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

Yes I Passed

So you can take these notes seriously now :)

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

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

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

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+

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

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

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

-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)

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

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)

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

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

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)

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

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

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

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%

Head and neck, unknown primary

Workup (PMID 19718744)
H&P
Direct laryngoscopy with biopsy
Sites to sample: tonsil (tonsillectomy preferred), nasopharynx, base of tongue, piriform sinus
PET CT
This will find primary lesion in about 50% of patients
Most common sites are tonsil and base of tongue

Hypopharynx

Anatomy

Portion of pharynx from the hyoid bone to cricoid cartilage

After cricoid, cervical esophagus begins

Subsites: piriform sinus (most common), postcricoid area, posterior pharyngeal wall

Epidemiology

~3,000 cases per year

Strong association with smoking; alcohol may potentiate the effects of smoking

Often locally advanced at diagnosis; 80% T3-4, 50%N+

Pathology

Nearly always squamous cell

Prognostic factors

Age (older is worse), site (piriform sinus better)

Treatment

Outcomes seem to be worse than other primary sites

EORTC performed a larynx preservation trial (chemoradiation vs. resection and adjuvant RT, PMID 8656441). Five year survival was about the same in both arms (30-35%).  In the larynx preservation arm, 60% of the patients were alive and had a larynx at five years.  

Larynx

Anatomy: Complicated!
Supraglottis = epiglottis, arytenoids and AE folds, false vocal cords, ventricle
True glottis = true vocal cords and anterior commissure
Subglottis = 5mm below free margin of true vocal cord extending down to the inferior border of cricoid
Staging system is slightly different for each subsite

Hoarseness: damage to several structures can lead to a hoarse voice
1) true vocal cord - even small/early lesions cause significant voice alteration
2) intrinsic muscles of larynx
3) cricoarytenoid muscle
4) recurrent laryngeal nerve - mediastinal tumors

Lymph node patterns of spread
~50% of patients are N0 at diagnosis
Levels II and III are most commonly involved
Clinically N0: ~20% will be found to have nodes in II and III if neck is dissected
N+: 50-60% in either II or III; 30% in IV

For true glottic cancers, nodal involvement is rare until the tumor grows outside the true cords
T1: risk of nodes approaches zero
T2: 2% have + nodes
T3-4: 20-30%

Types of laryngectomy
1) Total laryngectomy: removal of all laryngeal structures with pharyngeal reconstruction. Patients have a permanent tracheostomy and need voice prosthesis or learn esophageal speech. Typically performed for advanced lesions with irreversible laryngeal dysfunction.
2) Supraglottic partial laryngectomy: removes epiglottis, false cords, superior half of thyroid cartilage. This procedure is contraindicated in patients with lung disease since removal of the epiglottis results in chronic aspiration.
3) Supracricoid partial laryngectomy: removes true cords, false cords, entire cricoid cartilage, +/- epiglottis
4) Vertical hemilaryngectomy: removes one true cord, up to 1/3 of the opposite cord
5) Cordectomy: removal of only part of one true cord

RT alone for early stage cancers of the true glottis
Field extends from hyoid to cricoid and vertebral body to flashing the skin anteriorly
Fractionation is important in these patients
1) T1: Japanese trial randomized patients to 2Gy/day vs. 2.25Gy/day (PMID 16169681); total dose was 60 vs 56.25Gy for small lesions (involving less than 2/3 of the vocal cord) and 66 vs. 63Gy for larger tumors.  No effect was seen on survival but local control was better in the 2.25Gy arm (77 vs. 92%).
2) T2: same fields, different fractionation. Institutional retrospective data (MDACC) supports hyperfractionation. RTOG 9512 randomized to 70Gy in 35fx (2Gy/day) vs. 79.2Gy in 66 fx (1.2Gy b.i.d.).  This showed a strong trend (p = 0.07) to improved disease free survival in the hyperfractionated arm (57 vs 31%).  Local control was 79% for the hyperfx arm and 70% for the conventional arm with a p = 0.11.
3) T3N0: B/l neck nodal fields now need to be included, or neck dissection performed if the patient is having a laryngectomy. Role of chemotherapy and altered fractionation is controversial.

Locally advanced laryngeal cancer
Subsite no longer makes a difference
Laryngectomy is often performed if the larynx is already non-functional
Indications for adjuvant RT include thyroid cartilage invasion/T4 lesions, N2-3 disease, PNI or LVSI; chemo-RT indications are the same as they are anywhere in the head and neck (ECE, + margin)

Attempt at larynx preservation with concurrent chemoradiation is another option
Two famous laryngeal preservation trials have been performed

VA Larynx	RTOG 91-11
Any stage III - IV (T1N1 excluded)	Any stage III - IV (T1N1 excluded)
Induction chemo followed by RT vs. surgery followed by RT	RT only vs. concurrent CRT vs. induction chemo followed by RT

The VA larynx trial demonstrated that larynx preservation could be accomplished without compromising survival. In the RTOG trial, the highest rates of laryngectomy free survival were seen in the concurrent chemoradiation arm with overall survival equivalent among all arms (between 50-60% at five years).

Nasopharynx

Anatomy
Borders of the nasopharynx
-Superior: Floor of sphenoid sinus
-Inferior: Soft palate
-Anterior: Back of nasal cavity/choanae
-Posterior: Paravertebral fascia (?) covering body of C1
-Lateral: Torus tubarius - opening of Eustachian tubes; fossa of Rosenmuller lies posterior to the torus and is the most common site of origin
Skull base access through the foramen lacerum and foramen ovale then into the cavernous sinus
Cavernous sinus involvement is associated with CN III, IV, V-1. V-2, VI palsies
Parapharyngeal involvement can affect CN IX, X, XI, XII

Lymph node patterns of spread
>70% of patients have N+ disease
Most common: level II, RP, III, V, IV, I

Epidemiology
Endemic form (Southeast Asia): nonkeratinizing, incidence begins to increase in 30's, peaks in middle age, associated with EBV infection, possibly salted/preserved foods
Non-endemic form: keratinizing; bimodal age distribution (15-25 years and 50-59 years), associated with smoking

Pathology
WHO grading includes 3 distinct subtypes
Type 1 = keratinizing SCC
Type 2.1 = Nonkeratinizing but well differentiated
Type 2.2 = Nonkeratinizing, undifferentiated; lymphoepithelioma is a subtype of 2.2

Clinical
Nodal involvement in a large majority of patients (see above)
Most common site of metastasis is bone (unlike other SCC which like to go to the lung)
Symptoms: cranial nerve deficit (20%), hearing loss, epistaxis, stuffy nose
MRI gives better visualization of skull base structures than CT
Staging system is different from other SCC of the head and neck


Prognostic factors
T stage/volume of disease
N stage
Sex (female is better)
Age (younger better)
EBV titer (higher worse)
Histology (keratinizing worse)

Treatment, early stage disease
T1-2, N0-1
Gross disease gets 70Gy, clinically + neck 60Gy, prophylactic neck 50Gy
All patients should have prophylactic neck fields treated given the high rates of nodal mets
RP nodes and level V need to be covered

Treatment, advanced disease
T3-4Nx, TxN2-3
Chemoradiation
Intergroup regimen is the most commonly used (Intergroup 0099, PMID 9552031)
Cisplatin 100mg/m2 q3 weeks during RT to 70Gy
Then adjuvant cisplatin/5-FU
This was the first chemoradiation trial to show an OS benefit (47 vs 78% at 3yrs) in nasopharyngeal cancer. The trial has been criticized for a few reasons:
-RT only arm had worse survival than historical series
-High rate of distant metastatic disease
-High rates of toxicity with adjuvant chemo and late toxicities including hearing loss, endocrine insufficiency, and peripheral neuropathy
Subsequent meta-analysis also showed a benefit, but magnitude was much less (PMID 16377415)
Other regimens under study include induction chemo, altered fractionation

Common complications of nasopharynx cancer and therapy
Temporal lobe necrosis (associated with doses >2Gy/day, accelerated tx)
Cranial nerve palsy
Endocrinopathy
Hearing loss
Xerostomia
Carotid injury
Chronic epistaxis

Oropharynx

Anatomy/subsites
Soft palate - Tonsil - Base of tongue - Posterior and lateral pharyngeal walls

Lymph node patterns of spread
II, III, IV, retropharynx
Clinically N0 patients have about 20% risk in levels II, III, IV and 5-10% in retropharynx
Clinically N+ patients have 70% risk in level II, 40% in III, 25% in IV, 10% retropharynx

Epidemiology
15-16,000 cases per year
Tonsil is the most common subsite

Risk factors
HPV+ (strain 16; patients with HPV-associated oropharynx cancer have a much better prognosis) (PMID 20530316)
Smoking
Alcohol

Pathology
Vast majority of tumors are SCC

Clinical
Symptoms include sore throat, hoarseness, dysphagia, ear pain, hemoptysis, airway obstruction, neck mass
Do not forget panendoscopy and dental exam when evaluating pts with head and neck cancers

Oral cavity

Subsites/anatomy
Oral tongue - Retromolar trigone - Gingiva - Buccal mucosa - Floor of mouth - Hard palate

Boundary between oral tongue and base of tongue = circumvallate papillae

Posterior boundary of floor of mouth = anterior tonsillar pillar

Lymph node patterns of spread
For clinically N0, + nodes found in 15 - 20% at neck dissection
Nodal risk increases with size of tumor, depth of invasion
Most commonly involved levels are I, II; III and IV are more frequently involved in clinically N+ pts
Oral tongue lesions are associated with skip metastasis into levels II and III/IV

Upper lip --> preauricular and parotid nodes; level I
Lower lip --> level I
Oral tongue --> level I; level II directly (particularly in more posterior lesions); bilateral/crossed drainage is common; skip metastasis
Floor of mouth --> level I
Buccal mucosa --> parotid; level I
Retromolar trigone --> level II; retropharyngeal nodes
Hard palate --> Rare lymph node mets if lesion confined to the hard palate; I, II, retropharyngeal

Epidemiology
~12,000 cases per year (30% of all head and neck cancers)
5-year OS for all patients is about 60%

Risk factors
Tobacco
Alcohol
Betel nut chewing
HPV (6 and 16 subtypes)
Plummer-Vinson syndrome
Prior oral cavity cancer: elevated risk ~4% per year for another oral cavity cancer; patients are also at much higher risk for esophageal (RR ~20) and lung (RR~7) cancers

Pathology
95% of oral cavity tumors are squamous cell
Premalignant lesions include leukoplakia (5-20% risk of progression to cancer) and erythroplakia (much higher risk of progression to cancer, up to 50%)
Subtypes: basaloid thought to be more aggressive and verrucous possibly less aggressive

Prognostic factors
Nodal involvement*
Thickness of primary lesion, PNI, LVSI predict for LN involvement

Treatment
Surgery is the mainstay
Adjuvant RT is commonly indicated +/- chemotherapy

NCCN Recommendations for Adjuvant RT
T3-4 primary
N2-3 nodes
Perineural invasion
LVSI/tumor embolism
Nodal spread to level IV or V

NCCN Recommendations for Adjuvant Chemo + RT
Extracapsular nodal spread
Positive margins

Doses
Primary: at least 60Gy
ECE or +margin areas: 66Gy
Prophylactic neck: 50Gy
Positive neck: 60Gy

EORTC/RTOG pooled analysis (PMID 16161069)
Eligible patients:
EORTC: Stage III - IV; oral cavity or oropharynx primary with level IV node; +PNI; +LVSI
Both studies: + margin, + ECE
RTOG: Two or more positive nodes

Endpoints: EORTC was PFS; RTOG was OS

Randomization was RT +/- cisplatin based chemotherapy

Both studies showed a local control benefit to adding chemo (~70 vs 80% in both) as well as a PFS benefit (36 vs. 47% at 5 years in both trials).

Only the EORTC study showed a significant OS benefit at 5 years (40 vs 53% in EORTC; 47 vs 56% in RTOG).

For patients with ECE or positive margins, OS benefit was evident in both trials

When neither factor was present, no OS benefit was seen in either trial.

Cranial nerve basics

I: Olfactory
Sense of smell
Exits through cribriform plate

II: Optic
Sense of sight
Exits through optic canal

III: Oculomotor
Pupil constriction
All EOM's except lateral and lateral & down
Superior orbital fissure

IV: Trochlear
Lateral & downward eye movement
Superior orbital fissure
Only cranial nerve that decussates (unless you count partial decussation in optic chiasm

V-1: Trigeminal, ophthalmic branch
Sensation to upper face (crown of head extending to below the lower lid and tip of the nose)
Superior orbital fissure

V-2: Trigeminal, maxillary branch
Sensation to mid-face (lower lid to upper teeth, part of the bottom nose)
Foramen rotundum

V-3: Trigeminal, mandibular branch
Sensation to lower face (lower jaw and pre-auricular area)
Motor to the muscles of mastication
Foramen ovale

VI: Abducens
Lateral eye movement
Superior orbital fissure

VII: Facial, motor branch
Muscles of facial expression
Note that on physical exam, can differentiate between peripheral lesions of the facial nerve and lesions of the facial nerve nucleus in the brainstem by noting whether or not the forehead can wrinkle; if only the lower face is weak, suggests upper motor neuron lesion
Stylomastoid foramen, traverses parotid gland

VII: Facial, sensory branch
Taste to anterior 2/3 of tongue (via chorda tympani); stapedius m.; parasympathetic innervation of lacrimal and salivary glands
Acoustic meatus

VIII: Vestibulocochlear
Hearing and balance/vestibular sensation
Internal acoustic meatus (vestibular branch enters semicircular canal)

IX: Glossopharyngeal
Plain sensory, taste, parasympathetic and motor components
Afferent limb of gag reflex
Tympanic nerve (nerve of Jacobson) is a small branch supplying sensation to the middle ear; associated with ear pain in patients with pharyngeal lesions
Jugular foramen

X: Vagus
Visceral parasympathetic innervation, plain sensory, motor to larynx (via recurrent laryngeal nerve) and pharynx
Efferent limb of the gag reflex
Auricular branch (nerve of Arnold) supplies sensation to the inner ear; associated with ear pain in patients with laryngeal lesions
Jugular foramen

XI: Spinal accessory
Motor to sternocleidomastoid and trapezius muscles
Jugular foramen

XII: Hypoglossal
Motor to tongue
Hypoglossal canal

Nerves in the cavernous sinus: III, IV, V-1, V-2

Pediatric high grade glioma

Epidemiology
GBM represents about 5% of pediatric brain tumors
Brainstem gliomas ~10-15%


GBM is treated similarly to adults

Brainstem glioma
Dorsal, exophytic tumors are often indolent with a more favorable prognosis
Diffuse intrinsic brainstem glioma represents 70-80% of brainstem glioma, 2Y-OS ~20%
Failed regimens include dose escalation to 78Gy, multiple chemo regimens
XRT dose ~54Gy (to GTV + 1 - 1.5cm)

Pediatric low grade glioma

Epidemiology
Most common childhood brain tumor (~1000 per year in US)

Risk factors
NF1 (associated with optic glioma, cafe-au-lait spots)
Tuberous sclerosis (cortical tubers, subependymal giant cell astrocytoma, mental retardation)
Prior XRT

Juvenile pilocytic astrocytoma
WHO Grade 1
Most common glioma in children
Frequently seen in cerebellum, optic tract
Path: Rosenthal fibers; pilomyxoid variant may be more aggressive
Imaging: T2-bright cystic lesion with mural nodule
Observation is recommended after complete resection and frequently after subtotal resection in non-eloquent area

Diffuse/fibrillary astrocytoma
WHO Grade II
Brainstem, cerebral hemispheres
Associated with p53 mutation, LOH @ chromosome 17
May be observed after complete resection; RT for progressive tumor/subtotal or unresectable disease
Chemotherapy may stabilize disease in young children and allow deferral of RT

Optic glioma
Often indolent
Lesions in the posterior part of the pathway (hypothalamus and beyond into optic radiation and occipital cortex) may behave more aggressively
Surgery may be recommended if visual loss already exists and tumor is growing
Patients with intact vision usually given chemo and RT

Pineal tumors

Epidemiology
3-5% of CNS tumors in US
More common in Asia
Age 10-12 years
More common in males
Pineal region associated with non-germinomatous germ cell tumors
Suprasellar region associated with germinoma

Pathology
May be established by CSF or serum tumor markers
Non-germinomas: AFP => Yolk sac or mixed tumors; B-hCG => choriocarcinoma
Germinomas: better behaved; AFP elevation in CSF or serum rules out germinoma but patients can have slightly elevated B-hCG

Clinical
Pineal tumors associated with hydrocephalus, Parinaud's syndrome (upward gaze palsy, loss of accomodation, eyelid retraction; implies dorsal midbrain compression)
Suprasellar tumors associated with bitemporal hemianopsia, endocrine abnormalities (growth failure, DI, precocious puberty); hydrocephalus associated with very large tumors

Treatment, NG-GCT
Worse outcomes (except for mature teratoma which can be treated with resection and observation)
Chemo
CSI 36Gy + tumor boost to 54Gy

Treatment, G-GCT
Neither chemo nor RT alone have satisfactory outcomes
If chemo is used, CSI can be eliminated
In patients receiving chemo, whole ventricles treated to 25Gy with tumor boost to 45Gy
If no chemo given, CSI recommended (21Gy) with boost to gross tumor of 45Gy

Pineoblastoma
Subcategory of supratentorial PNET
Treated like high risk medulloblastoma

Medulloblastoma

Epidemiology
~400 cases per year in US (15 - 20% of childhood brain tumors)
Median age 6 years; seen rarely in adults
Unknown risk factors
Associated with Gorlin syndrome (AKA basal cell nevus syndrome; association with basal cell nevi, ulcerative colitis, multiple developmental abnormalities in addition to medullo)

Pathology
Small round blue cell tumor
Homer Wright rosettes

Clinical
Primarily seen in the posterior fossa (commonly in fourth ventricle and cerebellar vermis)
CSF seeding in about 1/3 of patients

Risk groups
Standard => All of: No CSF spread, less than 1.5cm2 of residual disease, older than three years
High risk => Either + CSF disease or resection leaving more than 1.5cm2 of residual tumor
Maximal resection is critical in both groups

Treatment, standard risk
23.4Gy CSI + concurrent vincristine
55.8Gy boost to residual disease --> adjuvant cisplatin/vincristine

Treatment, high risk
36Gy CSI + concurrent vincristine
55.8Gy boost to residual tumor --> adjuvant cisplatin/vincristine

Special cases of CNS-embryonal tumors
Supratentorial PNET: clinical outcomes worse than medulloblastoma but disease is treated similarly
Medulloblastoma in infants: use chemo to defer CSI
ATRT: histologically resembles PNET but behaves much more aggressively; pts typically younger
-Molecular findings are characteristic (del chr 22 or translocation involving INI1 gene on chr 22)

Ependymoma

Epidemiology
~200 cases per year in US
Most common in children < 5 years
Occasionally diagnosed in adults
No known risk factors

Pathology
Grade I - myxopapillary ependymoma; most commonly seen in filum terminale of spinal cord
Grade II - Ependymoma
Grade III - Anaplastic ependymoma

Clinical
Classic location is posterior fossa; 2/3 originate around the fourth ventricle
Risk of CSF seeding 5 to 10%

Staging
MRI of brain and spine should be done preoperatively to avoid post-surgical artefact that may mimic drop mets in the spine or elsewhere in the CNS
Postop MRI should be obtained within 48 hours
If no LP done before resection, wait 2 weeks after surgery to decrease the chance of postoperative false positive CSF findings

Prognostic factors
Extent of resection
Age (younger is worse)
Grade

Treatment
Maximal resection is essential
Myxopapillary tumors can be followed closely after complete resection
Other histologies, subtotal resections are usually given adjuvant RT
Since most lesions are located in the posterior fossa, cerebral cortex can usually be spared
Typical dose 59.4Gy (patients older than 18 mos); 54Gy (younger than 18 mos)
Target is tumor bed + 1cm
CSI not indicated; grade III patients may get adjuvant chemotherapy

Further reading:
St. Jude experience, PMID 19274783
Neurocognitive outcomes, PMID 15284268

CNS lymphoma

Epidemiology
About 3% of primary brain tumors
Incidence has increased over the past 20 years, probably secondary to aging population, increased incidence of immune suppressed patients (AIDS, transplants, etc)

Risk factors
Age greater than 60
Immune deficiency (HIV+ patients have tremendously increased risk for this disease)

Pathology
Over 90% of primary CNS lymphoma is diffuse large B cell type

Clinical
Most common presenting symptom is focal neurologic deficit
16 to 40% of patients have meningeal involvement
20% have ocular involvement

Staging
Brain MRI
LP
Ophthalmologic evaluation
CT of chest/abdomen/pelvis
Bone marrow biopsy
Bloodwork: CBC. CMP, LDH, HIV status

Imaging
Classic lesion is periventricular, brightly enhancing, diffuse
Most lesions are supratentorial

Prognostic factors
Age (older than 60 is worse)
PS (worse than 1)
Increased LDH
Increased CSF protein

Therapy
Avoid steroids before biopsy if possible
No benefit to debulking surgery
Current standard: high dose methotrexate; WBRT for salvage
High rates of neurotoxicity, especially in older patients

High grade glioma

Epidemiology
GBM: 12-13,000 cases per year
Grade III glioma: 3-4000 cases per year
Cranial RT is a risk factor
Incidence increases with age

Pathology
Anaplastic astrocytoma: no necrosis; fewer mitoses; less cellular; less pleomorphic
Anaplastic oligodendroglioma: perinuclear halos ("fried egg cells"); chicken wire appearance
GBM/Grade IV: necrosis, microvascular proliferation, high mitotic index, pleomorphic

Primary vs. secondary GBM
Primary: de novo, older patients, rapid development.  Associated with EGFR receptor, PTEN, p16 deletions
Secondary: arises in the context of prior lower grade tumor, younger patients; may have better prognosis but unknown if this is due to a lead-time effect.  Associated with p53 mutation, LOH at 19q, PDGFR, DCC.
Both types are associated with LOH at 10q, MDM2, Rb mutations

MGMT
DNA repair enzyme which demethylates O6-methylguanine
Repairs damage induced by temozolomide ... So mutated MGMT is FAVORABLE
In the EORTC temozolomide trial (PMID 19269895) MGMT mutation status was the strongest predictor of response to temozolomide.

Anaplastic oligodendroglioma
Characteristically associated with 1p19q deletion which greatly improves prognosis
RTOG 9402 (PMID 16782910) randomized patients with pure oligo or mixed OA tumors to RT alone vs. RT + PCV chemotherapy.  All patients with 1p19q deletion had improved OS.  No overall survival benefit was seen with the addition of PCV, but a PFS benefit to the addition of PCV was seen in the 1p19q deleted subgroup.

EORTC 26951 (PMID 16782911) was an identical randomization (RT +/- PCV) and showed similar results (improved OS in all 1p19q deleted patients; no OS improvement with chemo but a PFS improvement with chemo was seen in the whole group.  Interestingly the 1p19q deleted group did not have a significantly improved PFS with chemo).

Clinical presentation
Most common symptoms are headache, seizure, focal neuro deficit, cognitive decline
MRI shows enhancing heterogeneous mass typically with extensive edema and central necrosis

RTOG RPA for malignant glioma
Histology (AA vs. GBM)
Age (cutoff 50 years)
Mental status
KPS (cutoff at 70)
Duration of symptoms (less than three months is worse)

Long history of unsuccessful treatments
1) Dose escalation higher than 60Gy (although there appears to be dose response at 60 vs. 45Gy)
2) Hyperfractionation
3) SRS boost
4) Brachytherapy
5) Hypoxic radiosensitizers

Current standard
Maximum surgical debulking
Temozolomide has phase III proven OS benefit: 75mg/m2/day during RT then 150-200mg/m2/day afterwards; correct consolidation/maintenance dose remains under investigation
This regimen increases OS (27 vs 11% at 2 years, 10 vs 2% at 5 years) compared to RT only

RT technique
RTOG recommendations: edema +2cm to 44Gy then enhancement/residual tumor to another 16Gy

Low grade glioma

Epidemiology
~20,000 primary brain tumors are diagnosed each year
Peak incidence in 20's and 30's
LGG is more common than HGG
Associated with NF1, tuberous sclerosis

Pathology
Oligodendroglioma: favorable; 1p19q deletion in 60%
Astrocytoma: gemistocytic thought to be more aggressive than fibrillary/protoplasmic types; 1p19q deleted in 10%

Clinical
Headache, seizure*, neurologic deficits*

Prognostic factors (PMID 11956268)
1) Histology: 5Y-OS for pure oligo 70%, mixed OA 56%, pure astro 37%
2) Age: Older than 40 is worse
3) Tumor size: Bigger than 6cm is worse
4) Neurologic deficit: Having one is bad; seizures are a good prognostic factor in the absence of other deficits
5) Tumor crossing midline
6) Tumor enhancement
7) Extent of resection

Surgery
Diagnostic and therapeutic

Radiation
Timing of treatment (EORTC 22845, PMID 16168780): Randomization was to immediate RT vs. deferring RT until tumor progression.  Early RT improved PFS (median 5.3 vs. 3.4 years) but did not affect overall survival (7.4 vs 7.2 years).  Early RT patients also experienced better seizure control.  Rates of conversion to GBM were similar in the two arms.  No prospective QOL analysis was performed.

Dosing (EORTC 22844, PMID 8948338; Intergroup, PMID 11980997): Randomization was 45 vs. 59.4Gy in EORTC trial and 50.4 vs. 64.8Gy in Intergroup trial.  Neither study showed a significant benefit of dose escalation in terms of OS or PFS.  In the Intergroup trial, a higher incidence of radiation necrosis was seen in the high dose arm.

Chemo (RTOG 9802): Patients were randomized to RT 54Gy +/- PCV chemotherapy.  Initially, no improvement in PFS or OS was seen in the PCV group which also experienced higher toxicity. Updated results presented at ASCO 2014 showed a significant overall survival benefit to adjuvant PCV (13.3 vs. 7.8 years). Astrocytoma or mixed oligo/astrocytoma histology was associated with worse survival, as was male sex. Survival analysis based on 1p/19q deletion status is pending.

Brain metastasis

Epidemiology
Far more common than primary brain tumors, up to 100,000 cases per year and increasing
Most common primary sites are lung and breast

Clinical
Majority of patients have headache and/or neuro deficit

RTOG RPA classification (PMID 9128946)
Class I: All of: age less than 65, KPS higher than 70, controlled primary, brain is only site of metastatic disease; OS 7mos
Class II: Everyone who is not in Class I or Class III; OS 5 mos
Class III: KPS less than 70; OS 2 mos

Trials
1) WBRT +/- surgery (PMID 2405271) in patients with single brain mets: Adding surgery to WBRT had local control and overall survival benefit

2) Surgery +/- WBRT (PMID 9809728) in patients with single brain mets: Adding WBRT improved intracranial control (70 vs 18%), decreased rate of neurologic death, but had no impact on overall survival (pts still died of systemic disease)

3) WBRT +/- SRS (RTOG 9508, PMID 15158627) in patients with one to three brain mets: Adding SRS improved local control in all patients (80 vs 70%) but did not affect OS.  Results of the planned subgroup analysis did show a survival benefit to SRS in patients with a single brain met.  Post hoc (unplanned subgroup) analysis also suggested a survival benefit in patients with NSCLC, RPA class I, tumors > 2cm.  No increased toxicity was seen with the addition of SRS.

4) SRS +/- WBRT (PMID 16757720) in patients with one to four brain mets: Adding WBRT improved local control without affecting overall survival.  Companion neurocognitive analysis showed that tumor control was the most important factor predicting for neurocognitive outcome.  (PMID 17674975)

SRS Dosing (based on RTOG 9005, PMID 10802351)
Less than 2cm: 20Gy
Between 2 and 3cm: 18Gy
Between 3 and 4cm: 15Gy
Larger than 4cm: SRS is probably a bad plan

Acoustic neuroma

Epidemiology
2500 - 3000 cases/year in US
NF2: bilateral acoustic neuroma is essentially diagnostic of NF2

Pathology
Schwann cell/nerve sheath tumor

Clinical
Often incidentally discovered on brain MRI
Unilateral hearing loss
Large tumors cause CN VII, V palsies, brainstem compression

Surgery
Complete resection is curative
Complications: facial nerve palsy (40%), worsened hearing loss (60%)
Recurrence rate 30 -50% after subtotal resection

Radiosurgery
12 - 14Gy to margin
Pitt reports 5-year control > 95%
Facial N. palsy 0% for doses < 13Gy, 2% for doses > 13Gy
Hearing preservation in 70%
(PMID 11147876)

Fractionated RT
Consider if large tumor with brainstem compression, intact hearing
54Gy in 1.8Gy fractions also associated with > 95% tumor control (PMID 15987541)

Observation
Option in elderly/asymptomatic patients

Chordoma

Epidemiology
300 cases/year in US
More common in males
Rare in patients under 40

Pathology
Cell of origin is a remnant of the primitive notochord
Not to be confused with CHONDROMA (benign cartilaginous tumor) or CHONDROSARCOMA
Slow growing but invasive with ~25% pts developing mets

Clinical
Axial skeleton: 1/3 are cranial, usually clival; 1/2 sacrum and coccyx

Headache
Cranial nerve palsy
Bony destruction

Prognostic factors: extent of resection, +/- brainstem involvement

Therapy
Surgery recommended but usually subtotal
Adjuvant RT for residual disease, unresectable tumors
Dose is limited by neural structures; protons have been successful in dose escalation

Disease control with RT

	Chondrosarcoma	Chordoma
Photons (50-66Gy)
5Y-RFS	~90%	50-65%
5Y-OS	50 - 80%	40 - 60%
Protons (66 - 79 CGE)
5Y-RFS	~90%	60 - 75%
5Y-OS	~100%	80%

Craniopharyngioma

Epidemiology
3% of all pediatric brain tumors (~100 cases/year in US)
Peak age 5 - 14 years but can occur in adults

Pathology
Embryonic remnant of Rathke's pouch
Most common histology "adamantinomatous"...unfortunately this does not make you into Wolverine

Imaging
Mixed cystic and solid suprasellar mass
Usually calcified
Cyst often waxes and wanes during and after treatment

Clinical
Diabetes insipidus
Growth failure
Visual field deficits
Cognitive/behavioral changes
Large tumors can compress 3rd ventricle and cause hydrocephalus, increased ICP

Surgery
Complete resection --> 80-90% tumor control with a very high rate of complications (DI, hypothalamic insufficiency)

XRT
Indicated if resection is incomplete (true for most patients)
Rx 54 - 55.8Gy
Margin to PTV = 1.3 - 1.5cm
Cyst re-expansion occurs in up to 50% of pts receiving RT
Other side effects: cognitive deficit (worse in younger patients, larger tumors, more surgeries, +hydrocephalus)
Expected control rates for subtotal resection + adjuvant RT: 3-yr EFS ~90%

Further reading/Sources
St. Jude has the answers (no, really!): PMID 16506496

Pituitary adenoma

Epidemiology
3rd most common brain tumor after glioma, meningioma
Many tumors are clinically silent; ~10% of patients in autopsy series have occult pituitary adenoma (PMID 15760793)
More common in women

Risk Factors
Only known genetic association is MEN1 (mutation on 11q13; parathyroid tumors, pancreatic islet cell tumor, pituitary adenoma)

Anatomy/Physiology
Adenohypophysis: secretes GH, prolactin, TSH, ACTH, gonadotropins (FSH/LH); source of nearly all pituitary tumors
Neurohypophysis: secretes ADH, oxytocin

Clinical
Up to 70% are endocrinologically active although this percentage is decreasing as the proportion of tumors found incidentally on imaging has increased

Endocrinopathies (most to least common): prolactinoma, acromegaly (GH), Cushing's disease (ACTH), hyperthyroidism (TRH), hypergonadotropism (FSH/LH)...last two are quite rare

Hyperprolactinemia can occur with any sellar mass due to compression of the stalk (stops dopamine from reaching the pituitary and suppressing prolactin secretion).  This syndrome is usually associated with serum prolactin < ~150ng/mL.

Headache

Bitemporal hemianopsia 

Cavernous sinus extension (cranial nerve palsies III, IV, V-1, V-2, VI)

Treatment
Surgery is the mainstay

Indications for XRT
Residual or recurrent macroadenoma
Refractory endocrinopathy

RT: techniques and side effects
Nonfunctional macroadenoma gets 16Gy to 50% line (50.4-54Gy for fractionated RT)

Functioning tumors may need higher doses for control but control rates for secretory tumors are difficult to judge given wildly varying definitions of endocrinologic control in the literature (PMID 15871511)

Endocrinologic control is less likely than tumor growth control: 80-90% of non-secretory macroadenomas are controlled; ~70% of prolactinomas; 50-60% of GH, ACTH secreting tumors

SRS is contraindicated if anticipated dose to chiasm/optic N. is > 8Gy (usually corresponds to 5mm separation)

Post-treatment hypopituitarism is the most important complication

Meningioma

Epidemiology

Overall incidence ~ 2/100,000

Most common primary brain tumor

Risk factors
Age (most commonly dx'ed in 50's and 60's)
Females
NF type 2
Breast cancer

Prior cranial radiation: Israeli tinea capitis study (PMID 3173432) of 10,000 children who received xrt for tinea capitis (doesn't that sound so much classier than ringworm). Results below:

Type of cancer	Relative risk
Thyroid cancer	20
Meningioma	4.6
Malignant glioma	1.98

Buzzwords: Whorls, Psammoma bodies

Receptor profile: PR+ in 80%; PDGF; dopamine

WHO grading system: features associated with increased malignancy include loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, necrosis

WHO Grade	Alias	5-year recurrence %
WHO Grade 1	Benign	3%
WHO Grade 2	Atypical	38%
WHO Grade 3	Malignant	78%

Imaging

Bright, homogeneous enhancement (T1 MRI + gadolinium)

Dural tail

Possible calcifications

Difficult to correlate imaging with behavior; edema does not --> aggressiveness

Surgery

10-year LC after surgery (PMID 3403313): Complete excision 77%, subtotal resection 18%, subtotal resection + RT 82%

Simpson classification

Class	Extent of resection	Recurrence rate
1	All tumor and dural attachments	9%
2	GTR with dural cautery	19%
3	Subtotal	40%
4	Decompression only	N/A
5	Biopsy only	N/A

SRS

Contraindications: large tumor (>3.5cm), optic apparatus dose > 8Gy, extensive brainstem compression, elderly and asymptomatic patient (can just observe)

SRS for meningioma (PMID 18300891): Pitt has the definitive series, 972 patients

Rx dose: 14Gy to 50% line (at tumor margin)

Control rates: Grade 1 93%, Grade 2 50%, Grade 3 17%

Tumors that did not undergo biopsy: 97%

Optic nerve injury from SRS (PMID 12654424): 8gy 15Gy 75%

Fractionated RT: use in large tumors, compression of brain stem or near optic structures

Grade 1 dose: 54Gy

Grades 2-3: 60Gy

Further reading: Intro section to current RTOG phase II protocol 0539

Night Before Boards

Letting the Internet answer some important questions:

1) Is procrastination bad?

Fifty-seven educators agree, Procrastination Is Bad. W.G. Sommers makes it sound pretty sexy though: "[cramming is]...an intense and private ritual...that comprises climactic cramming and a secret, if often uncelebrated, victory..." Do tell me more, Dr. Sommers!

Also, WikiHow thinks you can totally get away with it:

2) Is the practice of generating board recalls illegal?

Probably, if you believe the American Board of Internal Medicine. The prospect of losing your specialty license does take a bit of the fun out of paying it forward by writing down a few questions for your junior colleagues. Stupid copyrights.