Skin Cancer: Merkel Cell Carcinoma

Summary:
Wide local excision should always be followed by irradiation. This is an aggressive tumor with high likelihood of locoregional disease at presentation and high rates of recurrence. Adjuvant chemotherapy is controversial and generally not very effective.

Prognosis:
5 year overall survival
Stage I: 80%
Stage II: 60%
Stage III: 40%
Stage IV: 20%
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Etiology:
This is a neuro-endocrine tumor characterized by small-cell cancer cells on pathology. This tumor is generally rare, so high level evidence to guide practice is lacking. Mortality rates are high and double of that expected with melanomas (33 vs 15%).

There is a Merkel Cell Polyomavirus, which suggests a viral etiology. Additionally, immunocompromised individuals seem to be at greater risk.

Approximately 50% present with locoregional disease involving lymph nodes. 30% present with metastatic disease, while only 20% present with localized disease,

Work-up

• Complete history/physical
• CBC, LFTs, RFTs, PT/PTT/INR
• Biopsy
• CT chest
• Anatomical CT for assessment of nodes
  

TNM
T1: < 2 cm
T2: 2 - 5 cm
T3: > 5 cm
T4: Invades bone, muscle, cartilage

N1a:micrometastasis
N1b: macrometastasis
N2: In transit metastasis (between tumor and regional LN or distal to primary)

Staging
Stage IA: T1pN0
Stage IB: T1cN0
Stage IIA: T2-3pN0
Stage IIB: T2-3cN0
Stage IIC: T4N0
Stage IIIA: TxN1a
Stage IIIB: TxN1b; TxN2
Stage IV: TxNxM1

Management:
Wide local excision with 1 - 2 cm margins.
Sentinel lymph node biopsy is bare minimum in all cases. A full lymph node dissection is indicated in the presence of a clinically detectable node (physical exam or CT) or in the presence of a positive SLNBx.

Adjuvant radiation is indicated in all Merkel Cell Cases regardless of margin status or LN status. Doses should be similar to head and neck doses.
Gross disease = 70 Gy
Positive margins or extra-capsular extension = 66 Gy
Negative margins = 60 Gy
Elective nodal irradiation = 50-56 Gy

Volumes:
GTV = gross tumor volume
CTV High Dose = GTV + 1 cm + any LN level with positive LNs
CTV Int Dose = First echelon LN's adjacent to gross disease
CTV Low Dose = Elective nodal irradiation
PTVs = 0.5 - 0.7 cm around CTVs

Chemotherapy:
Regimens are cisplatin and etoposide based as this is a small-cell neuroendocrine tumor. Outcomes and response rates aren't great for these tumors, so it's controversial when chemotherapy is best started.

Skin Cancer: Treatment: BCC and SCC

Summary:
The mainstay of treatment is wide local excision for SCC and BCC with adequate margins. Radiation is an acceptable alternative for non-surgical candidates or tumors in locations where post-operative cosmesis is an issue (primarily ear, nose, lip). Topical treatments are also alternatives, but local control rates are inferior to surgery and radiation.

Indications for post-operative XRT in BCC or SCC are:

• Perineural invasion
  
• Positive margins (not amenable to surgery)
  
• +LNs or +ECE
  
• > T3 (cartilage, bone invasion)
• Recurrent disease

Local Control Rates:

• T1: 95%
• T2: 80%
• T3: 55%
  

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Surgery
Wide local excision and Moh's microsurgery are good options for surgical resection. Adequate margins are required for good local control. BCC requires margins of 4 mm. SCC margins should be 5 mm.

XRT:
Primary radiation is an appropriate alternative to surgery. Local control rates are comparable, but may be slightly inferior (around 98 vs 95%). This is likely because in retrospective studies these were non-resectable tumors or larger tumors compared to surgical series.

A standard dose is 50 Gy in 20 fractions. If the tumor is large or there are concerns for cosmesis you can use 66 Gy in 33 fractions. A less protracted regimen could be 45Gy in 15 or 35 in 5 fractions.

Adjuvant Radiation is indicated in the post-operative setting when there is positive LN involvement or extracapsular extension and perineural invasion. Additionally, in instances where there is bony or muscle invasion or recurrent disease, adjuvant treatment can be added.

Planning Issues:
Primary lesions can be treated with either orthovoltage or electrons. Availability of both allows more treatment options when it comes to difficult locations in the head and neck area. Familiarity with the dosimetry for both is vital for picking the appropriate treatment modality.

Volumes for Electrons:
GTV = gross tumor volume
CTV = 0.5 - 1 cm around GTV
PTV = 0.5 cm
Penumbra = 1 cm

Basically you need a 1 cm penumbra to account for isodose constriction at depth.
Dose is usually prescribe to 90% isodose at depth
When picking an electron energy make sure you cover a few milimetres below the tumor depth.
Don't forget to account for a bolus to bring up the skin dose, particularly for lower MeV electrons.
Don't forget to use wax covered (to minimize back scatter) shield for underlying structures (eyes, lips, mastoid, etc.).

Electron rules of thumb:
Energy/2 = Depth of Rp dose
Energy/3 = Depth of 80% isodose
Energy/4 = Depth of 90% isodose
(Energy/2) + 1 = Thickness for lead shield
(Energy/2) = Thickness for cerrobend shield

Volumes for Orthovoltage:
GTV = gross tumor volume
CTV = 0.5 - 1 cm around GTV
PTV = 0.3 cm
Penumbra = 0.2 cm

Prescribe dose to surface for orthovoltage.
PTV can be smaller because collimation is almost at skin surface.
Penumbra can be smaller because there is no constriction of isodoses at depth.
F-factor is 1 for cartilage, but 4-5 for bone. Dose delivered to bone is higher. F-factor is less of an issure for higher energy orthovoltage beams.
120 kVp will give 100% at surface, and decreases by 10% every 0.5 cm
1 mm shielding is adequate for 120 kVp
240 kVp gives 100% at surface, and decreases by 10% every 1 cm
2 mm shielding is adequate for 240 kVp

Skin Cancer - Staging: Basal cell and Squamous cell carcinomas

The AJCC 7th Edition (2009) has changed the TNM staging to incorporate risk factors. Tumor size has less importance.

T1: < 2 cm
T2: > 2 cm or > 1 risk factor
T3: Invades maxilla, mandible, orbit, temporal bone
T4: Perineural invasion of skull base, axial skeletal invasion

N1: single ipsilateral LN < 3 cm
N2a: Single ipsilateral LN 3 - 6 cm
N2b: Multiple ipsilateral LN < 6 cm
N2c: Multiple bilateral LNs < 6 cm
N3: LN > 6 cm

Stage I: T1N0
Stage II: T2N0
Stage III: T3N0; T1-3xN1
Stage IV: T4N0; TxN2; TxN3; TxNxM1

Risk Factors:

• Invasion: > 2 mm thick, Clark level IV or V; PNI
• Differentiation: Poorly differentiated or undifferentiated
  
• Location: Ear or non-hair bearing lip

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Work-up:
History + Physical exam
Biopsy: excisional or punch
CBC, LFTs, RFTs, PT/PTT/INR
Imaging only if clinical LNs or multiple risks: Regional CT and CXR

Rectal Cancer - Staging

2009 AJCC 7th Edition

T1 - Submucosal invasion

T2 -Suscularis propria

T3 - Serosal invasion, invades peri-rectal fat

T4a - Invades peritoneal viscera

T4b - Invades local structures

N1 - 1-3 lymph nodes

N2a - 4 - 7 lymph nodes

N2b - > 7 LNs

M1a - Metastasis to one site

M1b - Metastasis to more than one site or peritoneum

Stage I - T1-2N0

Stage IIa - T3N0

Stage IIb - T4aN0

Stage IIIa - T1-2N1, T1N2a

Stage IIIb - T3-4aN1, T2-3N2a, T1-2N2b

Stage IIIc - T4aN2a, T3-4aN2b, T4bN1-2

Stage IVa - TxNxM1a

Stage IVb - TxNxM1b

==================================

Investigations:

CT abdo/pelvis

EUS or MRI pelvis

CXR

CBC, LFTs, SMA7, RFTs, CEA

Colonoscopy

Esophageal Cancer - Management

Early Stage Resectable tumors (Tis, T1a, T1b upper esophagus N0)

• Surgical resection
• Post-operative RT is indicated for positive margins!
  

Resectable esophageal cancers (>T1bN0)

• Surgical resection
• Definitive chemoradiation (if non-surgical candidate)
• Pre-operative chemoradiation (40 Gy / 15 Fx)
  
• Pre-operative chemotherapy - controversial
  

You need to re-stage these patients with CT or PET-CT before surgery (assess response, rule out mets)

Lower GE junction cancers

• Peri-operative ECF chemotherapy (MAGIC Trial)
• Post-operative chemoradiation (MacDonald trial)
  

Palliative Esophageal Cancer

• Brachytherapy 20 Gy / 5 fractions (obstruction)
  
• External beam 30 Gy / 10 fractions (bleeding and obstruction)
  
• Stenting and/or dilatation (obstruction)
  
• Resection in very selected patients (bleeding or obstruction)
• Chemotherapy (obstruction)

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Pre-operative Chemoradiation
There is a lot of conflicting data for pre-operative chemoradiation. Even meta-analyses show conflicting results in terms of overall survival. In general, most show small, but statistically small improvements in overall survival.

Two major Phase III studies compared chemoradiation to chemoradiation followed by surgery for Squamous cell esophageal cancers. Both studies failed to show a survival benefit for the addition of surgery.

Bundenne (FFCD 9102) treated 450 patients with 2 cycles cisplatin and 5FU and 46 Gy. Patients were then randomized to either surgery or an additional 3 cycles of chemo and 20 Gy radiation. There was no overall survival benefit (40 vs 34%) and a higher treatment-related mortality for the surgery group (9 vs 1%).

Stahl treated 200 patients with 3 cycles induction 5-FU, cisplatin, etoposide and leucovorin. Patients were then randomized to either >66 Gy radiation and cisplatin/etoposide or 40 Gy and cisplatin/etoposide followed by surgery. This study demonstrated better local control for the surgery group (65 vs 40%), but ultimately there was no difference in overall survival (~25% @ 3 years).

If you are going to go this route, a recent meta-analysis by Gebski showed a significant benefit at 2 years overall survival with an absolute improvement of 13% and a hazard ratio of 0.81. When analyzed for sub-type, adenocarcinomas benefit. The two studies above were negative, but included only squamous cell cancers. Basically, this is still investigational, but it is fair to say that this may be viable treatment option and these patients should be enrolled into any active protocols.

Pre-operative Chemotherapy
Similarly, there is conflicting data for pre-operative chemotherapy. Gebski's meta-analysis also looked at pre-op chemo. There is a 2 year absolute 7% overall survival benefit for adding chemotherapy pre-surgery for adenocarcinomas.

Definitive Chemoradiation
The RTOG 8501 trial compared 64 Gy alone to 50.4 Gy and concurrent 5FU/cisplatin x 4 cycles. This trial included 260 patients with T1-3N0-1M0 esophageal cancers. This trial demonstrated superiority of chemoradiation over radiation alone. There were improvements in 5 year overall survival 27% vs 0%.

A follow-up study INT0123 looked at radiation dose escalation with concurrent chemoradiation. Essentially it was cisplatin and 5 FU combined with either 64 Gy or 50.4 Gy. This study demonstrated a lower 2 year overall survival rate for the higher-dose arm (30% vs 40% each) and equivalent local relapse rates (~50%).


Lower GE Junction Esophageal Cancer

Peri-operative Chemotherapy
The MRC randomized 500 patients to either surgery alone or to surgery and peri-operative ECF chemotherapy (3 cycles pre + 3 cycles post) in the MAGIC trial. This study demonstrated an improvement in overall survival at 5 years (36 vs 23%). As a caveat, only 15% of these patients were GE junction tumors, most were gastric cancers.

Post-operative Chemoradiation
MacDonald's trial for gastric and gastro-esophageal junction cancers compared surgery alone vs post-op chemoradiation (45 Gy in 25 fx + 5FU/LV given 1 wk pre-RT, then during wk 1 & 5 of RT, and 2 more cycles). 3-year survival was 50% vs 40% favoring chemorads. Relapse rates were also better at 50 vs 30%. This is standard treatment for post-operative GE junction cancers.

Treatment Volumes as per RTOG 0436
GTV = gross tumor
CTV = 4 cm longitudinally and 1 cm radially around primary tumor and 1cm expansion around any nodes

• Cervical esophageal cancers (10-15 cm): include the supraclavicular lymph nodes
• Middle esophageal cancers (15-30 cm): paraesophageal nodes
  
• Distal esophagus cancers (> 30 cm) : include celiac nodes
  

PTV = CTV + 1 cm

Technique:
Plan 1: Use AP/PA fields for first up to 39.6 Gy
Plan 2: Use AP and 2 posterior obliques up to 50.4 Gy
Basically want to spare the spinal cord!

Cervical esophageal cancers (cover supraclavicular LNs):
RTOG0436 recommends:
0 to 39.6 Gy: AP/PA
39.6 to 50.4 Gy: 2 anterior obliques, 1 PA field + electron boost to cover supraclavicular nodes

Esophageal Cancer - Staging

Esophageal cancer patients tend to have locally advanced at time of presentation as there is no serosa covering the esophagus to act as a physical barrier. Intramural lymphatics allow for early access and spread of tumor to lymphatics even in tumors invading the lamina propria (T1a) or the submucosa (T1b) .

Squamous cell and adenocarcinoma are the two most common histologies in esophageal cancer. Adenocarcinomas represent 75% and SCCs represent ~25% of all esophageal cancers. SCC carries a worse prognosis. The risk factors are different for each entity.

Squamous cell carcinoma risk factors include: smoking, alcohol use, Achalasia (esophageal motility disorder), tylosis (hyperkeratinization of palms and soles), prior thoracic irradiation, prior head and neck cancer, and Plummer-Vinson syndrome (iron-deficiency anemia, glossitis, esophageal webs).

Adenocarcinoma risk factors include: smoking, gastric reflux, Barrett's esophagus, prior thoracic irradiation.

Other rare histologies include: lymphoma, sarcoma (leimyosarcomas most common), melanoma, neuroendocrine (small cell), adenoid cystic, mucoepidermoid carcinoma

Initial presenting symptoms are invariably dysphagia and weight loss. Other symptoms include cough, odynophagia and hemoptysis. Voice hoarseness suggests likely involvement of the left recurrent laryngeal nerve.

Initial work-up after full history and physical include:

• CBC, LFTs, SMA7, albumin, protein, Alk phos
  
• Endoscopic ultrasound + biopsy
• Panendoscopy
• CT chest and abdo
  
• PET scan is better than CT for assessing nodes and mets (Sensitivity ~90%)
• Barium swallow
• PFTs pre-RT

Anatomy
The Cervical Esophagus is found 15 to 20 cm from the incisors it is bounded by the hypopharynx and the sternal notch. The Upper Thoracic Esophagus is found from 20 - 25 cm bounded by the sternal notch and the Azygous vein. The Middle Thoracic Esophagus is at 25 - 30 cm bounded by the Azygous Vein and the Pulmonary Arteries. The Lower Thoracic Esophagus is at 30 - 40 cm bounded by the Pulmonary Arteries and the GE Junction.


TNM Staging
T1a = lamina propria
T1b = submucosa invasion
T2 = invades muscularis propria
T3 = invades advetitia (no serosa)
T4a = Resectable tumor invading pleura, pericardium, diaphragm
T4b = Unresectable tumor invading adjacent structures (ie trachea, aorta, vertebra)

N1 = 1-2 regional LN
N2 = 3-6 regional LN
N3 = > 6 regional LN

AJCC Staging (The 2009 7th ed AJCC stages SCC and Adenoca's differently and adds Grade and location as criteria.... really annoying)

SCC incorporates both grade and location (for stage I & II)
Stage IA: T1N0 G1
Stage IB: T1N0 G2-3; T2-3N0 G1 L
Stage IIA: T2-3N0 G2-3 L; T2-3N0 G1 U/M
Stage IIB: T2-3N0 G2-3 U/M; T1-2N1
Stage IIIA: T3N1; T4aN0; T1-2N2
Stage IIIB: T3N2
Stage IIIC: T4aN1-2; T4bNx; TxN3
Stage IV: TxNxM1

Adenocarcinomas only use grade for Stage I & II
Stage IA: T1N0 G1-2
Stage IB: T1N0 G3; T2N0 G1-2
Stage IIA: T2N0 G3
Stage IIB: T3N0; T1-2N1
Stage IIIA: T3N1; T1-2N2; T4aN0
Stage IIIB: T3N2
Stage IIIC: T4aN1-2; T4bNx; TxN3
Stage IV: TxNxM1

Justifications for using such a complicated staging system.... data analysis demonstrates that prognosis is affected by grade, location, and histological cancer type.

5-year OS
Stage I: 50-60%
Stage II: 40%
Stage III: 20%
Stage IV: <5%

Prognosis is the same between SCC and Adenocarcinoma because of the changes to the TNM staging system. This wasn't the case before the change.

Oropharngeal Cancer - Locally Advanced

Summary:
For locally advanced oropharyngeal cancers the primary treatment option is concurrent chemoradiation at 70 Gy in 35 fractions with cisplatin every 3 weeks as per the Adelstein trial.

If the patient can not tolerate chemotherapy than there are two reasonable options either altered fractionation as per the Fu RTOG 90-03 study or combining cetuximab with radiation as per the Bonner study.

Finally, induction taxotere, cisplatin, and 5-FU chemotherapy can be considered for locally advanced tumors provided the patient can tolerate the expected toxicities.

Conventional radiation alone is a poor choice given the number of options listed above as it is proven to be inferior for both survival and local control.

Surgery should generally be reserved for salvage as the associated morbidity is universally unacceptable.

____________________

Locally advanced oropharyngeal cancers include stage III and stage IV tumors
Stage III = T3N0, T1-3N1
Stage IVA = T4aN0, T4aN1, T1-4aN2
Stage IVB = T4bNx, TxN3

These tumors have a 5 year overall survival of 30-40%. Local recurrence remains high and radiation therapy alone is not sufficient for adequate tumor control.

Treatment options include:

1. Chemoradiation - 70 Gy in 35 fractions with cisplatin
2. Altered fractionation - concomitant boost or hyperfractionation
3. Radiation and cetuximab
4. Induction chemotherapy followed by radiation or chemoradiation
   
5. Conventional radiation alone
6. Surgery +/- post-operative chemotherapy and radiation as indicated

Chemoradiation:
Concurrent chemoradiation is the mainstay of treatment in most locally advanced head and neck tumors and oropharyngeal cancers is no exception. The MACH-NC meta-analysis of 93 randomized trials by Pignon of locally advanced head and neck trials have demonstrated a significant benefit of chemoradiation compared to radiation alone. The latest 2009 update shows an absolute improvement of 6.5% in overall survival when concurrent radiation is used.

The French GORTEC study is an oropharynx specific study consisting of stage III and IV tumors. It compared conventional radiation to concurrent carboplatin/5-FU and conventional radiation. This demonstrated an improvement in 5 year overall survival from 16% to 22% and an improvement in local control from 25% to 50%.

A standard regimen is based of the Adestein Intergroup trial. This 2-arm study compared conventional radiation to concurrent chemoradiation and to split-course concurrent chemoradiation in unresectable head and neck cancers. This study demonstrated worse toxicity for the chemoradiation arm, but an improved 3 year overall survival of 40% to 20% in favor of the chemoradiation arm. The split-course arm was worse compared to the concurrent arm and was most likely due to tumor repopulation during the treatment break. The concurrent radiation arm gives cisplatin every three weeks on days 1, 22, 43.

Altered Fractionation:
This includes either concomitant boost or hyperfractionation with the goal of shortening treatment time or dose escalation, respectively. The RTOG 90-03 study by Fu provides level I evidence to support the use of either concomitant boost or hyperfractionation. In this study of locally advanced head and neck cancers these two regimens were superior when compared to conventional fractionation and split course hyperfractionation. Overall survival was improved at 8 years from 30% to 35%. Local control was improved at 8 years from 40 to 50%.

An EORTC study by Horiot included Stage II and III oropharyngeal cancers. This study compared hyperfractionated treated 80.5 Gy using 1.15 Gy fractions BID to conventional 70 Gy in 35 fractions. This also demonstrated a trend for improvement in 5 year overall survival 3o% to 38% and a significant improvement in local control 40% to 60%.

Cetuximab and Radiation
Bonner compared conventional radiation alone to conventional radiation combined with cetuximab (250mg/m2 weekly). The 2009 update demonstrated a 5 year overall survival of 45% vs 35%. Local control rates are improved from 40 to 50%. The update also correlated cetuximab related rash with an improvement in survival (HR = 0.5).

Induction Chemotherapy
Induction chemotherapy is largely used to reduce tumor burden and to improve rates of organ preservation. The MACH-NC meta-analysis shows a small absolute benefit of 2% for overall survival when induction chemotherapy is added. This is an option for patients with locally advanced tumors who can tolerate induction chemotherapy in addition to definitive treatment.

The two principal studies looking at induction chemotherapy added taxotere to a cisplatin and 5-FU regimen. Vermorken's EORTC trial compared cisplatin 5-FU induction to taxotere, cisplatin and 5-FU for three cycles. This study followed the induction chemotherapy with conventional or altered fractionation radiotherapy. The results demonstrated an improvement in overall survival of 37% vs 24%% and improved response rates 68% vs 54%. The TPF regimen was less toxic likely due to the decreased doses of cisplatin and 5-FU.

A second study published in the same issue was Posner's study. This study was essentially the same as Vermorken's study in regards to the induction chemotherapy. This study used concurrent chemoradiation instead of radiation alone after the induction chemotherapy. This study showed 3 year overall survval of 60% vs 50% in favor of the docetaxel/taxotere arm. Local control was better as well at 50% vs 40%.

Volumes:
All cases should be treated by IMRT.
GTV = gross tumor
CTV70 = GTV + 2 cm
CTV64 = Adjacent lymph node levels
CTV 56 = Elective nodal irradiation

PTV = CTV + 0.5 mm

Salivary Gland Carcinomas

Summary:
These tumors regardless of stage should be managed surgically upfront.

Indications to add adjuvant radiation are:

• Grade 3 tumor
• Positive margins
• Positive lymph nodes
• Tumor > 4 cm
• Adenoid cystic histology

Indications to add ipsilateral neck irradiation include:

• Grade 3 tumor
• Tumor > 4 cm.
  

Non-surgical candidates can be treated with definitive radiation.

Remember to cover cranial nerves VII (parotid) or V3 (submandibular) up to the skull base for adenoid cystic histologies.

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As a general rule of thumb, the smaller the salivary gland, the greater the chance that a tumor is malignant. Submental (80%) > submandibular (80%) > parotid (20%).

Parotid gland tumors are mostly benign adenomas. These tumors can be resected and observed without additional treatment. The deeper and the more posterior a tumor is located in the parotid, the more likely it is malignant.

As part of the work up of a salivary gland mass, the patient should have a full history and physical. Initial workup includes a CT neck and chest. A FNA biopsy sent to cytology (to improve diagnostic rate). An MRI to help delineate and soft tissue extension. General blood work including a CBC, RFTs, LFTs, TSH and electrolye panel.

Staging:
T1: < 2 cm
T2: 2 - 4 cm
T3: > 4 cm
T4a: Invades mandible, ear canal, facial nerve
T4b: Encases carotid, invades skull base or pterygoid plates

N1: Single LN <> 6 cm

Stage I = T1N0
Stage II = T2N0
Stage III = T3N0, T1-3N1
Stage IVa = T4aN0, T4aN1, T1-4aN2
Stage IVb = T4bNx, TxN3
Stage IVc = TxNxM1

Surgery
Malignant salivary gland tumors are resected with margins > 5 mm as initial management. A full neck dissection is not required if elective nodal irradiation is planned. Parotid tumors should have a level IIA neck dissection. For submandibular gland tumors, a neck dissection can be considered for high grade or large tumors.

Adjuvant Radiation
Adjuvant radiation is indicated for:

• High grade tumors
• Large primary tumors (T3 or T4)
• Positive margins
• Positive lymph nodes
  
• Adenoid cystic or Squamous cell histology

Elective nodal irradiation should be offered to:

• Tumors > 4cm (T3 or T4)
• High grade tumors (they harbor microscopic disease in 50%)
• Squamous cell histology (50% recurrence without XRT to ipsilateral neck).

Adenoid Cystic Carcinoma
UCSF reviewed their Adenoid cystic cases and found that T4 tumors, perineural invasion, major nerve involvement and omission of adjuvant radiation where all predictors of recurrence (this makes sense). Hence, all Adenoid cystic carcinomas should receive adjuant XRT. These tumors rarely recur locally or involve regional lymph nodes, so elective nodal irradiation should not be routinely offered. However, they have a tendency to spread perineurally along cranial nerves in 50% of cases. Treatment volumes should include the cranial nerves to the skull base. Cranial nerve VII should be included up to stylohyoid foramen in Parotid tumors. The lingual branch of cranial nerve V3 should be included up to it's entry in the skull base or Meckel's Cave (represented by the arrows in the figures below) in Submandibular tumors.



Radiation Dose

• Gross disease should be treated with 70 Gy in 35 fractions
• Positive margins or extracapsular extension should be treated with 66 Gy in 33 fractions
• Negative margin tumor bed should receive 60 Gy in 30 fractions
  
• Elective neck treatment should receive 50 Gy in 25 fractions.

Parotid LN Volumes include I - IV in node negative tumors. Level V should be added if a LN is positive. Submandibular LN volumes include IA, IB, II, III. Levels IV and V should be added if a LN is positive.

Ideally, patients should be treated with IMRT techniques. If this is not available, wedge pair techniques are adequate when the volume to treat has a depth less than 7 cm. Otherwise, you can consider a mixed photon/electron technique.

Complications:
Xerostomia, cranial nerve paresthesia

Prognosis:
5 year overall survival

• Stage I = 75%
• Stage II = 60%
• Stage III = 50%
• Stage IV = 30%
  

5 year local control
Mucoepidermoid = 80% with radiation and 40% without radiation
Adenoid cystic = 75% with radiation and 25% without radiation

Most recurrences will occur distantly and not locally.

Head And Neck Initial Evaluation

A full history and physical should be obtained from the patient. Important points on history include: smoking and alcohol habits, a history of chewing tobacco, betel nuts, paan or arecca. Presenting symptoms are varied and range by site. There may be a change in voice quality, dysphagia, odynophagia, referred otalgia, bleeding, ulcer, weight loss and a painless neck mass. It is also important to get an idea of the patient's performance status as this may give an indication of how well a patient may tolerate an aggressive treatment.

Physical exam is also guided on presenting symptoms, but should include a full general exam. A full neck exam of all lymphatic stations should be completed. Lymph nodes should be described in terms of size, mobility, and consistency. An oral exam includes examining the oral and buccal mucosa and evaluating the dentition. The pallatine fossas can be examined. Manual palpation of the base of tongue is required if this is a suspected site of tumor. Laryngoscopy should be performed to evaluate the nasopharynx, oropharnx and hypopharynx. Vocal cords, base of tongue and epiglottis can be visualized.

Initial work-up includes biopsy of either the primary mass or a palpable lymph node. A fine needle aspirate is adequate for diagnosis. Routine blood work includes a CBC, electrolytes, Ca, Phosphate and Mg, liver function, renal function, baseline TSH, PT/PTT/INR. HPV testing can be considered. A CT scan of the neck and chest should be part of the initial imaging. MRI of the neck will help stage the tumor and evaluate for soft tissue invasion. A PET-CT can be performed particularly if there are borderline suspicious lymph nodes, but is not indicated as a routine for all patients.

Finally, the patient may need evaluation by medical oncology, dentistry, audiology, gastroenterology (or radiology) for prophylactic PEG placement in patients receiving chemotherapy and a consult to GI for pan-endoscopy to rule out synchronous primaries.

Small Cell Lung Cancer - Extensive Stage

Summary:
Extensive stage small cell lung cancer is best managed by cisplatin and etoposide chemotherapy.

Prophylactic cranial irradiation of 25 Gy in 10 fractions should be offered to all patients who have any response to chemotherapy on the basis that it improves survival rates.

In an exam setting, DO NOT offer thoracic irradiation for these patients. There is no good evidence to support this practice, even though this is done in clinical practice to prevent obstructive symptoms.

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Extensive Stage Small Cell Lung Cancer is defined as disease that can not be encompassed within one radiation port. The decision to consider contralateral mediastinal or supraclavicular lymph nodes as extensive or limited stage disease is controversy and management decisions are largely clinician and patient dependent.

Management of extensive stage small cell lung cancer is primarily by cisplatin & etoposide chemotherapy for 4 - 6 cycles. Patients who have any kind of response to chemotherapy should receive prophylactic cranial irradiation (PCI). There is no evidence to support the use of consolidative thoracic irradiation following chemotherapy. Instances where this is considered is based on the fact that many patients will relapse in the original sites of disease. Adding radiation will not affect survival, but will decrease the rate of local relapse.

PCI has been proven to increase survival at 2 years by the PCI EORTC trial. This study randomized patients with extensive stage small cell lung cancer who had demonstrable response to chemotherapy to either observation or PCI. The PCI ranged in dose from 20 Gy in 5 fractions to 30 Gy in 10 fractions. This study demonstrated a 27% 1 year survival rate for PCI compared to 13% for observation. Quality of life measures demonstrated more fatigue in the PCI arm, but no detectable changes in quality of life or neurotoxicity.

Dose of PCI is an extrapolation from limited stage SCLC, based on the EORTC study by Le Pechoux, demonstrated no difference between higher dose PCI 36 Gy in 18 fractions versus a standard regimen 25 Gy in 10 fractions.

There is no role for consolidative radiation after a patient has completed chemotherapy. The weight of the evidence shows no benefit in terms of overall survival. Some oncologists may consider consolidation radiation to decrease local relapse rates and avoid death by lung failure, but with the knowledge that this will not prolong survival.

Oropharyngeal Cancer - Early Stage

Summary:

Treatment options for early stage oropharyngeal cancers include:
1. Definitive Radiation alone 70 Gy in 35 fractions (preferred)
2. Definitive Radiation to 50 Gy then 20 - 30 Gy delivered via brachytherapy
3. Surgical resection with neck dissection +/- adjuvant chemoradiation or radiation as needed.

These patients can expect to do well, with good local control ~80 -100% and good overall survival 70-100% at 5 years

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Early stage oropharyngeal cancers include T1N0 and T2N0 tumors.

Treatment options include:

1. Definitive radiation alone
   
2. Surgical resection with neck dissection +/- chemoradiation or radiation adjuvantly

Since the oropharynx is a central structure that plays a key role in phonation, speech and swallowing definitive radiation is the preferred treatment modality to maximize function after curative treatment. Surgery may be an option for small, accessible tumors that can be resected with adequate margins without compromising function.

There is a lack of Level I or even Level II evidence to definitively guide treatment. Data comes from single institution retrospective analyses from the 1980's demonstrating high rates of control. Some of the older data have worse outcomes, but keep in mind that this pre-dates 3D CRT never mind IMRT and newer treatment techniques.

5 yr LC:
T1N0 = 90-100%
T2N0 = 70-90%

5yr OS:
T1: 80-100%
T2: 70-90%

Definitive radiation can be delivered as EBRT alone or in combination with brachytherapy. A standard dose for EBRT alone is 70 Gy in 35 fractions. There is experience and retrospective data showing that adding brachytherapy after 50 Gy of EBRT has good local control rates. Altered fractionation, such as concomitant boost may be considered; however, the reasoning is based on extrapolation primarily from RTOG 90-03. This study showed improved local control, but the study population was locally advanced tumors, although some were T3N0's.

Special considerations:
Soft palate and pharyngeal cancers tend to drain bilaterally to the neck and retropharyngeal lymphatics.

Early stage tonsillar cancers drain unilaterally. Bilateral drainage in advanced cancers.

Treatment Planning
Plan by IMRT!

GTV = Gross tumor & suspicious LNs
CTV70 = GTV + 1 cm
CTV64 = CTV70 + LN areas at risk (usually regional LN and LN region above and below)
CTV56 = LN region considered to be at lower risk (adjacent to CTV60 LN groups)

PTV = CTV + 3 mm

Oropharyngeal Cancers - Staging

T Stage
T1: < 2 cm largest diameter
T2: 2-4 cm
T3: > 4 cm
T4a: Invades medial pterygoid, mandible, deep muscle of tongue, larynx, hard palate
T4b: Invades lateral pterygoid, pterygoid plate, lateral wall of nasopharynx, skull base, encases carotid artery

N Stage
N1: single LN <> 6 cm

-------------------------
Early Stage
Stage I: T1N0
Stage II: T2N0

Locally Advanced
Stage III: T3N0, T1-3N1, T1-3N2
Stage IVa: T4aN0-2; T1-3N2
Stage IVb: T4bNx; TxN3

Metastatic
Stage IVc: TxNxM1

ENT Anatomy - Pharynx Part II: Hypopharynx

Hypopharynx or the Laryngopharynx

The hypopharynx is bounded superiorly by the superior aspect of the hyoid bone and inferiorly by the inferior aspect of the cricoid cartilage. Posteriorly it is bounded by the pharyngeal wall overlying the C4-C6 vertebral bodies. Laterally it is also bounded by the pharyngeal walls.

The hypopharynx encompasses 3 structures: 1) the piriform sinuses; 2) the pharyngeal walls 3) the post-cricoid region. The Piriform Sinuses are found lateral to the aryepiglottic folds and are bounded laterally by the pharyngeal walls. The post-cricoid is found below the aretynoids down to the inferior cricoid cartilage and posteriorly to the cricoid cartilage (obviously).

The larynx is composed of the epiglottis, thyroid cartilage, aretynoid cartilage and the cricoid cartilage. The corniculate cartilage sits on top of the aretynoids. The cuneiform cartilage is
located in the aryepiglottic folds and lateral to the corniculate cartilage. Note that the aretynoid, cricoid and thyroid cartilages can ossify, whereas the corniculate, cuneiform, epiglottis and the tips of the aretynoids will not ossify.

There are three important ligaments within the larynx: 1) Hyoepiglottic; 2) Cricothyroid; 3) Thyrohyoid.



The Larynx itself is divided into 3 sections:
1) Supraglottis - Tip of the epiglottis to the true vocal cords
2) Glottis - True vocal cords to 0.5 cm below the true vocal cords
3) Subglottis - 0.5 cm below the true vocal cords to the inferior cricoid

The False Vocal Cords are ventricular folds and are located superior to the true vocal cords. They do not vibrate, hence their name.


Innervation
The main nerve innervating the hypopharynx and larynx is the Vagus Nerve (CN X).
The Sensory component of CN X is the Internal Superior Laryngeal Nerve. The External Superior Laryngeal nerve branch is the motor component.

• Tumor involving the Piriform Sinus and involving the superior laryngeal can cause referred otalgia via the auricular branch of the vagus nerve.
• The External Superior Laryngeal innervates the cricothyroid muscle. This is responsible for stretching and tensing the vocal cords. Damage to the superior laryngeal can cause changes in phonation.
• Innervates the supraglottis and glottis
  

The motor component of CN X is the Recurrent Laryngeal Nerve.

• Innervates the remaining laryngeal muscles. Damage to the recurrent laryngeal nerve will cause hoarseness
• Innervates subglottis

Damage to both Recurrent and external superior laryngeal nerves results in no audible voice. Breathing is also compromised.



Lymphatics & Patterns of Spread
The true vocal cords have sparse lymphatic drainage. Tumors restricted only to the vocal cords do not have a propensity to spread to regional lymphatics (<5%). Tumor invading local structures surrounding the glottis will spread to Level II, III and IV lymphatics.

Supraglottic lesions will grow anteriorly into the pre-epiglottic space, valeculla or base of tongue. It can also grow circumferentially and invade the aryepiglottic folds and the piriform sinuses. Lymphatic drainage is typically to levels III & IV.

Subglottic lesions will grow and invade locally. That is inferiorly into the trachea, superiorly into the epiglottis and anteriorly into the thyroid or cricoid cartilage. Drainage here is to Levels III, IV and VI depending on the structures invaded.

Hypopharynx lesions can drain to II, III, IV, VI and RP nodal levels. There are no borders to invasion, so many of these tumors present as advanced cases. 20% will have distant mets at presentation compared to 1% for glottic cancers and 10% for supraglottic cancers.

ENT Anatomy - Pharynx Part I

The Pharynx is subdivided into three sites:
1. The Nasopharynx
2. The Oropharynx
3. The Hypopharynx





1. The Nasopharynx

The Nasopharynx is located posterior to the nasal cavity choanae (anterior border). It is bounded superiorly by the sphenoid sinus and inferiorly by the soft palate. The posterior wall overlies the base of skull including the clivus and atlas. The lateral walls are the nasopharyngeal mucosa. Located on the lateral walls is the Taurus Tubarius, which is the opening of the Eustachian Tube. Posterior to this is Rosenmueller's Fossa, which is a common site of origin for nasopharyngeal cancers. The roof of the nasopharynx is lined with adenoid lymphatics, which are a component of Waldeyer's ring.


The nasopharynx is innervated by the Glossopharyngeal Nerve (CN IX) and the Maxillary Nerve (CN V2).

Multiple foramen in this region act as potential points of entry for nasopharyngeal cancers. Notably the Foramen Lacerum, which allows entrance into the middle cranial fossa. Other foramen include Foramen Jugulare, Foramen Ovale, Foramen Spinosum, the Carotid Canals and the hypoglossal canals




2. The Oropharynx

The oropharynx is bounded superiorly by the soft palate and inferiorly by the superior aspect of the hyoid bone. The mucosa overlying the C2 and C3 verterbral bodies form the posterior wall. The anterior aspect consists of the anterior palatine pillar and the anterior edge of the soft palate.

The oropharynx consists of 4 subsites:
The soft palate, the tonsillar region, the base of tongue and the pharyngeal walls.

The soft palate includes the uvula. The tonsils are found between the anterior and posterior tonsillar pillars. The base of tongue encompasses the tongue found between the vallecula and the circumvallate papilla.


Lymphatic drainage of this region is primarily to the jugulodigastric lymph node or Level II lymph nodes. Pharyngeal walls are drained by the retropharyngeal. The retropharyngeal nodes consist of a medial and lateral component. The lateral component is also known as Rouviere Nodes. Drainage is primarily unilateral, unless a tumor invades midline structures where it may drain the bilateral cervical chains.

Innervation of this area is primarily via CN IX & X.


3. The Hypopharynx or Laryngopharynx

See next post...

ENT Anatomy: Temporal & Infratemporal Fossas

Temporal Fossa

This oval shaped fossa is bounded superiorly and posteriorly by the temporal lines. The frontal and zygomatic bones form the anterior boundary. Laterally, the fossa is covered by the temporal fascia. Inferiorly the floor is formed by portions of the sphenoid, frontal, temporal and parietal bones. The area where these four bones meet is the pterion. This is also the area where the temporalis muscle originates. Temporal muscle divides into a superficial and deep layer. The superficial layer attaches to the superior aspect of zygomatic arch. The deep layer extends inferiorly to become the masseter muscle.



Infratemporal Fossa

This space is bounded superiorly by the greater wing of the sphenoid and anteriorly by the infratemporal surface of the maxillary bone. The posterior wall is formed by the condyle of the mandible and the styloid process of the temporal bone. The lateral wall is the medial aspect of the ramus of the mandible. The medial wall is lateral pterygoid plate.



The Maxillary Artery originates from the external carotid and enters medially to the ramus of the mandible. The branches of the maxillary artery include the deep auricular artery, middle meningeal, inferior alveolar, deep temporal, buccal, infraorbital and posterior superior alveolar.

The Pterygoid Venous Plexus is also contained within the infratemporal fossa. This plexus of veins and nerves is located between the temporalis and lateral pterygoid muscles. The key structure is the Mandibular Nerve (CN V3). This enters the infratemporal fossa by the Foramen Ovale. This nerve is responsible for innervation of the muscles of mastication (temporalis, masseter, medial & lateral pterygoids). This nerve also divides into the auriculotemporal, inferior alveolar, lingual and buccal nerves.

One branch of the Maxillary nerve (CN V2) enters the infratemporal fossa, the Posterior Superior Alveolar Nerve.

The Otic Ganglion is a parasympathetic component of the glossopharyngeal nerve (CN IX). It is found medially to the foramen ovale. It is the secretory innervation for the parotid gland.

The Foramen Spinosum also opens into this fossa. It contains the middle meningeal artery and vein and the nervus spinosum, a branch of the mandibular nerve

ENT Anatomy: Parotid Gland

The parotid gland is a salivary gland overlying the masseter and posterior belly of digastric muscle. Saliva is delivered to the mouth via the parotid duct. The parotid bed is bounded by the ramus of the mandible anteriorly and the mastoid process posteriorly. Superiorly it is bounded by the external acoustic meatus. Medially, it is bounded by the styloid process of the temporal bone. Laterally it is covered by the overlying skin.

Traversing through the parotid gland is the facial nerve (CN VII). Within the gland, this nerve divides into a superior and inferior division innervating the temporal/zygomatic/buccal and mandibular/cervical branches respectively. This is particularly important in adenoid cystic carcinomas arising in the parotid gland. In these tumors, they will infiltrate peri-neurally and can track up to the stylohyoid foramen.


Venous drainage of the parotid gland is via the retromandibular vein. This vein joins the posterior auricular vein to form the external jugular vein.

Arterial supply of the parotid gland is via the external carotid artery, which enters the medial aspect of the gland. The external carotid artery then divides into the superficial temporal artery and the maxillary artery.

Innervation of the parotid gland is via the secretoy fibres of the otic ganglion, a parasympathetic component of the glossopharyngeal nerve (CN IX).

Lymphatic drainage is to the superficial and deep cervical chains.