obtains a rapid complete response to chemo)
-Liver mets (19.8Gy to whole liver)
-Bone mets (25.2Gy)
Bilateral (stage V):
Induction chemo
Nephron sparing surgery if at all possible
Osteosarcoma
Epidemiology
Most common primary bone tumor of children
700 cases per year
Slightly more common in boys
No racial differences
Adolescents
Risk factors
Prior RT
Hereditary retinoblastoma
Li-Fraumeni syndrome
Paget's disease (adults)
Pathology
Classic: higher grade
Periosteal: variant of classic
Parosteal: indolent, few mets
Clinical
Metaphysis of long bones
40% occur in the femur
90% of tumors are in the extremities
Codman's triangle = periosteal elevation
15% have mets at diagnosis, most common site is lung
Head and neck osteosarcoma seen more frequently in adult patients (mandible/maxilla); poor control with surgery alone and patients should receive chemotherapy
Pelvic and spine tumors are also more difficult to control (but rare)
Prognostic factors
Stage
Extent of necrosis after chemo
Therapy
1) Induction chemo: methotrexate, cisplatin, adriamycin, ifosfamide
2) Resection
3) More chemo
RT: Only for unresectable tumors, positive margin after surgery, palliation
Cade technique: RT with delayed amputation
Most common primary bone tumor of children
700 cases per year
Slightly more common in boys
No racial differences
Adolescents
Risk factors
Prior RT
Hereditary retinoblastoma
Li-Fraumeni syndrome
Paget's disease (adults)
Pathology
Classic: higher grade
Periosteal: variant of classic
Parosteal: indolent, few mets
Clinical
Metaphysis of long bones
40% occur in the femur
90% of tumors are in the extremities
Codman's triangle = periosteal elevation
15% have mets at diagnosis, most common site is lung
Head and neck osteosarcoma seen more frequently in adult patients (mandible/maxilla); poor control with surgery alone and patients should receive chemotherapy
Pelvic and spine tumors are also more difficult to control (but rare)
Prognostic factors
Stage
Extent of necrosis after chemo
Therapy
1) Induction chemo: methotrexate, cisplatin, adriamycin, ifosfamide
2) Resection
3) More chemo
RT: Only for unresectable tumors, positive margin after surgery, palliation
Cade technique: RT with delayed amputation
Ewing sarcoma
Epidemiology
2nd most common pediatric bone tumor (after osteosarcoma)
200 cases per year
Risk factors
57% males
Ages 8 - 25
Rare in blacks
Pathology
t11;22 (EWS gene) or t11;21 (ERG gene)
c-myc amplified
Staining: PAS+, S-100+, vimentin+, neuron specific enolase-, cytokeratin-
Clinical
Most common sites are pelvis (25%) and lower extremity (30%)
Diaphysis of the bone
On imaging: Onion-skinning = subperiosteal involvement; moth eaten bone
25% have mets at diagnosis
Prognostic factors
Unfavorable: tumor in pelvis or trunk, large mass, older age, poor chemo response, mets, unresectable tumor, VEGF+, p53, p16, p14 mutations
Therapy
1) Induction chemo: cyclophosphamide, adriamycin, vincristine, dactinomycin, ifosfamide, etoposide
Response to chemo is highly predictive of the ultimate outcome
2) Surgery: if at all possible
3) RT indications (always given with concurrent chemo)
-Unresectable tumor (55.8Gy)
-Positive or close margins
-Incomplete histologic response
RT technique:
-Whole bone RT is not necessary
-Typical field encompasses the pre-chemo volume + 2-4cm to 36-45Gy then boost residual disease/tumor bed to 50.4Gy or 55.8Gy (residual/unresectable tumor)
-Whole lung RT to 18Gy can be given for mets
2nd most common pediatric bone tumor (after osteosarcoma)
200 cases per year
Risk factors
57% males
Ages 8 - 25
Rare in blacks
Pathology
t11;22 (EWS gene) or t11;21 (ERG gene)
c-myc amplified
Staining: PAS+, S-100+, vimentin+, neuron specific enolase-, cytokeratin-
Clinical
Most common sites are pelvis (25%) and lower extremity (30%)
Diaphysis of the bone
On imaging: Onion-skinning = subperiosteal involvement; moth eaten bone
25% have mets at diagnosis
Prognostic factors
Unfavorable: tumor in pelvis or trunk, large mass, older age, poor chemo response, mets, unresectable tumor, VEGF+, p53, p16, p14 mutations
Therapy
1) Induction chemo: cyclophosphamide, adriamycin, vincristine, dactinomycin, ifosfamide, etoposide
Response to chemo is highly predictive of the ultimate outcome
2) Surgery: if at all possible
3) RT indications (always given with concurrent chemo)
-Unresectable tumor (55.8Gy)
-Positive or close margins
-Incomplete histologic response
RT technique:
-Whole bone RT is not necessary
-Typical field encompasses the pre-chemo volume + 2-4cm to 36-45Gy then boost residual disease/tumor bed to 50.4Gy or 55.8Gy (residual/unresectable tumor)
-Whole lung RT to 18Gy can be given for mets
Monday, August 30, 2010
Rhabdomyosarcoma
Epidemiology
Most common pediatric soft tissue sarcoma; 300-400 cases per year in US
Bimodal age distribution (ages 2-6 and second peak in adolescence)
Risk factors
Male
White
Genetic syndromes: Li-Fraumeni, Gorlin's syndrome; NF
Pathology
1) Embryonal
Most common histology
Infants
Intermediate prognosis (85% 5-year PFS)
Orbit, head and neck, GU sites
LOH 11p15.5; EGFR and fibrillin+
2) Alveolar
Second most common histology
Adolescents
Unfavorable prognosis (66% 5-year PFS)
Trunk, retroperitoneum, extremities
t2;13 is characteristic translocation
3) Spindle cell
Separate, favorable subset of embryonal rhabdo (90% 5-yr PFS)
Associated with paratesticular sites
4) Botyroid
Another favorable subset of embryonal tumors (90% 5-yr PFS)
Grape-like appearance
Mucous membranes (GU, ear, biliary tree)
5) Diffuse anaplastic
Rare and unfavorable subtype with 55% 5-year PFS
Prognostic factors
Histology
Stage
Tumor location:
Favorable sites
Orbit (can decrease dose to 45Gy)
Head and neck -- non-parameningeal sites
Paratesticular
Female GU
Unfavorable sites
Parameningeal (nasopharynx, nasal cavity, paranasal sinus, pterygopalatine fossa, infratemporal fossa, middle ear)
Bladder, prostate, perineal
Extremity
Paraspinal
Retroperitoneal
Thoracic
Therapy
Everyone gets chemo, even after complete resection
Surgery: Fewer than 20% of patients can have complete resection; 20% have resection with microscopic residual disease; 60% are unresectable/metastatic
Chemo: Most active regimen is VAC (vincristine, dactinomycin, cyclophosphamide); pelvic/unresectable tumors also receive adriamycin/cisplatin
Indications for radiation
Alveolar/undifferentiated histology (regardless of stage)
Any stage II or greater tumor
Doses: hyperfractionation has no proven benefit
Orbital tumors: 45Gy
Microscopic disease: 40-41.4Gy (newest IRS protocol decreasing to 36Gy)
Gross disease: 50.4 - 55.8Gy
Most common pediatric soft tissue sarcoma; 300-400 cases per year in US
Bimodal age distribution (ages 2-6 and second peak in adolescence)
Risk factors
Male
White
Genetic syndromes: Li-Fraumeni, Gorlin's syndrome; NF
Pathology
1) Embryonal
Most common histology
Infants
Intermediate prognosis (85% 5-year PFS)
Orbit, head and neck, GU sites
LOH 11p15.5; EGFR and fibrillin+
2) Alveolar
Second most common histology
Adolescents
Unfavorable prognosis (66% 5-year PFS)
Trunk, retroperitoneum, extremities
t2;13 is characteristic translocation
3) Spindle cell
Separate, favorable subset of embryonal rhabdo (90% 5-yr PFS)
Associated with paratesticular sites
4) Botyroid
Another favorable subset of embryonal tumors (90% 5-yr PFS)
Grape-like appearance
Mucous membranes (GU, ear, biliary tree)
5) Diffuse anaplastic
Rare and unfavorable subtype with 55% 5-year PFS
Prognostic factors
Histology
Stage
Tumor location:
Favorable sites
Orbit (can decrease dose to 45Gy)
Head and neck -- non-parameningeal sites
Paratesticular
Female GU
Unfavorable sites
Parameningeal (nasopharynx, nasal cavity, paranasal sinus, pterygopalatine fossa, infratemporal fossa, middle ear)
Bladder, prostate, perineal
Extremity
Paraspinal
Retroperitoneal
Thoracic
Therapy
Everyone gets chemo, even after complete resection
Surgery: Fewer than 20% of patients can have complete resection; 20% have resection with microscopic residual disease; 60% are unresectable/metastatic
Chemo: Most active regimen is VAC (vincristine, dactinomycin, cyclophosphamide); pelvic/unresectable tumors also receive adriamycin/cisplatin
Indications for radiation
Alveolar/undifferentiated histology (regardless of stage)
Any stage II or greater tumor
Doses: hyperfractionation has no proven benefit
Orbital tumors: 45Gy
Microscopic disease: 40-41.4Gy (newest IRS protocol decreasing to 36Gy)
Gross disease: 50.4 - 55.8Gy
Saturday, August 28, 2010
Leukemia
Epidemiology
Most common form of leukemia in adults: CLL; second most is AML
AML is the most common form of chemo-induced leukemia
In children, the most common leukemia is ALL
Risk factors
Radiation exposure
Prior chemotherapy
Smoking
Benzene exposure
Path buzzwords
CML: associated with Philadelphia chromosome and t9;22 which creates the bcr-abl hybrid
CLL: associated with CD5, CD20 (B cell markers)
AML: CD13, 33; t15;17 and t8;21 (which is favorable
ALL: Philadelphia chromosome+ is bad prognostic factor
APL: Variant of AML - retinoids and anthracyclines used to treat
Treatment
Chemo
CML: imatinib (Gleevec)
RT used for: transplant conditioning, chloroma (very low doses needed - ~12Gy), PCI (used rarely)
Most common form of leukemia in adults: CLL; second most is AML
AML is the most common form of chemo-induced leukemia
In children, the most common leukemia is ALL
Risk factors
Radiation exposure
Prior chemotherapy
Smoking
Benzene exposure
Path buzzwords
CML: associated with Philadelphia chromosome and t9;22 which creates the bcr-abl hybrid
CLL: associated with CD5, CD20 (B cell markers)
AML: CD13, 33; t15;17 and t8;21 (which is favorable
ALL: Philadelphia chromosome+ is bad prognostic factor
APL: Variant of AML - retinoids and anthracyclines used to treat
Treatment
Chemo
CML: imatinib (Gleevec)
RT used for: transplant conditioning, chloroma (very low doses needed - ~12Gy), PCI (used rarely)
Myeloma and plasmacytoma
Epidemiology
20,000 cases per year; 11,000 deaths in the US
Incidence is increasing
Risk factors
Age
Male sex
History of MGUS
More common in blacks
Diagnostic criteria for multiple myeloma
Patient needs one major and one minor or three minor criteria
Major criteria
Bone biopsy-proven plasmacytoma
Higher than 30% plasma cells on bone marrow biopsy
Monoclonal globulin spike
Minor criteria
Bone marrow with 10-30% plasma cells
Small M protein spike
Lytic bone lesions
Elevated IgM/IgA/IgG
The stage of multiple myeloma is affected by Hgb, serum calcium, Ig levels, renal function, B2-microglobulin concentrations
Myeloma vs. plasmacytoma
Bone vs. extramedullary plasmacytoma
20,000 cases per year; 11,000 deaths in the US
Incidence is increasing
Risk factors
Age
Male sex
History of MGUS
More common in blacks
Diagnostic criteria for multiple myeloma
Patient needs one major and one minor or three minor criteria
Major criteria
Bone biopsy-proven plasmacytoma
Higher than 30% plasma cells on bone marrow biopsy
Monoclonal globulin spike
Minor criteria
Bone marrow with 10-30% plasma cells
Small M protein spike
Lytic bone lesions
Elevated IgM/IgA/IgG
The stage of multiple myeloma is affected by Hgb, serum calcium, Ig levels, renal function, B2-microglobulin concentrations
Myeloma vs. plasmacytoma
| Multiple myeloma | Plasmacytoma | |
| Age | 60's-70's | 50's-60's |
| Number of bone lesions | Multiple | Single |
| Marrow | Increased plasma cells | Normal |
| RT dose | 25Gy | 40-45Gy |
Bone vs. extramedullary plasmacytoma
| Bone | Extramedullary | |
| Site | Spine | Head and neck |
| Rate of progression to MM | 60-80% | 10-40% |
| Dose | 40-45Gy | 45-50Gy |
| 10-year OS | 50% | 60-80% |
Tuesday, August 24, 2010
Non-Hodgkin lymphoma
Epidemiology
60,000 cases per year; 19,000 deaths in US
Incidence is rising (Aging population?)
Risk factors
Immune deficiency
Autoimmune disease
Multiple infectious associations
-EBV: Burkitt's, primary CNS lymphoma, T/NK cell lymphoma
-HTLV-1: Adult T-cell leukemia and lymphoma
-HHV-8: Kaposi's sarcoma, primary effusion lymphoma
-HCV: splenic marginal zone lymphoma
-H. pylori: gastric MALT lymphoma
-Borrelia, Chlamydia, Campylobacter sp: other mucosal MALT's
Chemical exposure: herbicides, dye, nitrates, arsenic, PVC
Prior RT or chemo
Prior HD
Pathology (most common subtypes)
1) Diffuse large B-cell lymphoma:
-Most common (30% of cases)
-B cell antigen positive (CD 19, 20, 45)
-bcl-6 rearrangement
2) Follicular lymphoma
-22% of cases
-considered low grade/indolent
-high rates of occult bone marrow involvement
-B cell origin
-t14;18 leads to transposition of bcl-2 which decreases apoptosis
3) Marginal zone/MALT
-10% of cases
-Most commonly involves stomach
-trisomy 3, t11;18
-H. pylori and Sjogren's syndrome associated
4) Peripheral T cell lymphoma
-10%
-Most common T cell lymphoma
-ALK+ confers favorable prognosis
5) Small lymphocytic lymphoma
-Thought to represent nodal focus of CLL
6) Mantle cell lymphoma
-t11;14 amplifies bcl-1 which increases cell cycling via cyclin D1
7) Burkitt's lymphoma
-Highly aggressive
-Endemic subtype (Africa) is EBV+
-t14;18 and c-myc amplification
Clinical
Most common sites: neck (70%), groin (60%), axilla (50%)
Most common extranodal sites: GI tract (25-35%), head and neck (20%)
B symptoms in 20-30%
Most patients get a bone marrow bx
International Prognostic Index (IPI) for DLBCL
Earn points for: older than 60, bad performance status (2-4), increased LDH, stage III-IV, more than 2 extranodal sites. 0-1 points has 5-yr OS 73%, 2 points 50%, 3 points 40%, 4-5 points 25%
IPI for follicular lymphoma
Risk factors: age (older than 60), stage III-IV, PS 3-4, hemoglobin under 12, increased LDH, more than 4 involved nodes. 0-1 points has 10-yr OS 70%, 2 points 50%, 3 or more points 35%.
Therapy
Early stage, indolent histology: involved field RT alone (30-40Gy) has local control rates above 80%; however this is a systemic disease and RT is not considered curative despite the durable responses
MALT: first line therapy for gastric MALT lymphoma is triple antibiotic therapy; if this fails, 30Gy to the whole stomach provides better than 90% control and is considered curative. For MALT's occurring outside the GI tract, 24-36Gy are typical doses.
DLBCL: subtype with best data regarding RT. However randomized data incorporating both RT and rituximab is not available.
-SWOG randomized patients with early stage DLBCL to CHOP x 8 vs. CHOP x 3 + RT. The initial report showed an OS benefit to RT (72 vs 82% at 5 years) which disappeared with longer (10-yr) follow-up.
-ECOG randomized patients with early stage DLBCL to CHOP x 8 vs. CHOP x 8 + RT (in complete responders; all partial responders received radiation). RT improved DFS (73 vs 56% at 6 years) with a trend to improved OS.
60,000 cases per year; 19,000 deaths in US
Incidence is rising (Aging population?)
Risk factors
Immune deficiency
Autoimmune disease
Multiple infectious associations
-EBV: Burkitt's, primary CNS lymphoma, T/NK cell lymphoma
-HTLV-1: Adult T-cell leukemia and lymphoma
-HHV-8: Kaposi's sarcoma, primary effusion lymphoma
-HCV: splenic marginal zone lymphoma
-H. pylori: gastric MALT lymphoma
-Borrelia, Chlamydia, Campylobacter sp: other mucosal MALT's
Chemical exposure: herbicides, dye, nitrates, arsenic, PVC
Prior RT or chemo
Prior HD
Pathology (most common subtypes)
1) Diffuse large B-cell lymphoma:
-Most common (30% of cases)
-B cell antigen positive (CD 19, 20, 45)
-bcl-6 rearrangement
2) Follicular lymphoma
-22% of cases
-considered low grade/indolent
-high rates of occult bone marrow involvement
-B cell origin
-t14;18 leads to transposition of bcl-2 which decreases apoptosis
3) Marginal zone/MALT
-10% of cases
-Most commonly involves stomach
-trisomy 3, t11;18
-H. pylori and Sjogren's syndrome associated
4) Peripheral T cell lymphoma
-10%
-Most common T cell lymphoma
-ALK+ confers favorable prognosis
5) Small lymphocytic lymphoma
-Thought to represent nodal focus of CLL
6) Mantle cell lymphoma
-t11;14 amplifies bcl-1 which increases cell cycling via cyclin D1
7) Burkitt's lymphoma
-Highly aggressive
-Endemic subtype (Africa) is EBV+
-t14;18 and c-myc amplification
Clinical
Most common sites: neck (70%), groin (60%), axilla (50%)
Most common extranodal sites: GI tract (25-35%), head and neck (20%)
B symptoms in 20-30%
Most patients get a bone marrow bx
International Prognostic Index (IPI) for DLBCL
Earn points for: older than 60, bad performance status (2-4), increased LDH, stage III-IV, more than 2 extranodal sites. 0-1 points has 5-yr OS 73%, 2 points 50%, 3 points 40%, 4-5 points 25%
IPI for follicular lymphoma
Risk factors: age (older than 60), stage III-IV, PS 3-4, hemoglobin under 12, increased LDH, more than 4 involved nodes. 0-1 points has 10-yr OS 70%, 2 points 50%, 3 or more points 35%.
Therapy
Early stage, indolent histology: involved field RT alone (30-40Gy) has local control rates above 80%; however this is a systemic disease and RT is not considered curative despite the durable responses
MALT: first line therapy for gastric MALT lymphoma is triple antibiotic therapy; if this fails, 30Gy to the whole stomach provides better than 90% control and is considered curative. For MALT's occurring outside the GI tract, 24-36Gy are typical doses.
DLBCL: subtype with best data regarding RT. However randomized data incorporating both RT and rituximab is not available.
-SWOG randomized patients with early stage DLBCL to CHOP x 8 vs. CHOP x 3 + RT. The initial report showed an OS benefit to RT (72 vs 82% at 5 years) which disappeared with longer (10-yr) follow-up.
-ECOG randomized patients with early stage DLBCL to CHOP x 8 vs. CHOP x 8 + RT (in complete responders; all partial responders received radiation). RT improved DFS (73 vs 56% at 6 years) with a trend to improved OS.
Monday, August 23, 2010
Hodgkin's disease
Epidemiology
8,000 cases/year in US
Risk factors
Male to female ratio is 1.3:1
Bimodal age peaks: 20's and 50's
Higher incidence in whites
Family history
EBV infection/history of mononucleosis
High socioeconomic status
Few siblings/Early birth order (affects immunity?)
Pathology
Classical HD (CD15+, CD30+) subtypes
1) Nodular sclerosing: Most common subtype in US
2) Mixed cellularity: Patients are slightly older, men; favorable histology; non-industrialized countries
3) Lymphocyte depleted: Very rare, older patients, worse prognosis
4) Lymphocyte rich: 4% of cases
Non-classical HD (CD15-, CD30-, CD20+, CD45+)
1) Lymphocyte predominant: Most favorable histology (RT alone can cure) but has a higher risk of transforming into NHL; typical presentation is with solitary peripheral node
Clinical
Most commonly involved nodes are cervical (80%) and mediastinal (50%)
Stage with PET-CT
Bone marrow bx if stage III-IV or abnormal CBC/B symptoms
B symptoms
-Recurrent fever higher than 100F
-More than 10% weight loss
-Recurrent drenching night sweats
Risk groupings
-EORTC: Favorable if stage I-II, younger than 50, ESR less than 50 with no B symptoms or less than 30 with B symptoms. Unfavorable if stage III-IV, 4 or more nodal regions involved, older than 50, ESR above cutoff, bulky disease
-German HD: Similar to EORTC without age limit and with 3 or more sites being unfavorable
-NCIC: Age cutoff at 40 for unfavorable; histology (mixed/LD bad); includes bulky mediastinal disease
Therapy
Early stage
-ABVD x 4 then consolidation RT to 30Gy
-Three European studies established involved field RT as equivalent to subtotal nodal RT
-Recently updated German HD Study Group protocol suggests that 20Gy can provide durable control
-Chemo alone is associated with worse relapse free survival and higher rates of failure requiring transplant but similar overall survival compared with CRT (Mumbia, GELA H9F, NCIC/ECOG)
Advanced/bulky/unfavorable
RT may be indicated in partial responders
Currently RT is not part of standard therapy for complete responders to chemo with stage III-IV disease
(Aleman trial)
Chemo regimens
MOPP = Mechlorethamine, vincristine, procarbazine, prednisone
-Side effects include n/v, neuropathy, infertility, second malignancy (AML)
ABVD = Adriamycin, bleomycin, vinblastine, dacarbazine
-Side effects include cardiac damage, pulmonary fibrosis (improved preservation of fertility and fewer second malignancies)
Stanford V = Mechlorethamine, adriamycin, vincristine, vinblastine, bleomycin, etoposide, prednisone
-RT is a critical part of the regimen (even for stage III-IV) because chemo intensity was lowered to include RT as part of the treatment protocol
Side effects of therapy
Pneumonitis: 5%
Pericarditis: 5% (unclear if still true with modern planning)
Hypothyroidism: 50%
Zoster: 10-15%
L'Hermitte's syndrome: 10-15%
Elevated risk of second cancers (Leukemia 800%, lymphoma 500%, lung cancer 10%, breast cancer 10%)
Elevated cardiac mortality (300%)
8,000 cases/year in US
Risk factors
Male to female ratio is 1.3:1
Bimodal age peaks: 20's and 50's
Higher incidence in whites
Family history
EBV infection/history of mononucleosis
High socioeconomic status
Few siblings/Early birth order (affects immunity?)
Pathology
Classical HD (CD15+, CD30+) subtypes
1) Nodular sclerosing: Most common subtype in US
2) Mixed cellularity: Patients are slightly older, men; favorable histology; non-industrialized countries
3) Lymphocyte depleted: Very rare, older patients, worse prognosis
4) Lymphocyte rich: 4% of cases
Non-classical HD (CD15-, CD30-, CD20+, CD45+)
1) Lymphocyte predominant: Most favorable histology (RT alone can cure) but has a higher risk of transforming into NHL; typical presentation is with solitary peripheral node
Clinical
Most commonly involved nodes are cervical (80%) and mediastinal (50%)
Stage with PET-CT
Bone marrow bx if stage III-IV or abnormal CBC/B symptoms
B symptoms
-Recurrent fever higher than 100F
-More than 10% weight loss
-Recurrent drenching night sweats
Risk groupings
-EORTC: Favorable if stage I-II, younger than 50, ESR less than 50 with no B symptoms or less than 30 with B symptoms. Unfavorable if stage III-IV, 4 or more nodal regions involved, older than 50, ESR above cutoff, bulky disease
-German HD: Similar to EORTC without age limit and with 3 or more sites being unfavorable
-NCIC: Age cutoff at 40 for unfavorable; histology (mixed/LD bad); includes bulky mediastinal disease
Therapy
Early stage
-ABVD x 4 then consolidation RT to 30Gy
-Three European studies established involved field RT as equivalent to subtotal nodal RT
-Recently updated German HD Study Group protocol suggests that 20Gy can provide durable control
-Chemo alone is associated with worse relapse free survival and higher rates of failure requiring transplant but similar overall survival compared with CRT (Mumbia, GELA H9F, NCIC/ECOG)
Advanced/bulky/unfavorable
RT may be indicated in partial responders
Currently RT is not part of standard therapy for complete responders to chemo with stage III-IV disease
(Aleman trial)
Chemo regimens
MOPP = Mechlorethamine, vincristine, procarbazine, prednisone
-Side effects include n/v, neuropathy, infertility, second malignancy (AML)
ABVD = Adriamycin, bleomycin, vinblastine, dacarbazine
-Side effects include cardiac damage, pulmonary fibrosis (improved preservation of fertility and fewer second malignancies)
Stanford V = Mechlorethamine, adriamycin, vincristine, vinblastine, bleomycin, etoposide, prednisone
-RT is a critical part of the regimen (even for stage III-IV) because chemo intensity was lowered to include RT as part of the treatment protocol
Side effects of therapy
Pneumonitis: 5%
Pericarditis: 5% (unclear if still true with modern planning)
Hypothyroidism: 50%
Zoster: 10-15%
L'Hermitte's syndrome: 10-15%
Elevated risk of second cancers (Leukemia 800%, lymphoma 500%, lung cancer 10%, breast cancer 10%)
Elevated cardiac mortality (300%)
Vulvar cancer
Nodal drainage
Superficial and deep inguinal nodes
Cloquet's node: superior-most deep inguinal node; lives under the inguinal ligament
Epidemiology
3700 cases, 900 deaths per year in US
Risk factors
The usual suspects: HPV, immune suppression, herpes simplex, prior vaginal/cervical cancer
Diabetes
Hypertension
Low SES
Smoking
Working in dry cleaning
Vulvar intraepithelial neoplasia, leukoplakia
Vulvar cancer associated with a higher incidence of non-gynecologic malignancy as well
Pathology
Labia most common site
Precursor lesion = lichen sclerosis
85% are squamous cell, 10% melanoma
Paget's disease of vulva: associated with underlying invasive cancer in 20-30%
Confluent lesions - highly invasive
Compact lesions - usually well differentiated
Fingerlike lesions - usually infiltrative with high rates of LVSI
Clinical
75% of palpable inguinal nodes are positive upon dissection
30% of patients with positive inguinal nodes have positive pelvic nodes
Prognostic factors: nodes are most important; tumor size and depth of invasion determine nodal risk; others include tumor grade, LVSI, age.
Therapy
Almost all patients require inguinal node dissection (can only omit if the tumor is less than 1mm deep)
Margins should be at least 1cm in fresh specimens, 8mm in fixed
There are two famous trials in vulvar cancer:
1) Patients who already had known inguinal disease after inguinal dissection were randomized to pelvic and bilateral groin RT to 50Gy. RT improved overall survival at two years (68 vs 54%). The largest advantage to RT was seen in patients with at least 2 nodes or fixed/ulcerated nodes.
2) Patients with clinically negative groins were randomized to radical vulvectomy with inguinal dissection vs. radical vulvectomy with inguinal RT to 50Gy. The trial was stopped early due to better survival in the surgery group (88 vs 63% at 3 years). There was a 0% risk of groin failure in the surgery group and an 18% risk in the RT group. This trial has been roundly criticized for the fact that the fields were prescribed to a depth of 3cm which is not deep enough to adequately cover the inguinal nodes in most women. Furthermore, if patients had + nodes on surgery, RT was given (20% of women).
Superficial and deep inguinal nodes
Cloquet's node: superior-most deep inguinal node; lives under the inguinal ligament
Epidemiology
3700 cases, 900 deaths per year in US
Risk factors
The usual suspects: HPV, immune suppression, herpes simplex, prior vaginal/cervical cancer
Diabetes
Hypertension
Low SES
Smoking
Working in dry cleaning
Vulvar intraepithelial neoplasia, leukoplakia
Vulvar cancer associated with a higher incidence of non-gynecologic malignancy as well
Pathology
Labia most common site
Precursor lesion = lichen sclerosis
85% are squamous cell, 10% melanoma
Paget's disease of vulva: associated with underlying invasive cancer in 20-30%
Confluent lesions - highly invasive
Compact lesions - usually well differentiated
Fingerlike lesions - usually infiltrative with high rates of LVSI
Clinical
75% of palpable inguinal nodes are positive upon dissection
30% of patients with positive inguinal nodes have positive pelvic nodes
Prognostic factors: nodes are most important; tumor size and depth of invasion determine nodal risk; others include tumor grade, LVSI, age.
Therapy
Almost all patients require inguinal node dissection (can only omit if the tumor is less than 1mm deep)
Margins should be at least 1cm in fresh specimens, 8mm in fixed
There are two famous trials in vulvar cancer:
1) Patients who already had known inguinal disease after inguinal dissection were randomized to pelvic and bilateral groin RT to 50Gy. RT improved overall survival at two years (68 vs 54%). The largest advantage to RT was seen in patients with at least 2 nodes or fixed/ulcerated nodes.
2) Patients with clinically negative groins were randomized to radical vulvectomy with inguinal dissection vs. radical vulvectomy with inguinal RT to 50Gy. The trial was stopped early due to better survival in the surgery group (88 vs 63% at 3 years). There was a 0% risk of groin failure in the surgery group and an 18% risk in the RT group. This trial has been roundly criticized for the fact that the fields were prescribed to a depth of 3cm which is not deep enough to adequately cover the inguinal nodes in most women. Furthermore, if patients had + nodes on surgery, RT was given (20% of women).
Sunday, August 22, 2010
Vaginal cancer
Nodal drainage
Proximal 1/3 drains to internal iliac via cervical lymphatics
Distal 1/3 drains to inguinal nodes and external iliac
Posterior to the presacral, perirectal nodes
Extensive communication along the entire vaginal nodal network
Epidemiology
2400 cases per year, 800 deaths
Risk factors
Age
HPV
Prior cervical cancer
Vaginal intraepithelial neoplasia
DES exposure associated with clear cell vaginal carcinoma
Vaginal adenosis
Chronic irritation leads to squamous cell ca
Pathology
80-90% are SCC with VAIN as precursor lesion and HPV association
To diagnose a vaginal SCC, no cervical or vulvar involvement may be present and patient cannot have a diagnosis of cervical cancer within the past 5 years (otherwise considered recurrent cervix ca)
Clear cell cancer: associated with DES, vaginal adenosis; usually in proximal 1/3 of vagina
Melanoma: second most common histology (3-5%); most commonly lower 1/3, anterior wall
Clinical
Goes to nodes early; node risk correlates with clinical stage
Stage I: 5-15% risk; Stage II: 30%
Nodal stage is the most important prognostic factor
Others include tumor grade, non-squamous histology
Treatment
VAIN/Carcinoma in situ: Surgery or brachytherapy alone (50-60Gy to whole vagina, 70-80Gy to tumor)
Stage I (Limited to vaginal wall): Brachy alone (60Gy to whole vagina, 20-30Gy tumor boost)
Stage II and up: requires WPRT because of high risk of nodal involvement; interstitial brachy often preferred; total dose to tumor 75-80Gy
Proximal 1/3 drains to internal iliac via cervical lymphatics
Distal 1/3 drains to inguinal nodes and external iliac
Posterior to the presacral, perirectal nodes
Extensive communication along the entire vaginal nodal network
Epidemiology
2400 cases per year, 800 deaths
Risk factors
Age
HPV
Prior cervical cancer
Vaginal intraepithelial neoplasia
DES exposure associated with clear cell vaginal carcinoma
Vaginal adenosis
Chronic irritation leads to squamous cell ca
Pathology
80-90% are SCC with VAIN as precursor lesion and HPV association
To diagnose a vaginal SCC, no cervical or vulvar involvement may be present and patient cannot have a diagnosis of cervical cancer within the past 5 years (otherwise considered recurrent cervix ca)
Clear cell cancer: associated with DES, vaginal adenosis; usually in proximal 1/3 of vagina
Melanoma: second most common histology (3-5%); most commonly lower 1/3, anterior wall
Clinical
Goes to nodes early; node risk correlates with clinical stage
Stage I: 5-15% risk; Stage II: 30%
Nodal stage is the most important prognostic factor
Others include tumor grade, non-squamous histology
Treatment
VAIN/Carcinoma in situ: Surgery or brachytherapy alone (50-60Gy to whole vagina, 70-80Gy to tumor)
Stage I (Limited to vaginal wall): Brachy alone (60Gy to whole vagina, 20-30Gy tumor boost)
Stage II and up: requires WPRT because of high risk of nodal involvement; interstitial brachy often preferred; total dose to tumor 75-80Gy
Cervical cancer
Epidemiology
11,000 cases per year in US; 3500 deaths
60,000 cases of cervical carcinoma in situ
Risk factors
HPV16 - squamous cell
HPV18 - adenocarcinoma
HIV
DES exposure - clear cell cancers of cervix and vagina
Smoking
Higher rates in black women
More common in younger women
Pathology
80% squamous, 10% adeno, 5% mixed adeno/squamous
Rare histologies include small cell (high rate of node mets; associated with HPV18)
Pap smear abnormalities
1) ASCUS: test for HPV; if + go to colposcopy; if negative repeat pap in 6 to 12 months
2) LGSIL: colposcopy
3) HGSIL: LEEP/conization
Prognostic factors
Age
Race
Socioeconomic status
Anemia
Tumor size
Cell type does not matter
Therapy
Microscopic disease
IA1: local excision only or simple hysterecomy (no PLND)
IA2: radical hysterectomy (removes uterus, cervix, parametria, upper vagina and do PLND)
Medically inoperable: brachy alone to 70Gy for IA1; brachy + WPRT for IA2
Localized, non-bulky disease
Single modality treatment is OK
Radical hysterectomy, or,
WPRT + brachy (total tumor dose 80-85Gy)
Risk factors which buy you radiation after hysterectomy
Deep stromal invasion (deeper than 1/3), LVSI, tumor larger than 4cm
Rotman: randomized patients with any of these risk factors to postop RT (WPRT 46 - 50.4Gy) vs. observation. RT had a significant PFS benefit (HR for progression 0.6) with a strong trend to improved OS (HR for death 0.7).
Risk factors which buy you chemo-radiation after hysterectomy
3 P's: positive margins, positive nodes, parametrial invasion
Peters: randomized women with any of these risk factors to postop RT (WPRT to 45Gy) vs. RT + concurrent cis/5-FU.
Chemotherapy had a significant OS benefit (81 vs 71% at 5 years) and PFS benefit (80 vs. 63% at 5 years) with increased acute toxicity (hematologic, GI)
Locally advanced/bulky disease
Therapy includes concurrent chemo/RT/brachy
Brachytherapy technique
Point A = 2cm superior and 2cm lateral to flange on tandem; represents uterine vessels
Point B = 2cm superior and 5cm lateral to flange on tandem; represents parametrium/pelvic sidewall
Bladder point = center of Foley balloon
Rectal point = 5mm posterior to the posterior edge of vaginal packing
Both bladder and rectal points should receive < 75Gy
You should be able to ID the sigmoid colon on a CT scan
A good implant:
-Tandem bisects colpostats on lateral view (at midline on the AP)
-Colpostats sit above the flange
-Sufficient anterior and posterior packing to separate the bladder/rectum from the high dose areas
LDR to HDR conversion ratio: 1:0.54
Most common HDR fractionation is 6Gy x 5
11,000 cases per year in US; 3500 deaths
60,000 cases of cervical carcinoma in situ
Risk factors
HPV16 - squamous cell
HPV18 - adenocarcinoma
HIV
DES exposure - clear cell cancers of cervix and vagina
Smoking
Higher rates in black women
More common in younger women
Pathology
80% squamous, 10% adeno, 5% mixed adeno/squamous
Rare histologies include small cell (high rate of node mets; associated with HPV18)
Pap smear abnormalities
1) ASCUS: test for HPV; if + go to colposcopy; if negative repeat pap in 6 to 12 months
2) LGSIL: colposcopy
3) HGSIL: LEEP/conization
Prognostic factors
Age
Race
Socioeconomic status
Anemia
Tumor size
Cell type does not matter
Therapy
Microscopic disease
IA1: local excision only or simple hysterecomy (no PLND)
IA2: radical hysterectomy (removes uterus, cervix, parametria, upper vagina and do PLND)
Medically inoperable: brachy alone to 70Gy for IA1; brachy + WPRT for IA2
Localized, non-bulky disease
Single modality treatment is OK
Radical hysterectomy, or,
WPRT + brachy (total tumor dose 80-85Gy)
Risk factors which buy you radiation after hysterectomy
Deep stromal invasion (deeper than 1/3), LVSI, tumor larger than 4cm
Rotman: randomized patients with any of these risk factors to postop RT (WPRT 46 - 50.4Gy) vs. observation. RT had a significant PFS benefit (HR for progression 0.6) with a strong trend to improved OS (HR for death 0.7).
Risk factors which buy you chemo-radiation after hysterectomy
3 P's: positive margins, positive nodes, parametrial invasion
Peters: randomized women with any of these risk factors to postop RT (WPRT to 45Gy) vs. RT + concurrent cis/5-FU.
Chemotherapy had a significant OS benefit (81 vs 71% at 5 years) and PFS benefit (80 vs. 63% at 5 years) with increased acute toxicity (hematologic, GI)
Locally advanced/bulky disease
Therapy includes concurrent chemo/RT/brachy
| Study | OS | PFS | |
| RTOG 7920 | WPRT | 55% | |
| WPRT + PA RT | 65% | ||
| RTOG 9001 | WPRT+PA RT | 43% | 43% |
| WPRT + Cis-5FU | 73% | 68% | |
| GOG 123 | RT then surgery | 75% | 68% |
| CRT then surgery | 85% | 82% |
Brachytherapy technique
Point A = 2cm superior and 2cm lateral to flange on tandem; represents uterine vessels
Point B = 2cm superior and 5cm lateral to flange on tandem; represents parametrium/pelvic sidewall
Bladder point = center of Foley balloon
Rectal point = 5mm posterior to the posterior edge of vaginal packing
Both bladder and rectal points should receive < 75Gy
You should be able to ID the sigmoid colon on a CT scan
A good implant:
-Tandem bisects colpostats on lateral view (at midline on the AP)
-Colpostats sit above the flange
-Sufficient anterior and posterior packing to separate the bladder/rectum from the high dose areas
LDR to HDR conversion ratio: 1:0.54
Most common HDR fractionation is 6Gy x 5
Monday, August 16, 2010
Testicular cancer
Anatomy
Lymph nodes:
-Right testicle goes directly to PA nodes
-Left testicle drains first to left renal hilum then to PA nodes
Epidemiology
8,000 cases per year, 300 deaths in US
Peak incidence at 15-34 years; non-germinomatous tumors tend to present younger
Worldwide, incidence is going up for unclear reasons
Risk factors
Cryptorchidism
Testicular trauma
Klinefelter's syndrome (Mediastinal germinoma)
Immune suppression
White males
Infertility
Family history
Prior testicular cancer
Pathology
Seminoma
Most common type (more than 50%)
15-30% of seminomas produce B-hCG but all are AFP negative
Spermatocytic subtype of seminoma presents in older men; surgery alone is curative
Non-seminomatous tumors
-Mixed histology is much more common than any of the individual tumors in pure form
-Embryonal tumors: PLAP+; AFP+ in 33%, B-hCG in 20%; about 3% of pure NGGCT
-Yolk sac tumors: elevated AFP; about 2% of pure NGGCT
-Teratoma: normal AFP (5%)
-Choriocarcinoma: elevated B-hCG; aggressive (less than 1%)
Half-lives of tumor markers
AFP: 5 days
B-hCG: 1 day
PLAP: 1 day
Clinical
85% of seminomas are stage I at diagnosis
Workup
Testicular ultrasound
CT of chest-abdomen-pelvis
Tumor markers, LDH
Fertility counseling
Radical inguinal orchiectomy is diagnostic and therapeutic for both seminoma and non-seminoma
Scrotal violation during surgery is associated with worse local control (3 vs 0.5% local failure rates) but no difference in overall survival
In patients with non-seminomatous histology, retroperitoneal LND is also performed
Prognostic factors
Histology
Tumor size
Rete testis invasion
Site of mets (lung vs. elsewhere)
Tumor marker levels
Mediastinal primaries do worse
Therapy
Stage I seminoma
Fields: PA only vs. PA and pelvic
-Identical 5-yr RFS (96%)
-Slightly better pelvic control in PA and pelvic arm (100% vs 98%)
-Statistically identical OS (99.3 vs 100%)
-Worse toxicity (nausea, longer delay in sperm count recovery) in PA and pelvic arm
Doses: 20 vs 30Gy
-Identical 5-year RFS (97%)
-Statistically identical pelvic control and overall survival
-Worse toxicity (lethargy, increased time out of work) in 30Gy arm
RT vs. carboplatin
-Statistically identical RFS (~95%), pelvic control, and overall survival
-Chemotherapy arm had fewer contralateral testicular tumors
Stage II seminoma
RT recommended for nodes less than 5cm (stage IIA-B)
Stage IIC and higher get chemo as do all non-seminomatous GCTs
Mediastinal seminoma: give higher doses to improve tumor control (40-50Gy??)
Testicular tolerance to radiation
Temporary drop in sperm count at 0.5Gy
Permanent oligospermia at 2Gy
Permanent sterility at 3-4Gy
Endocrine function maintained at least to 30Gy
Lymph nodes:
-Right testicle goes directly to PA nodes
-Left testicle drains first to left renal hilum then to PA nodes
Epidemiology
8,000 cases per year, 300 deaths in US
Peak incidence at 15-34 years; non-germinomatous tumors tend to present younger
Worldwide, incidence is going up for unclear reasons
Risk factors
Cryptorchidism
Testicular trauma
Klinefelter's syndrome (Mediastinal germinoma)
Immune suppression
White males
Infertility
Family history
Prior testicular cancer
Pathology
Seminoma
Most common type (more than 50%)
15-30% of seminomas produce B-hCG but all are AFP negative
Spermatocytic subtype of seminoma presents in older men; surgery alone is curative
Non-seminomatous tumors
-Mixed histology is much more common than any of the individual tumors in pure form
-Embryonal tumors: PLAP+; AFP+ in 33%, B-hCG in 20%; about 3% of pure NGGCT
-Yolk sac tumors: elevated AFP; about 2% of pure NGGCT
-Teratoma: normal AFP (5%)
-Choriocarcinoma: elevated B-hCG; aggressive (less than 1%)
Half-lives of tumor markers
AFP: 5 days
B-hCG: 1 day
PLAP: 1 day
Clinical
85% of seminomas are stage I at diagnosis
Workup
Testicular ultrasound
CT of chest-abdomen-pelvis
Tumor markers, LDH
Fertility counseling
Radical inguinal orchiectomy is diagnostic and therapeutic for both seminoma and non-seminoma
Scrotal violation during surgery is associated with worse local control (3 vs 0.5% local failure rates) but no difference in overall survival
In patients with non-seminomatous histology, retroperitoneal LND is also performed
Prognostic factors
Histology
Tumor size
Rete testis invasion
Site of mets (lung vs. elsewhere)
Tumor marker levels
Mediastinal primaries do worse
Therapy
Stage I seminoma
Fields: PA only vs. PA and pelvic
-Identical 5-yr RFS (96%)
-Slightly better pelvic control in PA and pelvic arm (100% vs 98%)
-Statistically identical OS (99.3 vs 100%)
-Worse toxicity (nausea, longer delay in sperm count recovery) in PA and pelvic arm
Doses: 20 vs 30Gy
-Identical 5-year RFS (97%)
-Statistically identical pelvic control and overall survival
-Worse toxicity (lethargy, increased time out of work) in 30Gy arm
RT vs. carboplatin
-Statistically identical RFS (~95%), pelvic control, and overall survival
-Chemotherapy arm had fewer contralateral testicular tumors
Stage II seminoma
RT recommended for nodes less than 5cm (stage IIA-B)
Stage IIC and higher get chemo as do all non-seminomatous GCTs
Mediastinal seminoma: give higher doses to improve tumor control (40-50Gy??)
Testicular tolerance to radiation
Temporary drop in sperm count at 0.5Gy
Permanent oligospermia at 2Gy
Permanent sterility at 3-4Gy
Endocrine function maintained at least to 30Gy
Thursday, August 5, 2010
Prostate cancer
Anatomy
Zones of the prostate
Peripheral: most common site of cancer
Transition: source of BPH and the median lobe; cancer rarely presents here
Central: surrounds the ejaculatory duct
Fibromuscular stroma: anterior
Nodal drainage
Obturator/internal iliac/periprostatic/external iliac
Roach formula for nodal risk
% LN involvement = 2/3 PSA + (Gleason score - 6) x 10
Epidemiology
Most common cancer in US men; 230,000 cases per year, 27,000 deaths
More common in black men
Risk factors
Age (most important) - median age of diagnosis is 68 years
Family history
High fat diet
Geographic: incidence high in Scandinavia, low in Asia
Pathology
Adenocarcinoma in the majority of patients (>90%)
Transitional cell, small cell, lymphoma, adenoid cystic, sarcoma are rare histologies
Clinical
Screening
DRE and PSA recommended starting at 50 (45 in black men, men with + family history)
PSA
Free PSA is lower in patients with cancer (usually <20%)
PSA density = serum PSA/prostate volume; higher PSA density is associated with the presence of cancer
PSA velocity = change in PSA over time; increases faster than 0.75ng/ml/year are associated with malignancy; PSA rise more than 2 ng/ml/year in patients with an established diagnosis of prostate cancer is associated with a worse prognosis
Workup
All patients: H&P, rectal exam, PSA, TRUS
Bone scan if PSA higher than 20
CT of abdomen/pelvis/prostate MRI in higher-risk patients
Chemoprevention
Finasteride decreases risk of prostate cancer in a randomized controlled trial
Higher proportion of Gleason 7-10 tumors in the finasteride group
Risk groups
D'Amico
-Low risk: PSA less than or equal to 10, Gleason 6 or less, T1 - T2a
-Intermediate risk: PSA 10 - 20 or Gleason 7 or T2b
-High risk: PSA higher than 20, Gleason 8 - 10, T2c and up
Other prognostic factors
% positive cores: predicts bRFS, OS
PSA velocity: predicts bRFS, OS
Treatment
Low risk - prostate only treatment
1) Prostatectomy
Scandinavian Prostate Cancer Group randomized men to observation vs. prostatectomy
RP improved survival in men under 65
2) Brachytherapy
Candidates for brachy as monotherapy: T1b-T2b, PSA less than 10, Gleason 6 or less
Candidates for brachy boost: T2c, Gleason 7 or higher, PSA 10 - 20
Contraindications: severe urinary obstructive symptoms, TURP defect, large median lobe, pubic arch interference, prostate larger than 60g, positive nodes, seminal vesicle invasion, inflammatory bowel disease (relative)
I-125
Half life 59 days
Rx dose for definitive therapy: 145Gy
Rx dose for boost: 110Gy
Pd-103
Half life 17 days
Rx dose for definitive therapy: 125Gy
Rx dose for boost: 100Gy
Randomized trial did not show any difference in tumor control nor toxicity between the two sources
Post-implant dosimetry
V100 should be greater than 90%
D90 is 140-145Gy for I-125 and 120-125Gy for Pd-103
Mean urethra dose should be less than 150% or V150 of urethra less than 50%
Rectum: V100 should be less than 1cc
3) External beam radiation
Dose escalation tested in multiple RCTs
-Pollak: 70 vs 78Gy to isocenter (3D-CRT technique)
bRFS improved in the high dose group
Subgroup analysis confirmed benefit only in patients with PSA greater than 10
-Protons: 70.2 vs. 79.2Gy (protons used for boost phase of treatment only)
Overall improved bRFS in high dose arm (5-yr bRFS 61 vs 80%)
Advantage was also seen in low risk pts with PSA less than 10, T2a disease, Gleason 6
-Dutch (Peeters) - 68 vs 78Gy
bRFS 54 vs 64% at 4 years
High risk
1) Androgen deprivation
GnRH analogues: leuprolide, goserelin; decrease pituitary secretion of LH and FSH; associated with flare of bone pain, hot flashes, decreased libido (acutely); gynecomastia, osteoporosis, muscle wasting, depression with long term use
Testosterone receptor blockers: flutamide, bicalutamide
Suppression of adrenal testosterone: ketoconazole
Trials of hormone therapy
EORTC (Bolla): High grade T1/2, any T3/4 randomized to 70Gy + 3 years ADT vs. 70Gy alone
-ADT improved OS (78 vs 62%) and CSS (94 vs 79%) at 5 years
RTOG 9202: T2c - T4 tumors randomized to 70Gy + 4 months ADT vs. 70Gy + 4 months + 2 years adjuvant ADT
-No benefit seen to prolonged ADT among all patients
-OS was improved in Gleason 8 - 10 patients (ad hoc analysis)
RTOG 8610: T2 - T4 tumors randomized to RT alone vs. RT + ADT
-Trend to improved 10 year OS in ADT group (43 vs 34%); improved CSS and bRFS
D'amico: High risk patients (PSA higher than 10, Gleason 7 or higher, ECE) randomized to 70Gy alone vs 70Gy + 6 months ADT
-Improved 5-year OS in ADT group (88 vs 78%)
RTOG 9413: 4 arm trial, whole pelvis/prostate only; neoadjuvant vs neoadjuvant and concurrent ADT
Best bRFS seen in whole pelvis + neoadjuvant and concurrent group
Benefit thought to be sequence dependent
Trial nearly impossible to interpret
Post-prostatectomy
SWOG: T3/+ margins randomized to RT (60 - 64Gy) vs observation (salvage RT given to 1/3 of the observation group)
-RT improved median OS (15.2 vs 13.3 years) and met-free survival (64 vs 57% at 10 years)
Benefits seen across all subgroups
EORTC: T3/+ margins randomized to 60Gy vs. observation
-5-year PFS improved in RT group (74 vs 53%)
Zones of the prostate
Peripheral: most common site of cancer
Transition: source of BPH and the median lobe; cancer rarely presents here
Central: surrounds the ejaculatory duct
Fibromuscular stroma: anterior
Nodal drainage
Obturator/internal iliac/periprostatic/external iliac
Roach formula for nodal risk
% LN involvement = 2/3 PSA + (Gleason score - 6) x 10
Epidemiology
Most common cancer in US men; 230,000 cases per year, 27,000 deaths
More common in black men
Risk factors
Age (most important) - median age of diagnosis is 68 years
Family history
High fat diet
Geographic: incidence high in Scandinavia, low in Asia
Pathology
Adenocarcinoma in the majority of patients (>90%)
Transitional cell, small cell, lymphoma, adenoid cystic, sarcoma are rare histologies
Clinical
Screening
DRE and PSA recommended starting at 50 (45 in black men, men with + family history)
PSA
Free PSA is lower in patients with cancer (usually <20%)
PSA density = serum PSA/prostate volume; higher PSA density is associated with the presence of cancer
PSA velocity = change in PSA over time; increases faster than 0.75ng/ml/year are associated with malignancy; PSA rise more than 2 ng/ml/year in patients with an established diagnosis of prostate cancer is associated with a worse prognosis
Workup
All patients: H&P, rectal exam, PSA, TRUS
Bone scan if PSA higher than 20
CT of abdomen/pelvis/prostate MRI in higher-risk patients
Chemoprevention
Finasteride decreases risk of prostate cancer in a randomized controlled trial
Higher proportion of Gleason 7-10 tumors in the finasteride group
Risk groups
D'Amico
-Low risk: PSA less than or equal to 10, Gleason 6 or less, T1 - T2a
-Intermediate risk: PSA 10 - 20 or Gleason 7 or T2b
-High risk: PSA higher than 20, Gleason 8 - 10, T2c and up
Other prognostic factors
% positive cores: predicts bRFS, OS
PSA velocity: predicts bRFS, OS
Treatment
Low risk - prostate only treatment
1) Prostatectomy
Scandinavian Prostate Cancer Group randomized men to observation vs. prostatectomy
RP improved survival in men under 65
2) Brachytherapy
Candidates for brachy as monotherapy: T1b-T2b, PSA less than 10, Gleason 6 or less
Candidates for brachy boost: T2c, Gleason 7 or higher, PSA 10 - 20
Contraindications: severe urinary obstructive symptoms, TURP defect, large median lobe, pubic arch interference, prostate larger than 60g, positive nodes, seminal vesicle invasion, inflammatory bowel disease (relative)
I-125
Half life 59 days
Rx dose for definitive therapy: 145Gy
Rx dose for boost: 110Gy
Pd-103
Half life 17 days
Rx dose for definitive therapy: 125Gy
Rx dose for boost: 100Gy
Randomized trial did not show any difference in tumor control nor toxicity between the two sources
Post-implant dosimetry
V100 should be greater than 90%
D90 is 140-145Gy for I-125 and 120-125Gy for Pd-103
Mean urethra dose should be less than 150% or V150 of urethra less than 50%
Rectum: V100 should be less than 1cc
3) External beam radiation
Dose escalation tested in multiple RCTs
-Pollak: 70 vs 78Gy to isocenter (3D-CRT technique)
bRFS improved in the high dose group
Subgroup analysis confirmed benefit only in patients with PSA greater than 10
-Protons: 70.2 vs. 79.2Gy (protons used for boost phase of treatment only)
Overall improved bRFS in high dose arm (5-yr bRFS 61 vs 80%)
Advantage was also seen in low risk pts with PSA less than 10, T2a disease, Gleason 6
-Dutch (Peeters) - 68 vs 78Gy
bRFS 54 vs 64% at 4 years
High risk
1) Androgen deprivation
GnRH analogues: leuprolide, goserelin; decrease pituitary secretion of LH and FSH; associated with flare of bone pain, hot flashes, decreased libido (acutely); gynecomastia, osteoporosis, muscle wasting, depression with long term use
Testosterone receptor blockers: flutamide, bicalutamide
Suppression of adrenal testosterone: ketoconazole
Trials of hormone therapy
EORTC (Bolla): High grade T1/2, any T3/4 randomized to 70Gy + 3 years ADT vs. 70Gy alone
-ADT improved OS (78 vs 62%) and CSS (94 vs 79%) at 5 years
RTOG 9202: T2c - T4 tumors randomized to 70Gy + 4 months ADT vs. 70Gy + 4 months + 2 years adjuvant ADT
-No benefit seen to prolonged ADT among all patients
-OS was improved in Gleason 8 - 10 patients (ad hoc analysis)
RTOG 8610: T2 - T4 tumors randomized to RT alone vs. RT + ADT
-Trend to improved 10 year OS in ADT group (43 vs 34%); improved CSS and bRFS
D'amico: High risk patients (PSA higher than 10, Gleason 7 or higher, ECE) randomized to 70Gy alone vs 70Gy + 6 months ADT
-Improved 5-year OS in ADT group (88 vs 78%)
RTOG 9413: 4 arm trial, whole pelvis/prostate only; neoadjuvant vs neoadjuvant and concurrent ADT
Best bRFS seen in whole pelvis + neoadjuvant and concurrent group
Benefit thought to be sequence dependent
Trial nearly impossible to interpret
Post-prostatectomy
SWOG: T3/+ margins randomized to RT (60 - 64Gy) vs observation (salvage RT given to 1/3 of the observation group)
-RT improved median OS (15.2 vs 13.3 years) and met-free survival (64 vs 57% at 10 years)
Benefits seen across all subgroups
EORTC: T3/+ margins randomized to 60Gy vs. observation
-5-year PFS improved in RT group (74 vs 53%)
Penile cancer
Epidemiology
~1,000 cases per year in the US
Risk factors
Lack of circumcision
Phimosis
HPV
Anatomy: lymph drainage
Skin of penis: to bilateral superficial groin
Glans: to both superficial and deep groin nodes
Clinical
Most common site is prepuce/glans
35% of patients have involved nodes at diagnosis
Nodal risk is proportional to primary size and depth of invasion
Bowen's disease: carcinoma in situ of the penile shaft; 25-50% of patients have a concomitant visceral malignancy
Erythroplasia of Queyrat: epidermoid carcinoma in situ of the glans/prepuce
Prognostic factors
Most important is nodal status (80-90% of node negative patients are cured, 40-50% of patients with inguinal nodes, and 30% of those with pelvic nodes)
Therapy
Removal of primary and bilateral groin dissection (LND is diagnostic and therapeutic)
~1,000 cases per year in the US
Risk factors
Lack of circumcision
Phimosis
HPV
Anatomy: lymph drainage
Skin of penis: to bilateral superficial groin
Glans: to both superficial and deep groin nodes
Clinical
Most common site is prepuce/glans
35% of patients have involved nodes at diagnosis
Nodal risk is proportional to primary size and depth of invasion
Bowen's disease: carcinoma in situ of the penile shaft; 25-50% of patients have a concomitant visceral malignancy
Erythroplasia of Queyrat: epidermoid carcinoma in situ of the glans/prepuce
Prognostic factors
Most important is nodal status (80-90% of node negative patients are cured, 40-50% of patients with inguinal nodes, and 30% of those with pelvic nodes)
Therapy
Removal of primary and bilateral groin dissection (LND is diagnostic and therapeutic)
Urethral cancer...the ancient nemesis of the inservice exam
Staging
T1: subepithelial connective tissue
T2: corpus spongiosum/prostate (males); periurethral muscle (females)
T3: Corpus cavernosum/beyond prostate capsule (males); anterior vagina/bladder neck (females)
T4: Invasion of adjacent organs
Pathology
Varies by location
Prostatic urethra: transitional cell
bulbomembranous urethra (proximally or posteriorly): adenocarcinoma; worse prognosis
distal urethra (anteriorly): squamous cell; better prognosis
The anterior/posterior prognostic distinction also holds in females
Epidemiology
Rare in both sexes but more common in women
May be associated with HPV infections
T1: subepithelial connective tissue
T2: corpus spongiosum/prostate (males); periurethral muscle (females)
T3: Corpus cavernosum/beyond prostate capsule (males); anterior vagina/bladder neck (females)
T4: Invasion of adjacent organs
Pathology
Varies by location
Prostatic urethra: transitional cell
bulbomembranous urethra (proximally or posteriorly): adenocarcinoma; worse prognosis
distal urethra (anteriorly): squamous cell; better prognosis
The anterior/posterior prognostic distinction also holds in females
Epidemiology
Rare in both sexes but more common in women
May be associated with HPV infections
Bladder cancer
Anatomy
Superior surface of bladder covered with peritoneum
Nodes: internal iliac/pelvic nodes
Epidemiology
67,000 cases per year in US
Risk factors
Smoking
Males
+ family history
Prior pelvic RT
Aromatic amine (arylamine exposure) -- dye workers, printers
Chronic inflammation associated with squamous cell ca
-Schistosomiasis
-Long term indwelling catheter
-Urinary tract stones
-Bladder diverticulum
Pathology
90% transitional cell, 5% squamous
1% adeno -- this has a strong association with persistent urachal remnant
Clinical
Most common symptom is gross painless hematuria
85% present with superficial (Ta/T1 disease)
Prognostic factors
Stage
Extent of TURBT
Multifocal tumor
Response to CRT
Therapy
Ta/Tis/T1: TURBT + intravesicular chemo or BCG
T2 and up: cystectomy vs. trimodality bladder preserving therapy
Cystectomy remains standard
Bladder preservation protocol
1) Maximum achievable TURBT
2) 40Gy to whole bladder/pelvic nodes with concurrent cisplatin
3) Repeat cystoscopy at 6 weeks after CRT
4) Complete responders complete CRT with whole pelvis RT to 45Gy + bladder boost to 55Gy and primary tumor boost to 65Gy
5) If residual disease is present (even Tis) cystectomy is performed
5) Consider adjuvant chemo (induction chemo does not change outcomes)
Contraindications for bladder preservation
1) Multifocal tumor
2) Concurrent upper urinary tract cancer
3) Adenopathy
4) Hydronephrosis
5) Renal failure
6) Non-functional bladder
RTOG bladder preservation outcomes
5-year OS - 54%; 10-year OS - 36%
5-year DSS - 63%; 10-year DSS - 59%
Pelvic failure 8% at 5 years
No cystectomy required secondary to RT-induced morbidity
Functional bladder preserved in ~60% of patients
Superior surface of bladder covered with peritoneum
Nodes: internal iliac/pelvic nodes
Epidemiology
67,000 cases per year in US
Risk factors
Smoking
Males
+ family history
Prior pelvic RT
Aromatic amine (arylamine exposure) -- dye workers, printers
Chronic inflammation associated with squamous cell ca
-Schistosomiasis
-Long term indwelling catheter
-Urinary tract stones
-Bladder diverticulum
Pathology
90% transitional cell, 5% squamous
1% adeno -- this has a strong association with persistent urachal remnant
Clinical
Most common symptom is gross painless hematuria
85% present with superficial (Ta/T1 disease)
Prognostic factors
Stage
Extent of TURBT
Multifocal tumor
Response to CRT
Therapy
Ta/Tis/T1: TURBT + intravesicular chemo or BCG
T2 and up: cystectomy vs. trimodality bladder preserving therapy
Cystectomy remains standard
Bladder preservation protocol
1) Maximum achievable TURBT
2) 40Gy to whole bladder/pelvic nodes with concurrent cisplatin
3) Repeat cystoscopy at 6 weeks after CRT
4) Complete responders complete CRT with whole pelvis RT to 45Gy + bladder boost to 55Gy and primary tumor boost to 65Gy
5) If residual disease is present (even Tis) cystectomy is performed
5) Consider adjuvant chemo (induction chemo does not change outcomes)
Contraindications for bladder preservation
1) Multifocal tumor
2) Concurrent upper urinary tract cancer
3) Adenopathy
4) Hydronephrosis
5) Renal failure
6) Non-functional bladder
RTOG bladder preservation outcomes
5-year OS - 54%; 10-year OS - 36%
5-year DSS - 63%; 10-year DSS - 59%
Pelvic failure 8% at 5 years
No cystectomy required secondary to RT-induced morbidity
Functional bladder preserved in ~60% of patients
Kidney cancer
Anatomy
Each kidney is surrounded by perinephric fat, then Gerota's fascia
Lymph drainage
-Right kidney: paracaval/aortocava;l
-Left kidney: para-aortic
Epidemiology
38,000 cases per year
Average age 55- 60
Risk factors
More common in men
Thorium, cadmium, petroleum exposure
Smoking
Obesity
Hypertension
Von Hippel-Lindau syndrome:
-28-45% of patients get renal cell ca (typically clear cell)
-Abnormality in short arm of chromosome 3 leads to uninhibited HIF
-Also associated with cerebellar hemangioblastoma, pheochromocytoma, pancreatic tumors
Renal pelvis/ureteral CA
1/3 of patients will get bladder cancer
Risk factors: men, smoking, phenol exposure
Pathology
Most primary renal cancers are adenocarcinoma (90%)
Most common histology: clear cell; papillary is more favorable, sarcomatoid worse
Renal pelvis/ureter: most common histology is transitional cell (>90%), SCC 7-8%
Clinical
Classic triad: hematuria, flank mass, pain; only occurs in 5-10% of patients
Most frequent symptom is isolated hematuria
Incidental diagnosis carries a favorable prognosis (7% of pts)
Lymph nodes involved in 10-25%
Renal vein involved in 25%; IVC in 5%
Disease is bilateral in 2-3%
Mets may regress spontaneously after nephrectomy
Prognostic factors
T/N/M stage
Tumor grade/cell type
Incidental diagnosis
IVC involvement above diaphragm
Treatment
Definitive surgery = radical nephrectomy and lymph node dissection
Removes kidney, adrenal gland, perinephric fat, Gerota's fascia
2 preop trials testing preoperative XRT were negative as were 2 trials testing adjuvant RT
Modern indications: unresectable primary, positive margins (adding radiation in these situations increases local control with questionable impact on overall survival)
Adjuvant chemo includes IL-2, sorafenib, sunitinib (both tyrosine kinase inhibitors)
Radiation nephropathy
TD 5/5 = ~20Gy
Pathologic features: glomerular sclerosis/tuft obliteration, tubular degeneration
Lab: increased BUN/Cre; microhematuria, proteinuria, casts
Late effects: hypertension, complete renal failure, anemia
Each kidney is surrounded by perinephric fat, then Gerota's fascia
Lymph drainage
-Right kidney: paracaval/aortocava;l
-Left kidney: para-aortic
Epidemiology
38,000 cases per year
Average age 55- 60
Risk factors
More common in men
Thorium, cadmium, petroleum exposure
Smoking
Obesity
Hypertension
Von Hippel-Lindau syndrome:
-28-45% of patients get renal cell ca (typically clear cell)
-Abnormality in short arm of chromosome 3 leads to uninhibited HIF
-Also associated with cerebellar hemangioblastoma, pheochromocytoma, pancreatic tumors
Renal pelvis/ureteral CA
1/3 of patients will get bladder cancer
Risk factors: men, smoking, phenol exposure
Pathology
Most primary renal cancers are adenocarcinoma (90%)
Most common histology: clear cell; papillary is more favorable, sarcomatoid worse
Renal pelvis/ureter: most common histology is transitional cell (>90%), SCC 7-8%
Clinical
Classic triad: hematuria, flank mass, pain; only occurs in 5-10% of patients
Most frequent symptom is isolated hematuria
Incidental diagnosis carries a favorable prognosis (7% of pts)
Lymph nodes involved in 10-25%
Renal vein involved in 25%; IVC in 5%
Disease is bilateral in 2-3%
Mets may regress spontaneously after nephrectomy
Prognostic factors
T/N/M stage
Tumor grade/cell type
Incidental diagnosis
IVC involvement above diaphragm
Treatment
Definitive surgery = radical nephrectomy and lymph node dissection
Removes kidney, adrenal gland, perinephric fat, Gerota's fascia
2 preop trials testing preoperative XRT were negative as were 2 trials testing adjuvant RT
Modern indications: unresectable primary, positive margins (adding radiation in these situations increases local control with questionable impact on overall survival)
Adjuvant chemo includes IL-2, sorafenib, sunitinib (both tyrosine kinase inhibitors)
Radiation nephropathy
TD 5/5 = ~20Gy
Pathologic features: glomerular sclerosis/tuft obliteration, tubular degeneration
Lab: increased BUN/Cre; microhematuria, proteinuria, casts
Late effects: hypertension, complete renal failure, anemia
Wednesday, August 4, 2010
Anal canal
Anatomy
Perianal skin/Anal margin: 5cm radius around anal verge
Anal verge: End of hair bearing skin, marks beginning of anal canal
Dentate line: transition from squamous to glandular mucosa; about 2cm inferior to anorectal ring
Regions from the dentate line and inferiorly drain to superficial inguinal nodes
Above the dentate line drain to perirectal and inferior mesenteric nodes
Most commonly involved nodes in anal canal cancers are the perirectal nodes (~50%); pelvic 30%, groin 30%; remember that groin nodes are considered N2 disease
Epidemiology
4600 cases per year
Incidence is rising
60% occur in women
Risk factors
HIV
HPV
Other STD's
Cervical/vulvar/vaginal cancers
Immune suppression
Smoking
Anal intercourse
Pathology
80% squamous cell
10% adeno...treated like rectal cancer (CRT then surgery not definitive CRT)
5% melanoma
5% other (sarcoma, lymphoma, etc)
Prognostic factors
T/N/M stage
Anemia
Poorly controlled HIV
Therapy
Early T1 tumors can be excised if wide enough margins for sphincter preservation
Otherwise definitive CRT is used
Nigro regimen
First trial to establish CRT as a viable organ preserving option
5-FU/MMC/30Gy in 15 fx
90% of patients cleared disease at six week biopsy
UKCCCR
RT only vs. RT/FU/MMC
CRT was superior in: local control (59 vs 36%)
Trend to improved OS (65 vs 58%) and improved CSS (72 vs 61%)
CRT increased acute toxicity (particularly hematologic); no change in late effects
EORTC
RT only vs. RT/FU/MMC
CRT associated with: higher complete response rates (80 vs 54%), higher LC at 5 years (68 vs 50%), 5-year colostomy free survival (72 vs 40%)
OS was identical in the two groups at 58% at 5 years
Intergroup
RT/FU/MMC vs. RT/FU only
Adding MMC was associated with: lower rates of + biopsy after treatment (8 vs. 15%); better colostomy free survival at 4 years (91 vs. 77%), better 4-year DFS (73 vs 51%)
MMC did not affect overall survival
Acute toxicity was also worse in the MMC arm
RTOG 9811 (PMID 23150707)
RT/FU/cisplatin vs. RT/FU/MMC
MMC group had better 5-year DFS (56 vs 48%) and better colostomy free survival (90 vs. 80% at 5 years) but worse acute toxicity
Fields:
T2N0
-Initial AP, to 30.6Gy: Superior = L5/S1, Inferior = 2cm below anus, Lateral to cover inguinals
-Initial PA, to 30.6Gy: Same sup/inf borders, Don't include inguinals
-Field reduction #1: Drop the top border to the SI joint...Continue treating the groins to 36Gy
-Field reduction #2: Block groin nodes, treat pelvic and perirectal nodes as well as tumor, to 45Gy
-Field reduction #3: Boost gross disease (Can skip boost if CR @ 45Gy?)
RT dosing
PTV1 = perineum, anus, b/l groins, whole pelvis: 30.6Gy
PTV2 = perineum, anus, b/l groin, whole pelvis: 36Gy for clinically negative nodes; 45Gy for + nodes
PTV3 = any gross disease (primary or lymph nodes): 55 - 59Gy (go higher for larger primaries)
Perianal skin/Anal margin: 5cm radius around anal verge
Anal verge: End of hair bearing skin, marks beginning of anal canal
Dentate line: transition from squamous to glandular mucosa; about 2cm inferior to anorectal ring
Regions from the dentate line and inferiorly drain to superficial inguinal nodes
Above the dentate line drain to perirectal and inferior mesenteric nodes
Most commonly involved nodes in anal canal cancers are the perirectal nodes (~50%); pelvic 30%, groin 30%; remember that groin nodes are considered N2 disease
Epidemiology
4600 cases per year
Incidence is rising
60% occur in women
Risk factors
HIV
HPV
Other STD's
Cervical/vulvar/vaginal cancers
Immune suppression
Smoking
Anal intercourse
Pathology
80% squamous cell
10% adeno...treated like rectal cancer (CRT then surgery not definitive CRT)
5% melanoma
5% other (sarcoma, lymphoma, etc)
Prognostic factors
T/N/M stage
Anemia
Poorly controlled HIV
Therapy
Early T1 tumors can be excised if wide enough margins for sphincter preservation
Otherwise definitive CRT is used
Nigro regimen
First trial to establish CRT as a viable organ preserving option
5-FU/MMC/30Gy in 15 fx
90% of patients cleared disease at six week biopsy
UKCCCR
RT only vs. RT/FU/MMC
CRT was superior in: local control (59 vs 36%)
Trend to improved OS (65 vs 58%) and improved CSS (72 vs 61%)
CRT increased acute toxicity (particularly hematologic); no change in late effects
EORTC
RT only vs. RT/FU/MMC
CRT associated with: higher complete response rates (80 vs 54%), higher LC at 5 years (68 vs 50%), 5-year colostomy free survival (72 vs 40%)
OS was identical in the two groups at 58% at 5 years
Intergroup
RT/FU/MMC vs. RT/FU only
Adding MMC was associated with: lower rates of + biopsy after treatment (8 vs. 15%); better colostomy free survival at 4 years (91 vs. 77%), better 4-year DFS (73 vs 51%)
MMC did not affect overall survival
Acute toxicity was also worse in the MMC arm
RTOG 9811 (PMID 23150707)
RT/FU/cisplatin vs. RT/FU/MMC
MMC group had better 5-year DFS (56 vs 48%) and better colostomy free survival (90 vs. 80% at 5 years) but worse acute toxicity
Fields:
T2N0
-Initial AP, to 30.6Gy: Superior = L5/S1, Inferior = 2cm below anus, Lateral to cover inguinals
-Initial PA, to 30.6Gy: Same sup/inf borders, Don't include inguinals
-Field reduction #1: Drop the top border to the SI joint...Continue treating the groins to 36Gy
-Field reduction #2: Block groin nodes, treat pelvic and perirectal nodes as well as tumor, to 45Gy
-Field reduction #3: Boost gross disease (Can skip boost if CR @ 45Gy?)
RT dosing
PTV1 = perineum, anus, b/l groins, whole pelvis: 30.6Gy
PTV2 = perineum, anus, b/l groin, whole pelvis: 36Gy for clinically negative nodes; 45Gy for + nodes
PTV3 = any gross disease (primary or lymph nodes): 55 - 59Gy (go higher for larger primaries)
Sunday, August 1, 2010
Rectal cancer
Prognostic factors
Location (distal is worse)
T/N/M stage
Grade
Signet cell carcinoma (bad)
LVSI
Circumferential/obstructing tumors
Fixed tumor
Imaging
EUS and MRI improve staging accuracy but both lose accuracy after neo-adjuvant treatment
Surgery
Total mesorectal excision (TME)
-Remove involved rectum and adjacent mesorectum along pelvic fascial planes
-2cm longitudinal margins considered adequate
-12 to 15 nodes considered adequate nodal dissection
-Radial margin status is a strong predictor for local control
Adjuvant trials
NSABP R-01: observation vs. chemoRT; chemoRT improved DFS and local control without impacting overall survival
NSABP R-02: chemo only vs. chemoRT: adding RT improved local control without changing survival
GITSG: observation vs. chemo only vs. RT only vs. chemoRT: ChemoRT improved OS, DFS, local control compared with observation arm
NCCTG: RT only vs. chemoRT: adding chemo improved OS, DFS, and local control
Preop trials
Swedish: 25Gy in 5fx followed by surgery vs. surgery alone (PMID 16110023)
RT improved local control (75 vs 88%) and overall survival (9-yr 48 vs 58%)
OS improvement may have been affected by the fact that TME was NOT performed in this study
Dutch: 25Gy in 5fx followed by TME vs. TME alone (PMID 10391155)
RT did not change OS but did improve local control; higher incidence of perineal complications in the RT arm
German: compared preop vs. postop chemoRT (PMID 15496622)
Preoperative chemoRT was associated with improved local control and improved toxicity without affecting overall survival
MRC/NCIC: (PMID 19269519) compared preop 5 Gy x 5 vs. postop 45 Gy chemo (patients with positive margins only)
Preoperative treatment was associated with significant improvements in local control and DFS, no effect on OS
TROG 0104 (PMID 2300801): compared preop short-course (5 Gy x 5) RT only vs. preop long course chemo-RT (45 Gy + capecitabine) in patients with T3N0-2 rectal cancer. 3-year overall survival rates were 74% and 70% for short-course and long course respectively (p-NS); local recurrence rates were 7.5% and 4.4% for short- and long-course respectively (p-NS) with much of the difference in local recurrence appearing to be driven by higher recurrence risk in low lying tumors receiving short course treatment; caveat of very small n's (12 local recurrences in short course group with 6 of these being in low lying lesions; 7 local recurrences in long course group with one of these in a low lying tumor). Similar late toxicity rates.
Location (distal is worse)
T/N/M stage
Grade
Signet cell carcinoma (bad)
LVSI
Circumferential/obstructing tumors
Fixed tumor
Imaging
EUS and MRI improve staging accuracy but both lose accuracy after neo-adjuvant treatment
Surgery
Total mesorectal excision (TME)
-Remove involved rectum and adjacent mesorectum along pelvic fascial planes
-2cm longitudinal margins considered adequate
-12 to 15 nodes considered adequate nodal dissection
-Radial margin status is a strong predictor for local control
Adjuvant trials
NSABP R-01: observation vs. chemoRT; chemoRT improved DFS and local control without impacting overall survival
NSABP R-02: chemo only vs. chemoRT: adding RT improved local control without changing survival
GITSG: observation vs. chemo only vs. RT only vs. chemoRT: ChemoRT improved OS, DFS, local control compared with observation arm
NCCTG: RT only vs. chemoRT: adding chemo improved OS, DFS, and local control
Preop trials
Swedish: 25Gy in 5fx followed by surgery vs. surgery alone (PMID 16110023)
RT improved local control (75 vs 88%) and overall survival (9-yr 48 vs 58%)
OS improvement may have been affected by the fact that TME was NOT performed in this study
Dutch: 25Gy in 5fx followed by TME vs. TME alone (PMID 10391155)
RT did not change OS but did improve local control; higher incidence of perineal complications in the RT arm
German: compared preop vs. postop chemoRT (PMID 15496622)
Preoperative chemoRT was associated with improved local control and improved toxicity without affecting overall survival
MRC/NCIC: (PMID 19269519) compared preop 5 Gy x 5 vs. postop 45 Gy chemo (patients with positive margins only)
Preoperative treatment was associated with significant improvements in local control and DFS, no effect on OS
TROG 0104 (PMID 2300801): compared preop short-course (5 Gy x 5) RT only vs. preop long course chemo-RT (45 Gy + capecitabine) in patients with T3N0-2 rectal cancer. 3-year overall survival rates were 74% and 70% for short-course and long course respectively (p-NS); local recurrence rates were 7.5% and 4.4% for short- and long-course respectively (p-NS) with much of the difference in local recurrence appearing to be driven by higher recurrence risk in low lying tumors receiving short course treatment; caveat of very small n's (12 local recurrences in short course group with 6 of these being in low lying lesions; 7 local recurrences in long course group with one of these in a low lying tumor). Similar late toxicity rates.
Colon cancer
Anatomy
Intraperitoneal segments of colon: transverse and sigmoid colon
Retroperitoneal: Ascending, descending colon; rectum (distal 1/3 of rectum has no peritoneal covering at all)
Rectum extends from peritoneal reflection of sigmoid to the anorectal ring (12 - 15cm long)
Nodal drainage: pericolic/mesenteric nodes for colon; perirectal, presacral, internal iliac (rectal)
Epidemiology
3rd most common cancer in US
~150,000 cases per year, 50,000 deaths
Risk factors
Age
Male sex
Family history
Obesity
High intake of processed meats
EtOH
Hereditary syndromes associated with colorectal cancer
Lynch syndrome
HNPCC
Familial adenomatous polyposis
Li-Fraumeni syndrome
Pathology
Vast majority of tumors are adenocarcinoma
Polyps increase the risk of colon cancer from 6% to 15% (lifetime)
Villous adenomas (villains) are at the highest risk of transforming into malignancies
Molecular biology: mutated APC, p53, ras, HNPCC (correlated with microsatellite instability)
Staging workup
Colonoscopy
EUS (rectal tumors only)
Bloodwork: CBC, LFT, CEA
CT chest/abdomen/pelvis or PET CT
Prognostic factors
Depth of invasion
Nodal stage
Colon cancer treatment
Role of xrt is limited
Primary therapy is surgical (hemicolectomy)
Adjuvant chemo indicated in stage III patients (any node+ or T3-4 disease)
Standard regimen is 5FU/leucovorin, oxaliplatin ("FOLFOX")
In tumors with adherence/invasion of adjacent structures (more common in ascending and descending colon where clearing radial margins is more difficult), adjuvant xrt may be indicated
Adjuvant RT for colon cancer
Intergroup 0130 (PMID 15249584)
Patients with completely resected colon cancer that was either adherent to adjacent structures, penetrated the serosa, or was node +, were assigned to chemo alone vs. chemoRT (50.4Gy to tumor bed and draining nodes)
5 year DFS (~50%) and OS (~60%) were not statistically different in the two arms
The study had to be closed early due to poor accrual
No benefit was seen in any subset of patients
Massachusetts General retrospective experience (PMID 10439171)
Benefit to adjuvant RT (for DFS and local control) was observed in patients who had:
-Tumor associated abscess or fistula
-Residual disease
-Serosal penetration
-Node + disease
Note that only about 30% of patients received chemo with radiation
Current indications for RT (usually given with concurrent 5FU)
1) tumor associated abscess/fistula
2) invasion of adjacent structures
3) positive margins
4) ability to identify a non-mobile target
Intraperitoneal segments of colon: transverse and sigmoid colon
Retroperitoneal: Ascending, descending colon; rectum (distal 1/3 of rectum has no peritoneal covering at all)
Rectum extends from peritoneal reflection of sigmoid to the anorectal ring (12 - 15cm long)
Nodal drainage: pericolic/mesenteric nodes for colon; perirectal, presacral, internal iliac (rectal)
Epidemiology
3rd most common cancer in US
~150,000 cases per year, 50,000 deaths
Risk factors
Age
Male sex
Family history
Obesity
High intake of processed meats
EtOH
Hereditary syndromes associated with colorectal cancer
Lynch syndrome
HNPCC
Familial adenomatous polyposis
Li-Fraumeni syndrome
Pathology
Vast majority of tumors are adenocarcinoma
Polyps increase the risk of colon cancer from 6% to 15% (lifetime)
Villous adenomas (villains) are at the highest risk of transforming into malignancies
Molecular biology: mutated APC, p53, ras, HNPCC (correlated with microsatellite instability)
Staging workup
Colonoscopy
EUS (rectal tumors only)
Bloodwork: CBC, LFT, CEA
CT chest/abdomen/pelvis or PET CT
Prognostic factors
Depth of invasion
Nodal stage
Colon cancer treatment
Role of xrt is limited
Primary therapy is surgical (hemicolectomy)
Adjuvant chemo indicated in stage III patients (any node+ or T3-4 disease)
Standard regimen is 5FU/leucovorin, oxaliplatin ("FOLFOX")
In tumors with adherence/invasion of adjacent structures (more common in ascending and descending colon where clearing radial margins is more difficult), adjuvant xrt may be indicated
Adjuvant RT for colon cancer
Intergroup 0130 (PMID 15249584)
Patients with completely resected colon cancer that was either adherent to adjacent structures, penetrated the serosa, or was node +, were assigned to chemo alone vs. chemoRT (50.4Gy to tumor bed and draining nodes)
5 year DFS (~50%) and OS (~60%) were not statistically different in the two arms
The study had to be closed early due to poor accrual
No benefit was seen in any subset of patients
Massachusetts General retrospective experience (PMID 10439171)
Benefit to adjuvant RT (for DFS and local control) was observed in patients who had:
-Tumor associated abscess or fistula
-Residual disease
-Serosal penetration
-Node + disease
Note that only about 30% of patients received chemo with radiation
Current indications for RT (usually given with concurrent 5FU)
1) tumor associated abscess/fistula
2) invasion of adjacent structures
3) positive margins
4) ability to identify a non-mobile target
Gall bladder cancer
Epidemiology
About 5,000 cases per year in US
Female to male ratio is 2.5:1
Risk factors
Porcelain gall bladder
Anomalous bile duct anatomy
Gall bladder polyps
Smoking
EtOH
Obesity
Salmonella and Helicobacter biliis infection
Treatment
Surgery is curative but resectability rates are low
For T1a disease (usually found incidentally at cholecystectomy), no adjuvant therapy is needed
CRT often given adjuvantly
About 5,000 cases per year in US
Female to male ratio is 2.5:1
Risk factors
Porcelain gall bladder
Anomalous bile duct anatomy
Gall bladder polyps
Smoking
EtOH
Obesity
Salmonella and Helicobacter biliis infection
Treatment
Surgery is curative but resectability rates are low
For T1a disease (usually found incidentally at cholecystectomy), no adjuvant therapy is needed
CRT often given adjuvantly
Cholangiocarcinoma
Epidemiology
About 5,000 cases per year in US
Most common location is at bifurcation of bile duct (Klatskin tumor, 65-70%)
Also occurs in the ampulla of Vater (25-30%) and intrahepatic bile duct (5-10%)
Risk factors
Primary sclerosing cholangitis
Schistosomiasis (liver fluke infestation)
Ulcerative colitis
Prior history of colon cancer
Pathology
Most tumors are adenocarcinomas
Sclerosing: associated with desmoplastic reaction, poor prognosis
Papillary: favorable prognosis
Tumor markers: CEA, CA19-9 elevation, no AFP elevation (helps to differentiate from HCC)
Treatment
Resection is the only cure (fewer than 1/3 of patients have resectable disease)
Neoadjuvant chemoradiation followed by liver transplant appears to improve survival in highly selected patients
Distal tumors are more frequently resectable
2010 trial showed survival improvement with cisplatin + gemcitabine vs. gemcitabine alone in locally advanced tumors (PMID 20375404)
No prospective CRT studies exist
About 5,000 cases per year in US
Most common location is at bifurcation of bile duct (Klatskin tumor, 65-70%)
Also occurs in the ampulla of Vater (25-30%) and intrahepatic bile duct (5-10%)
Risk factors
Primary sclerosing cholangitis
Schistosomiasis (liver fluke infestation)
Ulcerative colitis
Prior history of colon cancer
Pathology
Most tumors are adenocarcinomas
Sclerosing: associated with desmoplastic reaction, poor prognosis
Papillary: favorable prognosis
Tumor markers: CEA, CA19-9 elevation, no AFP elevation (helps to differentiate from HCC)
Treatment
Resection is the only cure (fewer than 1/3 of patients have resectable disease)
Neoadjuvant chemoradiation followed by liver transplant appears to improve survival in highly selected patients
Distal tumors are more frequently resectable
2010 trial showed survival improvement with cisplatin + gemcitabine vs. gemcitabine alone in locally advanced tumors (PMID 20375404)
No prospective CRT studies exist
Saturday, July 31, 2010
Hepatocellular cancer
Epidemiology
US incidence is increasing (8,000 - 10,000 cases per year)
8th most common cancer worldwide
Risk factors
HBV/HCV infection (HR~100); infection with both viruses synergistically increases risk of HCC
Any kind of cirrhosis (EtOH, hematochromatosis, Wilson's disease, viral, etc.)
Aflatoxin
Thorotrast
Hereditary liver disease
Clinical
No biopsy needed in patients with AFP higher than 200 and a liver mass
Consider screening with AFP and u/s in patients with cirrhosis and particularly HBV/HCV
Biopsy tract seeded in 2 - 5% of patients
Prognostic factors
Size and number of tumors
N/M stage
Underlying liver function
Presence of vascular invasion
Pathologic subtypes
Fibrolamellar: more favorable
Hepatoblastoma: most common liver tumor in children; associated with FAP phenotype
Rare liver tumors: Angiosarcoma (associated with thorotrast exposure); leiomyosarcoma (most commonly occurring sarcoma in the liver)
Treatment
Surgical resection or liver transplant is the only curative therapy
Criteria for transplant: one tumor smaller than 5cm or 2-3 tumors, each smaller than 3cm
Liver tolerance to radiation: dose and volume dependent; lower if pre-existing impairment
100% -- 35Gy
70% -- 42Gy
50% -- 50Gy
30% -- 70Gy
Radiation induced liver disease
RUQ pain
Ascites and hepatomegaly
No jaundice
Increased alk phos, AST; bilirubin is usually normal
Pathology: central veno-occlusive disease with secondary necrosis of hepatocytes
US incidence is increasing (8,000 - 10,000 cases per year)
8th most common cancer worldwide
Risk factors
HBV/HCV infection (HR~100); infection with both viruses synergistically increases risk of HCC
Any kind of cirrhosis (EtOH, hematochromatosis, Wilson's disease, viral, etc.)
Aflatoxin
Thorotrast
Hereditary liver disease
Clinical
No biopsy needed in patients with AFP higher than 200 and a liver mass
Consider screening with AFP and u/s in patients with cirrhosis and particularly HBV/HCV
Biopsy tract seeded in 2 - 5% of patients
Prognostic factors
Size and number of tumors
N/M stage
Underlying liver function
Presence of vascular invasion
Pathologic subtypes
Fibrolamellar: more favorable
Hepatoblastoma: most common liver tumor in children; associated with FAP phenotype
Rare liver tumors: Angiosarcoma (associated with thorotrast exposure); leiomyosarcoma (most commonly occurring sarcoma in the liver)
Treatment
Surgical resection or liver transplant is the only curative therapy
Criteria for transplant: one tumor smaller than 5cm or 2-3 tumors, each smaller than 3cm
Liver tolerance to radiation: dose and volume dependent; lower if pre-existing impairment
100% -- 35Gy
70% -- 42Gy
50% -- 50Gy
30% -- 70Gy
Radiation induced liver disease
RUQ pain
Ascites and hepatomegaly
No jaundice
Increased alk phos, AST; bilirubin is usually normal
Pathology: central veno-occlusive disease with secondary necrosis of hepatocytes
Pancreatic cancer
Epidemiology
32,000 cases per year, about the same number of deaths
20% of tumors are resectable, 20% of resected patients are long term survivors
Risk factors
Age (increased after 45 years)
Males (RR 1.3)
Smoking
Black men
Chronic pancreatitis
Family history
Diabetes
Anatomy
Retroperitoneal organ
Head lies in the curve of the duodenum
Tail approaches the spleen
Transverse colon and greater omentum lie in front
More than 2/3 of tumors are found in the head of the pancreas
Nodes: peripancreatic, porta hepatis, celiac, para-aortic, splenic (tail lesions)
Vascular structures determine resectability: SMV invasion may be resectable with experienced surgeon: lesions invading the SMA or celiac A. are generally considered unresectable
Pathology
90% of tumors are adenocarcinoma
Other histologies: neuroendocrine, cystadenocarcinoma, islet cell and other rare endocrine tumors
Tail and body lesions have a worse prognosis; peri-ampullary tumors are better
K-ras is activated in 90% of pancreatic cancers
Other abnormalities include p53, p16, DPC4, BRCA2 mutations
Clinical
Most common presentation is jaundice
Back pain suggests a more advanced lesion
Prognostic factors: resectability*; resection margin
Therapy
Surgery is the definitive treatment
Some controversy over what is the optimum adjuvant treatment
Key adjuvant trials
GITSG (PMID 4015380)
Randomization to 40Gy + 5FU (split course RT) vs. observation
CRT was associated with:
-improved overall survival, median 11 vs 20 months, 5-year 5 vs 19% and improved PFS
EORTC (PMID 17968163)
Randomization to observation vs. 40Gy + 5FU (split course RT)
Ampullary carcinomas also included (almost half the patients)
Other criticisms: no maintenance chemo, no margin assessment, 20% non-compliance rate
Trend to improved median (19 vs 24 months) and 2-yr OS (41 vs 51%)
ESPAC (original PMID 11716884; 5-year update PMID 15028824)
4-arm trial (CRT, CRT + maintenance chemo, chemo only, observation)
Not randomized with significant rate of cross-over between arms
Observation arm associated with the best survival
Trial has been extensively criticized
RTOG 9704 (PMID 21499862)
Randomization to 5-FU vs. gemcitabine + 50.4Gy RT
Five-year update showed trend to OS benefit in head of pancreas patients with gemcitabine therapy but overall survival was not improved in the entire cohort.
CONKO-001 (PMID 17227278)
Randomization was to adjuvant gemcitabine vs. observation (postop CA19-9 had to be less than 90)
Trend to improved OS in gemcitabine group (20 vs 23 months)
DFS was significantly improved with chemo (7 vs 14 months)
High rates of crossover to salvage gemcitabine in the observation arm
Hopkins/Mayo collaboration (PMID 2840672)
Retrospective analysis of 1,092 cases of resected pancreatic cancer
53% received adjuvant CRT
Patients treated with CRT were younger, more likely to have high grade disease and positive margins
Matched pair analysis showed that CRT was associated with improved median, 2-year, and 5-year overall survival compared with CRT (21.9 vs 14.3 months, 45.4 vs. 31.4%, and 25.4 vs. 12.2%, respectively)
Locally advanced/unresectable, non-metastatic pancreatic cancer
CRT has been shown to provide benefit in several trials:
Mayo Clinic: 40Gy EBRT +/- 5FU (PMID 4186452)
Median OS: 6 vs 10 months (better with chemo)
GITSG: 60Gy split course EBRT vs. 40Gy + 5FU vs. 60Gy + 5FU (PMID 7284971)
RT alone arm closed early (1-yr OS 11%); both CRT arms had similar survival (36/38%)
GITSG: 40Gy + adriamycin vs. 60Gy + 5FU (PMID 2864997)
Overall survival was similar but toxicity rates higher in adriamycin group
GITSG: SMF vs. 54Gy + concurrent 5FU and adjuvant SMF (PMID 2898536)
1-year OS improved in the RT group (41 vs 19%)
ECOG: 5-FU only vs. 5-FU + 40Gy
Median OS about 8 months in both groups
Only negative trial for CRT in locally advanced disease
Study also included patients with residual disease after resection
FFCD/CFRO phase III study (PMID 18467316):
119 patients randomized to 60Gy with concurrent 5FU/cisplatin --> maintenance gemcitabine vs. single agent gemcitabine chemotherapy alone
Median OS 8.6 vs 13 months in CRT--> chemo vs. chemo alone
1-year OS 32 vs 53% respectively
Chemoradiation arm associated with higher rates of grade 3/4 toxicity
32,000 cases per year, about the same number of deaths
20% of tumors are resectable, 20% of resected patients are long term survivors
Risk factors
Age (increased after 45 years)
Males (RR 1.3)
Smoking
Black men
Chronic pancreatitis
Family history
Diabetes
Anatomy
Retroperitoneal organ
Head lies in the curve of the duodenum
Tail approaches the spleen
Transverse colon and greater omentum lie in front
More than 2/3 of tumors are found in the head of the pancreas
Nodes: peripancreatic, porta hepatis, celiac, para-aortic, splenic (tail lesions)
Vascular structures determine resectability: SMV invasion may be resectable with experienced surgeon: lesions invading the SMA or celiac A. are generally considered unresectable
Pathology
90% of tumors are adenocarcinoma
Other histologies: neuroendocrine, cystadenocarcinoma, islet cell and other rare endocrine tumors
Tail and body lesions have a worse prognosis; peri-ampullary tumors are better
K-ras is activated in 90% of pancreatic cancers
Other abnormalities include p53, p16, DPC4, BRCA2 mutations
Clinical
Most common presentation is jaundice
Back pain suggests a more advanced lesion
Prognostic factors: resectability*; resection margin
Therapy
Surgery is the definitive treatment
Some controversy over what is the optimum adjuvant treatment
Key adjuvant trials
GITSG (PMID 4015380)
Randomization to 40Gy + 5FU (split course RT) vs. observation
CRT was associated with:
-improved overall survival, median 11 vs 20 months, 5-year 5 vs 19% and improved PFS
EORTC (PMID 17968163)
Randomization to observation vs. 40Gy + 5FU (split course RT)
Ampullary carcinomas also included (almost half the patients)
Other criticisms: no maintenance chemo, no margin assessment, 20% non-compliance rate
Trend to improved median (19 vs 24 months) and 2-yr OS (41 vs 51%)
ESPAC (original PMID 11716884; 5-year update PMID 15028824)
4-arm trial (CRT, CRT + maintenance chemo, chemo only, observation)
Not randomized with significant rate of cross-over between arms
Observation arm associated with the best survival
Trial has been extensively criticized
RTOG 9704 (PMID 21499862)
Randomization to 5-FU vs. gemcitabine + 50.4Gy RT
Five-year update showed trend to OS benefit in head of pancreas patients with gemcitabine therapy but overall survival was not improved in the entire cohort.
CONKO-001 (PMID 17227278)
Randomization was to adjuvant gemcitabine vs. observation (postop CA19-9 had to be less than 90)
Trend to improved OS in gemcitabine group (20 vs 23 months)
DFS was significantly improved with chemo (7 vs 14 months)
High rates of crossover to salvage gemcitabine in the observation arm
Hopkins/Mayo collaboration (PMID 2840672)
Retrospective analysis of 1,092 cases of resected pancreatic cancer
53% received adjuvant CRT
Patients treated with CRT were younger, more likely to have high grade disease and positive margins
Matched pair analysis showed that CRT was associated with improved median, 2-year, and 5-year overall survival compared with CRT (21.9 vs 14.3 months, 45.4 vs. 31.4%, and 25.4 vs. 12.2%, respectively)
Locally advanced/unresectable, non-metastatic pancreatic cancer
CRT has been shown to provide benefit in several trials:
Mayo Clinic: 40Gy EBRT +/- 5FU (PMID 4186452)
Median OS: 6 vs 10 months (better with chemo)
GITSG: 60Gy split course EBRT vs. 40Gy + 5FU vs. 60Gy + 5FU (PMID 7284971)
RT alone arm closed early (1-yr OS 11%); both CRT arms had similar survival (36/38%)
GITSG: 40Gy + adriamycin vs. 60Gy + 5FU (PMID 2864997)
Overall survival was similar but toxicity rates higher in adriamycin group
GITSG: SMF vs. 54Gy + concurrent 5FU and adjuvant SMF (PMID 2898536)
1-year OS improved in the RT group (41 vs 19%)
ECOG: 5-FU only vs. 5-FU + 40Gy
Median OS about 8 months in both groups
Only negative trial for CRT in locally advanced disease
Study also included patients with residual disease after resection
FFCD/CFRO phase III study (PMID 18467316):
119 patients randomized to 60Gy with concurrent 5FU/cisplatin --> maintenance gemcitabine vs. single agent gemcitabine chemotherapy alone
Median OS 8.6 vs 13 months in CRT--> chemo vs. chemo alone
1-year OS 32 vs 53% respectively
Chemoradiation arm associated with higher rates of grade 3/4 toxicity
Friday, July 30, 2010
Gastric cancer
Epidemiology
22,000 cases per year in US
Incidence is decreasing here although the incidence of GE junction cancers is increasing
Risk factors
Salted/preserved food
Lower socioeconomic status
Low intake of fruit and vegetables
Salted/preserved food
Pernicious anemia
Subtotal gastrectomy (Billroth II procedure)
H. pylori is associated with distal gastric cancer
Anatomy
Fundus/cardia: 35%
Body: 25%
Antrum: 40%
Nodes: celiac, gastrohepatic, gastroduodenal, splenic, porta hepatis, para-aortic
Pathology
90% of tumors are adenocarcinoma
Second most common type is lymphoma
Prognostic factors
T/N/M staging*
Linitis plastica
Aneuploidy (poor prognostic factor)
Surgery
Total vs. subtotal gastrectomy tested in a randomized trial (PMID 10450730) showed no survival advantage with total gastrectomy
D1 node dissection: perigastric nodes only
D2 node dissection: perigastric, splenic, celiac
D1 vs. D2 also tested in RCT (PMID 15082726) with no survival benefit seen to extended LND
Adjuvant treatment
Chemoradiation (PMID 11547741) "Macdonald trial"
Patients with T2 or greater tumors or with positive nodes after gastrectomy were randomized to chemoradiation (5FU/leucovorin + 45Gy) vs. observation
Chemoradiation was associated with:
-improved overall survival, 41% vs 50% at 3 years, median 27 vs, 36 months
-improved local control, 61% vs 19% at 3 years
-higher rates of distant metastasis as first failure, 18% vs. 33%
-Nodal targets: perigastric, celiac, local PA, porta hepatis, pancreaticoduodenal; in GE junction tumors can exclude pancreaticoduodenal nodes but must include paracardial and paraesophageal nodes; splenic nodes may be excluded if needed to spare left kidney in antral tumors.
Chemotherapy only (PMID 16822992) "MAGIC trial"
Distal esophageal as well as gastric cancer were eligible
Randomization was to perioperative epirubicin/5FU/cisplatin vs. surgery only
Chemotherapy was associated with
-improved 5-year PFS (18 vs 30%)
-improved 5-year OS (36 vs 23%)
-downstaging at the time of surgery
22,000 cases per year in US
Incidence is decreasing here although the incidence of GE junction cancers is increasing
Risk factors
Salted/preserved food
Lower socioeconomic status
Low intake of fruit and vegetables
Salted/preserved food
Pernicious anemia
Subtotal gastrectomy (Billroth II procedure)
H. pylori is associated with distal gastric cancer
Anatomy
Fundus/cardia: 35%
Body: 25%
Antrum: 40%
Nodes: celiac, gastrohepatic, gastroduodenal, splenic, porta hepatis, para-aortic
Pathology
90% of tumors are adenocarcinoma
Second most common type is lymphoma
Prognostic factors
T/N/M staging*
Linitis plastica
Aneuploidy (poor prognostic factor)
Surgery
Total vs. subtotal gastrectomy tested in a randomized trial (PMID 10450730) showed no survival advantage with total gastrectomy
D1 node dissection: perigastric nodes only
D2 node dissection: perigastric, splenic, celiac
D1 vs. D2 also tested in RCT (PMID 15082726) with no survival benefit seen to extended LND
Adjuvant treatment
Chemoradiation (PMID 11547741) "Macdonald trial"
Patients with T2 or greater tumors or with positive nodes after gastrectomy were randomized to chemoradiation (5FU/leucovorin + 45Gy) vs. observation
Chemoradiation was associated with:
-improved overall survival, 41% vs 50% at 3 years, median 27 vs, 36 months
-improved local control, 61% vs 19% at 3 years
-higher rates of distant metastasis as first failure, 18% vs. 33%
-Nodal targets: perigastric, celiac, local PA, porta hepatis, pancreaticoduodenal; in GE junction tumors can exclude pancreaticoduodenal nodes but must include paracardial and paraesophageal nodes; splenic nodes may be excluded if needed to spare left kidney in antral tumors.
Chemotherapy only (PMID 16822992) "MAGIC trial"
Distal esophageal as well as gastric cancer were eligible
Randomization was to perioperative epirubicin/5FU/cisplatin vs. surgery only
Chemotherapy was associated with
-improved 5-year PFS (18 vs 30%)
-improved 5-year OS (36 vs 23%)
-downstaging at the time of surgery
Esophageal cancer
Epidemiology
16,000 cases/year in US
Male to female ratio = 3:1
Adenocarcinoma is increasing in incidence and has replaced SCC as the most common histology
Squamous cell risk factors
Regional (Caucasus, North China)
Black men
Alcohol
Smoking
Plummer-Vinson syndrome
Nitrate containing foods
Achalasia
Lye injury
Tylosis
Head and neck cancer
Adenocarcinoma risk factors
GERD/Barrett's esophagus
White males
Anatomy
Cervical esophagus: cricopharyngeus muscle (15cm from incisors) to sternal notch (18cm)
Thoracic esophagus: Sternal notch to carina (25cm); risk of TE fistula exists here and bronchoscopy is an essential part of the staging
Distal esophagus: Carina to GE junction (40cm)
Siewert classes (for GE junction region tumors):
-I: More than 1cm above GE junction; higher incidence of mediastinal nodes
-II: Crosses GE junction (1cm above to 2cm below)
-III: Below GE junction (more than 2cm); celiac nodes usually involved
Multiple permutations of therapy (chemo/RT/surgery)
1) Chemo-RT vs RT only: RTOG 8501 (RT to entire esophagus, 50.4Gy+/- cis-5FU chemo
Chemo-RT had a significant improvement in 5-year OS (26 vs 0%) but was associated with a significant increase in acute and late toxicity
2) Neoadjuvant chemo vs. surgery only: no clear benefit to added chemo
3) Neoadjuvant RT vs. surgery only: no clear benefit to added RT
4) Neoadjuvant chemo-RT vs. surgery only: 5 randomized trials
-2 showed survival benefit (Walsh, CALGB)
-Equivocal: Urba, Bosset, Burmeister
-Meta-analysis showed OS, LC benefit
5) Chemo-RT vs. chemoRT + surgery: two trials
-French: worse survival in trimodality arm
-German: surgery improved local control but did not show OS benefit
6) Dose escalation
-Minsky: cis/5FU + 50.4Gy vs. 64.8Gy
High dose arm associated with worse OS, 13 vs. 18 months
All deaths in high dose arm occurred before completion of tx
-Gaspar: cis/5FU + 50Gy + 5Gy x 3 or 20Gy x 1
-Fistula rate was 18% at one year
-Local failure was high at 63%
Fields
GTV + 5 cm sup/inf along the esophagus, 2 to 2.5 cm radially
For distal tumors the celiac axis and gastrohepatic ligament nodes should be included
16,000 cases/year in US
Male to female ratio = 3:1
Adenocarcinoma is increasing in incidence and has replaced SCC as the most common histology
Squamous cell risk factors
Regional (Caucasus, North China)
Black men
Alcohol
Smoking
Plummer-Vinson syndrome
Nitrate containing foods
Achalasia
Lye injury
Tylosis
Head and neck cancer
Adenocarcinoma risk factors
GERD/Barrett's esophagus
White males
Anatomy
Cervical esophagus: cricopharyngeus muscle (15cm from incisors) to sternal notch (18cm)
Thoracic esophagus: Sternal notch to carina (25cm); risk of TE fistula exists here and bronchoscopy is an essential part of the staging
Distal esophagus: Carina to GE junction (40cm)
Siewert classes (for GE junction region tumors):
-I: More than 1cm above GE junction; higher incidence of mediastinal nodes
-II: Crosses GE junction (1cm above to 2cm below)
-III: Below GE junction (more than 2cm); celiac nodes usually involved
Multiple permutations of therapy (chemo/RT/surgery)
1) Chemo-RT vs RT only: RTOG 8501 (RT to entire esophagus, 50.4Gy+/- cis-5FU chemo
Chemo-RT had a significant improvement in 5-year OS (26 vs 0%) but was associated with a significant increase in acute and late toxicity
2) Neoadjuvant chemo vs. surgery only: no clear benefit to added chemo
3) Neoadjuvant RT vs. surgery only: no clear benefit to added RT
4) Neoadjuvant chemo-RT vs. surgery only: 5 randomized trials
-2 showed survival benefit (Walsh, CALGB)
-Equivocal: Urba, Bosset, Burmeister
-Meta-analysis showed OS, LC benefit
5) Chemo-RT vs. chemoRT + surgery: two trials
-French: worse survival in trimodality arm
-German: surgery improved local control but did not show OS benefit
6) Dose escalation
-Minsky: cis/5FU + 50.4Gy vs. 64.8Gy
High dose arm associated with worse OS, 13 vs. 18 months
All deaths in high dose arm occurred before completion of tx
-Gaspar: cis/5FU + 50Gy + 5Gy x 3 or 20Gy x 1
-Fistula rate was 18% at one year
-Local failure was high at 63%
Fields
GTV + 5 cm sup/inf along the esophagus, 2 to 2.5 cm radially
For distal tumors the celiac axis and gastrohepatic ligament nodes should be included
Locally advanced invasive breast cancer
Epidemiology
Decreasing percentage of tumors are diagnosed at stage T3 or greater probably due to increasing mammography rates
Inflammatory breast cancer represents about 2% of all breast cancers (4,000 cases per year)
-incidence is increasing slightly for unknown reasons
-more common in black women (who are overall at higher risk for presenting with advanced stage disease)
-associated with high rates of nodal involvement and metastases
Stages
T3 = 2 to 5cm breast tumor
T4a = chest wall invasion (pec muscles do not count) T4b = skin invasion T4c = both
T4d = inflammatory breast cancer
-rapid progression of erythema, edema, and warmth
-underlying mass may or may not be present
-inflammatory disease is associated with invasion of the dermal lymphatics on pathology but this is not necessary to make the diagnosis in a patient who has bx proven breast cancer with the appropriate clinical findings
-30% have mets at diagnosis
-tumors tend to be ER-, high grade, highly proliferative
Neoadjuvant chemotherapy
Recommended in most LABC patients
NSABP B-18: patients with operable breast cancer assigned to AC chemo either before or after surgery
-DFS and OS were equivalent regardless of when chemo was given
-60% of patients were BCT candidates at the time of study entry
-20% of non-BCT patients were converted to BCT by the use of preoperative chemo, however a trend to increased rates of first recurrence as an in-breast tumor recurrence was noted in this group
-EORTC replicated these results
Postmastectomy radiation trials
1) Danish 82b: premenopausal T3/T4 with + nodes randomized to mastectomy + CMF +/- RT
RT improved 10-year DFS (34 vs 48%)
and 10-year OS (45 vs 54%)
decreased local failure (26 vs 5%)
Most common site of recurrence in patients not receiving radiation was the chest wall
Adequacy of LN dissection has been questioned
2) Danish 82c: postmenopausal T3/T4 with + nodes randomized to mastectomy + tam +/- RT
RT improved 10-year DFS (24 vs 36%)
and 10-year OS (36 vs 45%)
decreased local failure (35 vs 8%)
No survival benefit was seen for RT in patients with 0-3 positive nodes
3) British Columbia: premenopausal women, N+, randomized to mastectomy + CMF +/- RT
RT increased 10-year OS (37 vs 47%)
decreased local failure (39 vs 13%)
Indications for PMRT
Absolute: Four or more positive nodes; positive margins; inflammatory carcinoma; T4 primary; ECE
Gray area: 1-3 nodes
Tiebreakers: large tumors (T3), younger patients, less than ten nodes dissected, more than 20% of nodes involved, high grade, ER-, LVSI+
Decreasing percentage of tumors are diagnosed at stage T3 or greater probably due to increasing mammography rates
Inflammatory breast cancer represents about 2% of all breast cancers (4,000 cases per year)
-incidence is increasing slightly for unknown reasons
-more common in black women (who are overall at higher risk for presenting with advanced stage disease)
-associated with high rates of nodal involvement and metastases
Stages
T3 = 2 to 5cm breast tumor
T4a = chest wall invasion (pec muscles do not count) T4b = skin invasion T4c = both
T4d = inflammatory breast cancer
-rapid progression of erythema, edema, and warmth
-underlying mass may or may not be present
-inflammatory disease is associated with invasion of the dermal lymphatics on pathology but this is not necessary to make the diagnosis in a patient who has bx proven breast cancer with the appropriate clinical findings
-30% have mets at diagnosis
-tumors tend to be ER-, high grade, highly proliferative
Neoadjuvant chemotherapy
Recommended in most LABC patients
NSABP B-18: patients with operable breast cancer assigned to AC chemo either before or after surgery
-DFS and OS were equivalent regardless of when chemo was given
-60% of patients were BCT candidates at the time of study entry
-20% of non-BCT patients were converted to BCT by the use of preoperative chemo, however a trend to increased rates of first recurrence as an in-breast tumor recurrence was noted in this group
-EORTC replicated these results
Postmastectomy radiation trials
1) Danish 82b: premenopausal T3/T4 with + nodes randomized to mastectomy + CMF +/- RT
RT improved 10-year DFS (34 vs 48%)
and 10-year OS (45 vs 54%)
decreased local failure (26 vs 5%)
Most common site of recurrence in patients not receiving radiation was the chest wall
Adequacy of LN dissection has been questioned
2) Danish 82c: postmenopausal T3/T4 with + nodes randomized to mastectomy + tam +/- RT
RT improved 10-year DFS (24 vs 36%)
and 10-year OS (36 vs 45%)
decreased local failure (35 vs 8%)
No survival benefit was seen for RT in patients with 0-3 positive nodes
3) British Columbia: premenopausal women, N+, randomized to mastectomy + CMF +/- RT
RT increased 10-year OS (37 vs 47%)
decreased local failure (39 vs 13%)
Indications for PMRT
Absolute: Four or more positive nodes; positive margins; inflammatory carcinoma; T4 primary; ECE
Gray area: 1-3 nodes
Tiebreakers: large tumors (T3), younger patients, less than ten nodes dissected, more than 20% of nodes involved, high grade, ER-, LVSI+
Thursday, July 29, 2010
Early stage invasive breast cancer
Pathology
1) microinvasive breast cancer: extends less than 1mm into basement membrane; considered subset of T1 (T1mic)
2) invasive ductal carcinoma: most common; frequently has DCIS component; extensive intraductal component is defined as more than 25% of the sample containing DCIS; if margins are negative, EIC does not predict for local recurrence
3) invasive lobular carcinoma: often mammographically silent; higher rates of being ER+ than IDC; cells are lined up in rows
4) invasive micropapillary carcinoma: rare but thought to be more aggressive
5) metaplastic carcinoma: also rare; high rates of Her-2-neu+, ER/PR-
6) metaplastic sarcomatoid carcinoma: rare, aggressive
7) spindle cell carcinoma: low metastatic potential but can recur locally
8) cystosarcoma phylloydes: despite sarcoma nomenclature can usually be excised and observed
9) medullary carcinoma: more favorable subtype; poorly differentiated appearing but encapsulated and associated with a pronounced lymphocytic infiltrate; associated with BRCA1 mutated patients
10) tubular carcinoma: also favorable histology
Prognostic factors
1) Tumor size: predicts nodal risk, OS, DFS, mets
2) Axillary nodes: the most important prognostic factor for OS and DFS across multiple trials
3) Histology: tubular, mucinous, medullary are favorable; metaplastic and undifferentiated are worse; LVSI also predicts local recurrence
4) Other pathologic poor prognostic indicators: high grade, ER/PR-, Her2+ (in node + patients), higher proliferative indices, DNA aneuploidy
5) Age: younger patients have a higher risk of local recurrence; young age is also associated with higher grade tumors which have worse survival; age may not be a prognostic factor independently of grade
6) Race: black women are at higher risk of having triple negative phenotype, tend to be higher stage at diagnosis; breast cancer has a lower overall incidence in black women in the US but a higher mortality rate
Impact of improved local control on survival
EBCTG analysis: 42,000 patients, 78 randomized controlled trials
RT showed ~5% overall survival benefit at 15 years for both mastectomy and breast conservation pts
Estimated that one death from breast cancer is prevented for every 4 local recurrences prevented by the addition of RT
Early stage invasive: contraindications for breast conservation
1) pregnancy
2) prior breast or chest RT (dose dependent)
3) active scleroderma or lupus
4) inability to resect to negative margins/multicentric disease
5) large tumor to breast ratio secondary to poor cosmetic outcomes
Trials establishing BCT as equivalent to mastectomy
1) Veronesi (Milan): mastectomy vs. quadrantectomy + axillary dissection + RT
20-yr OS: 41% 42%
20-yr LR: 2% 9%
2) NSABP B-06: mastectomy vs. lumpectomy vs. lumpectomy + RT
20-yr OS: 48% 48% 48%
20-yr IBTR: 15% 39% 14%
3) Meta-analysis (Vinh-Hung et al): 9,000 patients in 15 trials
Radiation increased local control by a factor of 3 compared with lumpectomy alone
8.6% excess mortality is observed in patients who have lumpectomy without RT
4) NSABP B-21: arms were lumpectomy + RT (LR 9%), lumpectomy + tamoxifen (LR 17%), lumpectomy + RT and tamoxifen (LR 3%) with equivalent OS across all arms
Breast conservation in older patients
1) Hughes: patients older than 70 randomized to L + tam (5Y OS 86%, DFS 96%) vs. L + tam + RT (5Y OS 87%, 5Y DFS 99%); difference in DFS was statistically significant but small in magnitude
2) Fyles: patients older than 50 randomized to L + RT + tam (5Y LC 99.4%) vs. L + tam (5Y LC 92.3%); overall survival was the same in both groups (better than 95%)
Boost vs. no boost
EORTC trial randomized patients with complete excision to 50Gy +/- 16Gy boost
-LC in boost arm was 93.8% vs. 89.8% in 50Gy alone arm
and patients with positive margins to 50Gy + 10Gy vs. 26Gy
-LC in the low dose arm was 82.5% vs. 89.2% in the high dose
Predictors of local failure: young age, not receiving boost; margins did not appear to matter
The greatest benefit to boost was seen in younger women, but all ages appeared to benefit
Extra RT did not affect survival
Hypofractionation
NCIC randomized early stage patients to 42.5Gy (16fx) vs. 50Gy (25fx)
-Identical disease control and cosmesis at 5 years
-Patients with separations greater than 25cm were excluded
1) microinvasive breast cancer: extends less than 1mm into basement membrane; considered subset of T1 (T1mic)
2) invasive ductal carcinoma: most common; frequently has DCIS component; extensive intraductal component is defined as more than 25% of the sample containing DCIS; if margins are negative, EIC does not predict for local recurrence
3) invasive lobular carcinoma: often mammographically silent; higher rates of being ER+ than IDC; cells are lined up in rows
4) invasive micropapillary carcinoma: rare but thought to be more aggressive
5) metaplastic carcinoma: also rare; high rates of Her-2-neu+, ER/PR-
6) metaplastic sarcomatoid carcinoma: rare, aggressive
7) spindle cell carcinoma: low metastatic potential but can recur locally
8) cystosarcoma phylloydes: despite sarcoma nomenclature can usually be excised and observed
9) medullary carcinoma: more favorable subtype; poorly differentiated appearing but encapsulated and associated with a pronounced lymphocytic infiltrate; associated with BRCA1 mutated patients
10) tubular carcinoma: also favorable histology
Prognostic factors
1) Tumor size: predicts nodal risk, OS, DFS, mets
2) Axillary nodes: the most important prognostic factor for OS and DFS across multiple trials
3) Histology: tubular, mucinous, medullary are favorable; metaplastic and undifferentiated are worse; LVSI also predicts local recurrence
4) Other pathologic poor prognostic indicators: high grade, ER/PR-, Her2+ (in node + patients), higher proliferative indices, DNA aneuploidy
5) Age: younger patients have a higher risk of local recurrence; young age is also associated with higher grade tumors which have worse survival; age may not be a prognostic factor independently of grade
6) Race: black women are at higher risk of having triple negative phenotype, tend to be higher stage at diagnosis; breast cancer has a lower overall incidence in black women in the US but a higher mortality rate
Impact of improved local control on survival
EBCTG analysis: 42,000 patients, 78 randomized controlled trials
RT showed ~5% overall survival benefit at 15 years for both mastectomy and breast conservation pts
Estimated that one death from breast cancer is prevented for every 4 local recurrences prevented by the addition of RT
Early stage invasive: contraindications for breast conservation
1) pregnancy
2) prior breast or chest RT (dose dependent)
3) active scleroderma or lupus
4) inability to resect to negative margins/multicentric disease
5) large tumor to breast ratio secondary to poor cosmetic outcomes
Trials establishing BCT as equivalent to mastectomy
1) Veronesi (Milan): mastectomy vs. quadrantectomy + axillary dissection + RT
20-yr OS: 41% 42%
20-yr LR: 2% 9%
2) NSABP B-06: mastectomy vs. lumpectomy vs. lumpectomy + RT
20-yr OS: 48% 48% 48%
20-yr IBTR: 15% 39% 14%
3) Meta-analysis (Vinh-Hung et al): 9,000 patients in 15 trials
Radiation increased local control by a factor of 3 compared with lumpectomy alone
8.6% excess mortality is observed in patients who have lumpectomy without RT
4) NSABP B-21: arms were lumpectomy + RT (LR 9%), lumpectomy + tamoxifen (LR 17%), lumpectomy + RT and tamoxifen (LR 3%) with equivalent OS across all arms
Breast conservation in older patients
1) Hughes: patients older than 70 randomized to L + tam (5Y OS 86%, DFS 96%) vs. L + tam + RT (5Y OS 87%, 5Y DFS 99%); difference in DFS was statistically significant but small in magnitude
2) Fyles: patients older than 50 randomized to L + RT + tam (5Y LC 99.4%) vs. L + tam (5Y LC 92.3%); overall survival was the same in both groups (better than 95%)
Boost vs. no boost
EORTC trial randomized patients with complete excision to 50Gy +/- 16Gy boost
-LC in boost arm was 93.8% vs. 89.8% in 50Gy alone arm
and patients with positive margins to 50Gy + 10Gy vs. 26Gy
-LC in the low dose arm was 82.5% vs. 89.2% in the high dose
Predictors of local failure: young age, not receiving boost; margins did not appear to matter
The greatest benefit to boost was seen in younger women, but all ages appeared to benefit
Extra RT did not affect survival
Hypofractionation
NCIC randomized early stage patients to 42.5Gy (16fx) vs. 50Gy (25fx)
-Identical disease control and cosmesis at 5 years
-Patients with separations greater than 25cm were excluded
DCIS and LCIS
Lobular carcinoma in situ
<15% of in situ breast cancer
Frequently multicentric (90%) and bilateral (35%)
Most cases are in premenopausal women; average age at dx is 45
Risk factors similar to invasive cancer
Usually incidental finding in biopsy and not associated with a particular mammographic abnormality
LCIS is a marker for an increased risk of invasive breast cancer but it is unclear if it represents a true pre-malignant lesion
Treatment for isolated LCIS is close observation with regular mammograms/MRI; consider chemoprevention with SERM's
If another histology is present, LCIS can be essentially ignored and the lesion is treated according to whatever other histology is present
The presence of LCIS is not thought to change the outcome of other types of breast tumors
Paget's disease of the nipple...a traditional pitfall
Crusting, eczematoid nipple
-If no underlying mass is present, 66-86% of patients have an underlying DCIS
-If an underlying mass is present, 90% are found to have invasive breast cancer
Can be managed with breast conservation, but the entire nipple-areola complex must be excised
Paget's occurs in fewer than 5% of breast cancer cases
Ductal carcinoma in situ
60,000 cases per year; incidence has increased greatly as screening mammography has become more popular
Same risk factors as invasive cancer
All DCIS are considered to be premalignant lesions with a 36% estimated rate of transformation to IDC in 10 years
Subtypes: comedonecrosis, solid, cribriform, micropapillary, papillary
Rates of ER+ and PR+ decrease with grade; rates of Her-2-neu+ increase with grade
Mastectomy may be required for multicentric DCIS (multicentric = more than one quadrant of the breast; multifocal = more than one lesion in a single quadrant)
Otherwise, breast conservation is often performed
No clear groups in whom RT can be withheld (Van Nuys criteria)
Short tabular summary of large randomized DCIS trials
<15% of in situ breast cancer
Frequently multicentric (90%) and bilateral (35%)
Most cases are in premenopausal women; average age at dx is 45
Risk factors similar to invasive cancer
Usually incidental finding in biopsy and not associated with a particular mammographic abnormality
LCIS is a marker for an increased risk of invasive breast cancer but it is unclear if it represents a true pre-malignant lesion
Treatment for isolated LCIS is close observation with regular mammograms/MRI; consider chemoprevention with SERM's
If another histology is present, LCIS can be essentially ignored and the lesion is treated according to whatever other histology is present
The presence of LCIS is not thought to change the outcome of other types of breast tumors
Paget's disease of the nipple...a traditional pitfall
Crusting, eczematoid nipple
-If no underlying mass is present, 66-86% of patients have an underlying DCIS
-If an underlying mass is present, 90% are found to have invasive breast cancer
Can be managed with breast conservation, but the entire nipple-areola complex must be excised
Paget's occurs in fewer than 5% of breast cancer cases
Ductal carcinoma in situ
60,000 cases per year; incidence has increased greatly as screening mammography has become more popular
Same risk factors as invasive cancer
All DCIS are considered to be premalignant lesions with a 36% estimated rate of transformation to IDC in 10 years
Subtypes: comedonecrosis, solid, cribriform, micropapillary, papillary
Rates of ER+ and PR+ decrease with grade; rates of Her-2-neu+ increase with grade
Mastectomy may be required for multicentric DCIS (multicentric = more than one quadrant of the breast; multifocal = more than one lesion in a single quadrant)
Otherwise, breast conservation is often performed
No clear groups in whom RT can be withheld (Van Nuys criteria)
Short tabular summary of large randomized DCIS trials
| Group | Lumpectomy only | L + RT | Factors predicting recurrence |
| NSABP B-17 | 32% | 16% | comedonecrosis, margins, tumor larger than 1cm |
| EORTC 10853 | 25% | 15% | age, grade, margins |
| Trials using RT and hormones | |||
| UKCCCR | 14% (RT only) | 6% (RT + tam) | |
| NSABP B-24 | 13% (RT only> | 8% (RT + tam) |
Breast - General
Anatomy
Sits atop the pectoralis muscles (invasion of the pectoralis does not count as chest wall invasion for T4 disease). Pec minor attaches at coracoid process and ribs 3, 4, and 5
Most breast tumors develop at the interface between ducts and lobules ("terminal ductal lobular unit")
Most common location is the axillary tail
Cooper's ligaments are connective tissue within the breast parenchyma; involvement can cause skin dimpling even if the skin is not actually involved
Lymph node drainage
Axillary levels I, II, III (demarcated by pec. minor; Level III is medial, II under the muscle, I lateral)
Infrapectoral or Rotter's nodes
Supraclavicular nodes (usually involved only after the axilla is involved)
Internal mammary nodes (medial/central/inferior tumors)
A standard axillary dissection removes levels II and III
Risk of axillary involvement depends on tumor size, grade, and patient age
Internal mammary risk depends on tumor size, location, + axillary nodes
Supraclavicular risk depends on number of axillary nodes involved (4 or more), involvement of the apex of the axilla, tumor grade, extracapsular extension
Epidemiology
Most common cancer in US women: 210,000 invasive cases, 60,000 in situ cases, 40,000 deaths
Screening has been associated with a large increase in cases in the US in the 1990's
Male breast cancer - 1700 cases, 460 deaths
Mortality from breast cancer is decreasing
Risk factors
1) Age*
2) Estrogen excess (early menarche, late menopause, nulliparity, older age at first pregnancy, HRT)
3) Personal history of breast cancer
4) Family history of breast cancer
5) Personal history of atypical ductal hyperplasia
6) RT to chest (especially during adolescence)
7) Obesity
8) Alcohol
Risk factors for bilateral disease
1) Invasive lobular histology
2) Age
3) + family history
4) Multicentric disease
5) Parity
6) PR+
7) High grade tumors
Genetic syndromes associated with breast cancer
1) Li-Fraumeni syndrome
-p53 mutation
-Breast cancer is the most common malignancy in Li-Fraumeni patients (up to 90% risk)
2) BRCA-1
-65-85% lifetime breast cancer risk
-50% ovarian cancer risk
-Increased rates of colon and prostate tumors
-Associated with triple negative (basal) phenotype
3) BRCA-2
-Similar 65-85% breast cancer risk as BRCA-1 patients
-Also have elevated risk of ovarian cancer, but less so than BRCA-1
-Associated with pancreatic cancer, male breast cancer
BRCA 1 and 2 mutated patients account for 5-10% of all breast cancer cases
Chemoprevention
Tamoxifen: NSABP P-1
-Decreased risk of invasive and in situ cancer by 50% vs. placebo in women with a Gail model risk of 1.67% in 5 years or who had LCIS
-Raloxifene vs. tamoxifen: NSABP P-2
Sits atop the pectoralis muscles (invasion of the pectoralis does not count as chest wall invasion for T4 disease). Pec minor attaches at coracoid process and ribs 3, 4, and 5
Most breast tumors develop at the interface between ducts and lobules ("terminal ductal lobular unit")
Most common location is the axillary tail
Cooper's ligaments are connective tissue within the breast parenchyma; involvement can cause skin dimpling even if the skin is not actually involved
Lymph node drainage
Axillary levels I, II, III (demarcated by pec. minor; Level III is medial, II under the muscle, I lateral)
Infrapectoral or Rotter's nodes
Supraclavicular nodes (usually involved only after the axilla is involved)
Internal mammary nodes (medial/central/inferior tumors)
A standard axillary dissection removes levels II and III
Risk of axillary involvement depends on tumor size, grade, and patient age
Internal mammary risk depends on tumor size, location, + axillary nodes
Supraclavicular risk depends on number of axillary nodes involved (4 or more), involvement of the apex of the axilla, tumor grade, extracapsular extension
Epidemiology
Most common cancer in US women: 210,000 invasive cases, 60,000 in situ cases, 40,000 deaths
Screening has been associated with a large increase in cases in the US in the 1990's
Male breast cancer - 1700 cases, 460 deaths
Mortality from breast cancer is decreasing
Risk factors
1) Age*
2) Estrogen excess (early menarche, late menopause, nulliparity, older age at first pregnancy, HRT)
3) Personal history of breast cancer
4) Family history of breast cancer
5) Personal history of atypical ductal hyperplasia
6) RT to chest (especially during adolescence)
7) Obesity
8) Alcohol
Risk factors for bilateral disease
1) Invasive lobular histology
2) Age
3) + family history
4) Multicentric disease
5) Parity
6) PR+
7) High grade tumors
Genetic syndromes associated with breast cancer
1) Li-Fraumeni syndrome
-p53 mutation
-Breast cancer is the most common malignancy in Li-Fraumeni patients (up to 90% risk)
2) BRCA-1
-65-85% lifetime breast cancer risk
-50% ovarian cancer risk
-Increased rates of colon and prostate tumors
-Associated with triple negative (basal) phenotype
3) BRCA-2
-Similar 65-85% breast cancer risk as BRCA-1 patients
-Also have elevated risk of ovarian cancer, but less so than BRCA-1
-Associated with pancreatic cancer, male breast cancer
BRCA 1 and 2 mutated patients account for 5-10% of all breast cancer cases
Chemoprevention
Tamoxifen: NSABP P-1
-Decreased risk of invasive and in situ cancer by 50% vs. placebo in women with a Gail model risk of 1.67% in 5 years or who had LCIS
-Raloxifene vs. tamoxifen: NSABP P-2
-Equal to tamoxifen in ability to prevent breast cancer
-Fewer adverse events: VTE, uterine cancer, cataract surgery all decreased in raloxifene group
Birads criteria
0 = further imaging recommended
1 = no mammographic abnormality
2 = benign abnormality
3 = likely benign abnormality; short follow up recommended
4 = suspicious abnormality, biopsy recommended
5 = highly suspicious abnormality
6 = biopsy proven cancer
Radiographic findings suggestive of malignancy
Calcifications: 100-300um; rodlike, tubular, branching, punctate; clustered microcalcifications
Spiculated mass
Hypoechoic mass (on u/s)
Contralateral breast cancer is found in 1-2% of patients
Workup
All patients: B/L mammogram and ultrasound; +/- MRI
MRI is more useful in younger patients or women with dense breasts
Imaging of the breast is followed by guided core needle biopsy
For DCIS patients: no further staging is needed if DCIS alone confirmed at lumpectomy
For early-stage invasive patients: staging is completed by chest x-ray, CBC, CMP; tumor excision and sentinel mymph node biopsy
For locally advanced patients: CT of chest/abdomen/pelvis or PET scan; bone scan; CBC/CMP; brain MRI considered if neurologic symptoms or mets elsewhere; neoadjuvant chemo often given (more later)
Friday, July 23, 2010
Mesothelioma
2500-3000 cases per year in US. Incidence is rising and expected to peak in 2025.
90% of cases are attributed to asbestos exposure
Tumor spreads along chest tube and biopsy tracks
Epithelioid histology has a better prognosis than sarcomatoid or mixed types
Definitive surgery is extrapleural pneumonectomy; adjuvant radiation is often given (45Gy)
Pemetrexed and cisplatin chemotherapy improves survival (compared with cisplatin alone) in non-surgical patients
Avoid contralateral lung if giving postoperative RT
90% of cases are attributed to asbestos exposure
Tumor spreads along chest tube and biopsy tracks
Epithelioid histology has a better prognosis than sarcomatoid or mixed types
Definitive surgery is extrapleural pneumonectomy; adjuvant radiation is often given (45Gy)
Pemetrexed and cisplatin chemotherapy improves survival (compared with cisplatin alone) in non-surgical patients
Avoid contralateral lung if giving postoperative RT
Mediastinal tumors
Histology varies by location
Anterior (4 T's): thymoma, thyroid (goiter), teratoma, lymphoma ("terrible lymphoma")
Middle: tracheal, esophageal, lymphoma/lymph node metastasis
Posterior: neurogenic tumors, mesenchymal tumors
The mediastinum is the most common site for extragonadal germ cell tumors
Cell type is the most important prognostic factor (non-germinomatous types fare worse)
Anterior (4 T's): thymoma, thyroid (goiter), teratoma, lymphoma ("terrible lymphoma")
Middle: tracheal, esophageal, lymphoma/lymph node metastasis
Posterior: neurogenic tumors, mesenchymal tumors
The mediastinum is the most common site for extragonadal germ cell tumors
Cell type is the most important prognostic factor (non-germinomatous types fare worse)
Primary tracheal tumors
Most frequent in distal 1/3 of trachea
Histologies: squamous cell most common (50% of patients; tends to occur distally); adenoid cystic (25%; proximal; younger patients)
Primary treatment is surgical
50% 5-yr OS for completely resected ACC
25% 5-yr OS for completely resected SCC
Thursday, July 22, 2010
Non-small cell lung cancer
Epidemiology
Second most common cancer in both men and women (after prostate and breast respectively)
180-200,000 cases per year
Most common cause of cancer death in both sexes
Risk factors
Smoking
Radon
Asbestos
Prior aerodigestive tract cancers
Pathology
Adenocarcinoma
-Most common subtype
-Tends to be peripheral
-Often seen in female nonsmokers
-Variants include bronchioalveolar carcinoma, large cell cancer
Squamous cell carcinoma
-Relative decrease in incidence over recent years
-Smokers
-Proximal lesion
Nodal stations
1 - supraclavicular
2, 4 - paratracheal
3 - posterior mediastinum
6 - anterior mediastinum
5 - AP window
7 - subcarinal
10 - hilar
11, 12 - lobar, interlobar
Clinical
Screening trials of CT in high risk patients are ongoing
Sputum cytology and serial CXR have been unsuccessfully tried as screening tests
30-40% of patients have metastatic disease
Additional 35-40% are stage III
SVC syndrome: most commonly caused by SCLC, then squamous cell ca
Pancoast tumor: apical sulcus tumor associated with brachial plexopathy, Horner's syndrome (compression of cervical sympathetic ganglion causing miosis, ptosis, anhidrosis), shoulder pain (secondary to chest wall invasion); most tumors are squamous cell
Paraneoplastic syndromes associated with NSCLC: hypercalcemia (PTHrP, bone metastasis), hypertrophic osteoarthropathy, gynecomastia (associated with large cell subtype)
Prognostic factors
Performance status*
Stage
Weight loss (+/-)
Cellular markers: k-ras p 53, erb, Ki-67
Therapy: very early stage tumors (T1-2, N0)
Preferred treatment: anatomic lobectomy
Wedge resection vs. lobectomy was tested in a randomized trial (Lung Cancer Study Group; PMID 7677489)
Increased local recurrence rates were observed in the wedge resection group (17 vs. 6%); trend to higher overall and cancer-specific mortality rates in the wedge resection group as well
FEV1 is a common criteria for determining if a patient is an operative candidate (limits vary, common criteria is greater than 40% of predicted or at least 1.2L)
Conventionally fractionated postage stamp RT leads to poor outcomes
SBRT is associated with 85-90% local control rates in medically inoperable patients
Proximally located tumors were associated with higher rates of toxicity (including grade 5 toxicity) in initial RTOG trials of SBRT; investigation is continuing as to which gentler fractionation regimens may be appropriate for patients with proximal tumors
Use of adjuvant chemotherapy after lobectomy for node negative patients continues to evolve; patients with large tumors will usually be given chemo
Therapy: early T, node positive
T1-2, N1: chemotherapy is indicated
T1-2, N2: consider adding postoperative radiation
PORT meta-analysis (PMID 15846628) - 2232 patients, 10 trials
Postoperative radiation was detrimental to survival in stage I patients
Benefit was seen for N2 patients
Unclear results in stage III
Criticisms: included studies which used outdated (2-D) treatment techniques;
Therapy: stage III tumors (T3-4Nx; TxN2-3)
I ran out of gas on my notes here
Concurrent CRT with radiation dose escalation is generally recommended
Absolute benefit to concurrent vs. sequential treatment is small, but statistically significant
In terms of treatment planning, lung volume irradiated is a strong predictor of developing radiation pneumonitis; V20 is a commonly used criteria
Therapy: superior sulcus tumors
3% of all lung cancers
MRI is more accurate than CT for assessing chest wall, vertebral invasion
SWOG protocol (PMID 17235046):
-T3-4, N0-1 patients
-45Gy + cisplatin/etoposide x 2 cycles was given preoperatively
-92% of patients went on to complete resection
-65% had path CR or minimal residual disease
-5yr OS was 44% for patients and 54% for those with a complete resection
For unresectable superior sulcus tumors, radiation doses ~66Gy + concurrent chemo are associated with reasonable local control but worse OS compared with resected patients
Chemotherapy agents
1) pemetrexed: worse survival in squamous cell histology
2) gefitinib: EGFR inhibitor; benefit only in about 10% of patients who express mutated EGFR
3) erlotinib: another EGFR inhibitor; sensitive patients also EGFR-mutated; tend to be young, female, Asian, non smokers
4) bevacizumab: associated with pulmonary hemorrhage in squamous cell patients
Second most common cancer in both men and women (after prostate and breast respectively)
180-200,000 cases per year
Most common cause of cancer death in both sexes
Risk factors
Smoking
Radon
Asbestos
Prior aerodigestive tract cancers
Pathology
Adenocarcinoma
-Most common subtype
-Tends to be peripheral
-Often seen in female nonsmokers
-Variants include bronchioalveolar carcinoma, large cell cancer
Squamous cell carcinoma
-Relative decrease in incidence over recent years
-Smokers
-Proximal lesion
Nodal stations
1 - supraclavicular
2, 4 - paratracheal
3 - posterior mediastinum
6 - anterior mediastinum
5 - AP window
7 - subcarinal
10 - hilar
11, 12 - lobar, interlobar
Clinical
Screening trials of CT in high risk patients are ongoing
Sputum cytology and serial CXR have been unsuccessfully tried as screening tests
30-40% of patients have metastatic disease
Additional 35-40% are stage III
SVC syndrome: most commonly caused by SCLC, then squamous cell ca
Pancoast tumor: apical sulcus tumor associated with brachial plexopathy, Horner's syndrome (compression of cervical sympathetic ganglion causing miosis, ptosis, anhidrosis), shoulder pain (secondary to chest wall invasion); most tumors are squamous cell
Paraneoplastic syndromes associated with NSCLC: hypercalcemia (PTHrP, bone metastasis), hypertrophic osteoarthropathy, gynecomastia (associated with large cell subtype)
Prognostic factors
Performance status*
Stage
Weight loss (+/-)
Cellular markers: k-ras p 53, erb, Ki-67
Therapy: very early stage tumors (T1-2, N0)
Preferred treatment: anatomic lobectomy
Wedge resection vs. lobectomy was tested in a randomized trial (Lung Cancer Study Group; PMID 7677489)
Increased local recurrence rates were observed in the wedge resection group (17 vs. 6%); trend to higher overall and cancer-specific mortality rates in the wedge resection group as well
FEV1 is a common criteria for determining if a patient is an operative candidate (limits vary, common criteria is greater than 40% of predicted or at least 1.2L)
Conventionally fractionated postage stamp RT leads to poor outcomes
SBRT is associated with 85-90% local control rates in medically inoperable patients
Proximally located tumors were associated with higher rates of toxicity (including grade 5 toxicity) in initial RTOG trials of SBRT; investigation is continuing as to which gentler fractionation regimens may be appropriate for patients with proximal tumors
Use of adjuvant chemotherapy after lobectomy for node negative patients continues to evolve; patients with large tumors will usually be given chemo
Therapy: early T, node positive
T1-2, N1: chemotherapy is indicated
T1-2, N2: consider adding postoperative radiation
PORT meta-analysis (PMID 15846628) - 2232 patients, 10 trials
Postoperative radiation was detrimental to survival in stage I patients
Benefit was seen for N2 patients
Unclear results in stage III
Criticisms: included studies which used outdated (2-D) treatment techniques;
Therapy: stage III tumors (T3-4Nx; TxN2-3)
I ran out of gas on my notes here
Concurrent CRT with radiation dose escalation is generally recommended
Absolute benefit to concurrent vs. sequential treatment is small, but statistically significant
In terms of treatment planning, lung volume irradiated is a strong predictor of developing radiation pneumonitis; V20 is a commonly used criteria
Therapy: superior sulcus tumors
3% of all lung cancers
MRI is more accurate than CT for assessing chest wall, vertebral invasion
SWOG protocol (PMID 17235046):
-T3-4, N0-1 patients
-45Gy + cisplatin/etoposide x 2 cycles was given preoperatively
-92% of patients went on to complete resection
-65% had path CR or minimal residual disease
-5yr OS was 44% for patients and 54% for those with a complete resection
For unresectable superior sulcus tumors, radiation doses ~66Gy + concurrent chemo are associated with reasonable local control but worse OS compared with resected patients
Chemotherapy agents
1) pemetrexed: worse survival in squamous cell histology
2) gefitinib: EGFR inhibitor; benefit only in about 10% of patients who express mutated EGFR
3) erlotinib: another EGFR inhibitor; sensitive patients also EGFR-mutated; tend to be young, female, Asian, non smokers
4) bevacizumab: associated with pulmonary hemorrhage in squamous cell patients
Wednesday, July 21, 2010
Small cell lung cancer
Epidemiology
40,000 cases/year (about 20-25% of all lung cancer cases)
25% of patients have limited stage disease at diagnosis
Smoking is the major risk factor
Pathology
Classic: small round blue cell tumor; chemo/radiation sensitive
Variant: < 5% of cases
Mixed: treat like NSCLC
Prognostic factors
Stage* (extensive vs. limited)
Pleural effusion; patients with + pleural fluid cytology in turn do worse than negative
Performance status
Sex - women do better
Increased LDH - worse
Paraneoplastic syndrome - worse
Paraneoplastic syndromes - SCLC is famous for these
1) SIADH: hyponatremia, hypervolemia, excessive thirst despite hyponatremia, concentrated urine
2) Cushing's syndrome: ectopic ACTH secretion; usual symptoms of corticosteroid excess; if you don't know what these are you have not been seeing many radiation oncology patients
3) Lambert-Eaton syndrome: antibodies against the pre-synaptic calcium channel; weakness improves with exertion (c/w myasthenia gravis, where symptoms get worse)
4) Limbic encephalopathy, paraneoplastic cerebellar degeneration: Anti-Hu, anti-Yo Ab's in CSF
5) Subacute sensory neuropathy
Staging
PET-CT
Always obtain brain MRI
Bone marrow bx if advanced stage/cytopenic/LDH
Therapy
Fractionation
Phase III trial compared 45Gy at 1.8Gy/day to 45Gy at 1.5Gy b.i.d. (PMID 9920950)
Both arms got concurrent cisplatin/etoposide q3wks x 4 cycles
Twice daily fractionation was associated with increased overall survival (15 vs 24% at 5 years) and improved local control
Major toxicity was esophagitis
Timing
NCI Canada and Japanese Cooperative Oncology Group both performed early (concurrent) vs. late (sequential) thoracic RT RCT's; both showed increased OS for early RT. Meta-analysis showed a benefit for concurrent early RT assuming platinum based chemotherapy regimen is used (PMID 17513057)
PCI in limited stage SCLC
Meta-analysis showed decreased risk of death (HR 0.84), decreased risk of brain mets (HR 0.46) among patients with limited stage SCLC given PCI (PMID 10441063)
RTOG trial 0212 compared 25Gy in 10fx vs 36Gy in 18fx vs. 36Gy/24fx (1.5Gy b.i.d.) (PMID 19386548)
This showed no difference in the incidence of brain metastasis among the arms
Higher mortality was seen in the high dose arms (due to disease progression not neurotoxicity)
PCI in extensive stage SCLC
EORTC randomized trial demonstrated PFS and OS benefit (1-yr OS 27 vs 13%) as well as a decreased incidence of brain mets in patients with complete or partial response of extensive stage SCLC to induction chemo who received PCI (PMID 17699816)
40,000 cases/year (about 20-25% of all lung cancer cases)
25% of patients have limited stage disease at diagnosis
Smoking is the major risk factor
Pathology
Classic: small round blue cell tumor; chemo/radiation sensitive
Variant: < 5% of cases
Mixed: treat like NSCLC
Prognostic factors
Stage* (extensive vs. limited)
Pleural effusion; patients with + pleural fluid cytology in turn do worse than negative
Performance status
Sex - women do better
Increased LDH - worse
Paraneoplastic syndrome - worse
Paraneoplastic syndromes - SCLC is famous for these
1) SIADH: hyponatremia, hypervolemia, excessive thirst despite hyponatremia, concentrated urine
2) Cushing's syndrome: ectopic ACTH secretion; usual symptoms of corticosteroid excess; if you don't know what these are you have not been seeing many radiation oncology patients
3) Lambert-Eaton syndrome: antibodies against the pre-synaptic calcium channel; weakness improves with exertion (c/w myasthenia gravis, where symptoms get worse)
4) Limbic encephalopathy, paraneoplastic cerebellar degeneration: Anti-Hu, anti-Yo Ab's in CSF
5) Subacute sensory neuropathy
Staging
PET-CT
Always obtain brain MRI
Bone marrow bx if advanced stage/cytopenic/LDH
Therapy
Fractionation
Phase III trial compared 45Gy at 1.8Gy/day to 45Gy at 1.5Gy b.i.d. (PMID 9920950)
Both arms got concurrent cisplatin/etoposide q3wks x 4 cycles
Twice daily fractionation was associated with increased overall survival (15 vs 24% at 5 years) and improved local control
Major toxicity was esophagitis
Timing
NCI Canada and Japanese Cooperative Oncology Group both performed early (concurrent) vs. late (sequential) thoracic RT RCT's; both showed increased OS for early RT. Meta-analysis showed a benefit for concurrent early RT assuming platinum based chemotherapy regimen is used (PMID 17513057)
PCI in limited stage SCLC
Meta-analysis showed decreased risk of death (HR 0.84), decreased risk of brain mets (HR 0.46) among patients with limited stage SCLC given PCI (PMID 10441063)
RTOG trial 0212 compared 25Gy in 10fx vs 36Gy in 18fx vs. 36Gy/24fx (1.5Gy b.i.d.) (PMID 19386548)
This showed no difference in the incidence of brain metastasis among the arms
Higher mortality was seen in the high dose arms (due to disease progression not neurotoxicity)
PCI in extensive stage SCLC
EORTC randomized trial demonstrated PFS and OS benefit (1-yr OS 27 vs 13%) as well as a decreased incidence of brain mets in patients with complete or partial response of extensive stage SCLC to induction chemo who received PCI (PMID 17699816)
Thyroid
Epidemiology
About 30,000 cases per year in the US; 1500 deaths
Incidence is increasing, possibly related to an increase in imaging studies leading to incidental finding of thyroid lesion
Risk factors
Well established relationship to radiation exposure especially in childhood
Histology is usually papillary adenocarcinoma
HLA-DR7 is associated with non-radiation associated papillary thyroid cancer
Lymph node drainage
Pretracheal and delphian nodes in addition to II, III, IV
Pathology
1) Papillary
Most common subtype (papillary is popular)
Associated with radiation exposure
Excellent prognosis
Two to four times more common in women
Tall cell, insular subtypes cary a worse prognosis
Propensity for lymph node spread
2) Follicular
Strongest affinity for I-131
Also more common in women (2-3x)
Associated with hematogenous mets (lymph node mets are rare)
Hurthle cell, clear cell are variants
3) Medullary
Parafollicular/C cells
Does not concentrate I-131 but can be treated with I-131 anyway due to uptake in the rest of the thyroid gland
Associated with MEN-II
4) Anaplastic
Highly aggressive
Associated with transformed goiter
5) Radiation-induced
Similar histologic distribution as sporadic cases
Tumors may have a greater tendency to invade and recur
Treated the same as other thyroid cancers
Treatment
All patients: surgery, exogenous thyroid hormone (to suppress stimulation of the thyroid gland)
I-131 ablation if tumor is greater than 1cm, has capsular invasion, vascular invasion, positive margins, positive nodes, recurrent disease
External radiation if tumor does not concentrate I-131; multiply recurrent; bulky/unresectable disease
About 30,000 cases per year in the US; 1500 deaths
Incidence is increasing, possibly related to an increase in imaging studies leading to incidental finding of thyroid lesion
Risk factors
Well established relationship to radiation exposure especially in childhood
Histology is usually papillary adenocarcinoma
HLA-DR7 is associated with non-radiation associated papillary thyroid cancer
Lymph node drainage
Pretracheal and delphian nodes in addition to II, III, IV
Pathology
1) Papillary
Most common subtype (papillary is popular)
Associated with radiation exposure
Excellent prognosis
Two to four times more common in women
Tall cell, insular subtypes cary a worse prognosis
Propensity for lymph node spread
2) Follicular
Strongest affinity for I-131
Also more common in women (2-3x)
Associated with hematogenous mets (lymph node mets are rare)
Hurthle cell, clear cell are variants
3) Medullary
Parafollicular/C cells
Does not concentrate I-131 but can be treated with I-131 anyway due to uptake in the rest of the thyroid gland
Associated with MEN-II
4) Anaplastic
Highly aggressive
Associated with transformed goiter
5) Radiation-induced
Similar histologic distribution as sporadic cases
Tumors may have a greater tendency to invade and recur
Treated the same as other thyroid cancers
Treatment
All patients: surgery, exogenous thyroid hormone (to suppress stimulation of the thyroid gland)
I-131 ablation if tumor is greater than 1cm, has capsular invasion, vascular invasion, positive margins, positive nodes, recurrent disease
External radiation if tumor does not concentrate I-131; multiply recurrent; bulky/unresectable disease
Tuesday, July 20, 2010
Nasal cavity/paranasal sinuses: a collection of random onco-facts
~4500 cases per year
Maxillary sinus is the most common site
Risk factors: smoking, wood dust, nickel (nasal cavity); thorotrast (maxillary sinus)
Nodal drainage
-Nasal cavity: To retropharynx, intercalated nodes ("moustache" nodes), level I
-Esthesioneuroblastoma: similar
-Maxillary sinus: nodal involvement is rare
-Ohngren's line: imaginary line extending from medial canthus to the angle of mandible; tumors above this line are in the "superstructure" and more likely to involve orbit/ethmoid sinus/base of skull and be unresectable
Maxillary sinus is the most common site
Risk factors: smoking, wood dust, nickel (nasal cavity); thorotrast (maxillary sinus)
Nodal drainage
-Nasal cavity: To retropharynx, intercalated nodes ("moustache" nodes), level I
-Esthesioneuroblastoma: similar
-Maxillary sinus: nodal involvement is rare
-Ohngren's line: imaginary line extending from medial canthus to the angle of mandible; tumors above this line are in the "superstructure" and more likely to involve orbit/ethmoid sinus/base of skull and be unresectable
Salivary gland tumors
Epidemiology
5% of all head and neck cancers in the US
1) Parotid: 70% of salivary gland tumors; 25% of parotid tumors are malignant; muco-epidermoid is the most common histology
2) Submandibular: 8% of salivary gland tumors; 40% are malignant
3) Minor salivary glands: 22% of tumors; 65% are malignant; adenoid cystic is the most common histology
Pathology
1) Pleomorphic adenoma: low malignant potential; RT used for recurrent tumors
2) Low grade tumors: acinic cell carcinoma, low grade mucoepidermoid
3) High grade tumors: adenoid cystic, high grade mucoepidermoid, undifferentiated
Clinical
Features associated with malignant salivary gland mass: short duration of symptoms, pain, facial nerve weakness, enlarged neck nodes, children, skin involvement
Prognostic factors
T/N stage, histology, age (older is worse), facial nerve involvement, surgical margin status
RT doses
Pleomorphic adenoma: 60Gy
Malignant tumors: 60-66Gy depending on margins; cranial nerve should be treated if clinically involved; lesions involving the minor salivary glands of the palate and paranasal sinus may have a higher rate of cranial nerve invasion
5% of all head and neck cancers in the US
1) Parotid: 70% of salivary gland tumors; 25% of parotid tumors are malignant; muco-epidermoid is the most common histology
2) Submandibular: 8% of salivary gland tumors; 40% are malignant
3) Minor salivary glands: 22% of tumors; 65% are malignant; adenoid cystic is the most common histology
Pathology
1) Pleomorphic adenoma: low malignant potential; RT used for recurrent tumors
2) Low grade tumors: acinic cell carcinoma, low grade mucoepidermoid
3) High grade tumors: adenoid cystic, high grade mucoepidermoid, undifferentiated
Clinical
Features associated with malignant salivary gland mass: short duration of symptoms, pain, facial nerve weakness, enlarged neck nodes, children, skin involvement
Prognostic factors
T/N stage, histology, age (older is worse), facial nerve involvement, surgical margin status
RT doses
Pleomorphic adenoma: 60Gy
Malignant tumors: 60-66Gy depending on margins; cranial nerve should be treated if clinically involved; lesions involving the minor salivary glands of the palate and paranasal sinus may have a higher rate of cranial nerve invasion
| Outcome | Parotid | Submandibular | Minor |
| LC | 60-90% | 40-80% | 60-80% |
| OS 5/10 yrs | 50-80%/40-60% | 30-60%/20-50% | 50-80/40-60% |
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