HEAD AND NECK CANCERS Updated May 2016 by Dr. Daniel Yokom (PGY­5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Raymond Jang (Staff Medical Oncologist, University of Toronto) and Dr. Desiree Hao (Staff Medical Oncologist, University of Calgary) DISCLAIMER: The following are study notes compiled by the above PGY­5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. NOTE: Head and neck squamous cell carcinoma (HNSCC) and EBV­related nasopharyngeal carcinoma (NPC) are very different and will be discussed separately Head and Neck Squamous Cell Carcinoma

A) PUBLIC HEALTH

EPIDEMIOLOGY (1) ­ Incidence:

o In 2010 over 4000 Canadians were diagnosed with HNSCC o HPV­associated HNSCC usually diagnosed at a younger age o Increasing incidence of HPV­associated HNSCC (primarily oropharyngeal) while tobacco

related incidence is declining (2) o Male:Female > 3:1 depending on anatomical site

­ Mortality: o In 2010 over 1500 Canadians died from HNSCC

RISK FACTORS

o Smoking o HPV o EtOH

PREVENTION & SCREENING ­ Prevention:

o Smoking and EtOH cessation o HPV vaccine and methods to reduce HPV exposure

­ Screening: o No screening recommendations in Canada or United States.

B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS ­ Common Symptoms:

o Palpable mass or lymph node o Weight loss o Often depends on primary, for example:

Laryngeal: hoarseness or other changes in the voice, cough, difficult or noisy breathing

Oropharyngeal: sore throat lasting longer than a few weeks, feeling that something is stuck in the throat, difficult or painful swallowing, ear pain

Oral cavity: non­healing ulcer or mass INVESTIGATIONS

­ Physical exam: o Oral cavity o Head and neck lymph nodes o Cranial nerve exam

­ Laboratory: o Routine BW, hepatitis screen

­ Diagnostic Imaging: o CT head and neck o MRI neck for oropharyngeal, may be necessary for other sites o CT chest (stage II or higher) o PET scan for HNSCC primary unknown o CT abdomen and bone scan are not routinely performed

­ Diagnostic Procedures: o Endoscopy and biopsy o Consider FNA of suspicious lymph nodes for staging

­ Other: o Ensure women with HPV+ HNSCC have routine surveillance for cervical cancer – pelvic

exam and pap smear.

PATHOLOGY & MOLECULAR BIOLOGY ­ Common Histology:

o Vast majority are squamous cell carcinoma and discussion in this chapter pertains to SCC. o Differential includes adenocarcinoma, melanoma, sarcoma, lymphoma

­ Common Metastatic Sites: o Local recurrence and lymph nodes o Lung o Bone

­ Relevant Molecular Biology: o HPV testing using IHC for p16(3)

STAGING Staging for HNSCC is complex as it is different for each anatomical site. General rules to follow: N1 = one LN less than 3 cm N2a = one LN >3 cm and < 6 cm N2b = multiple ipsilateral LN; all < 6 cm N2c = bilateral or contralateral LN; all <6cm N3 = LN > 6cm T1­3 N1 = Stage III T1­3 N2­3 = Stage IV T4 any N = Stage IV Any distant metastatic site = Stage IVC NOTE: New staging recommendations for HPV+ oropharyngeal cancer to be published in 2016 (4)

C) TREATMENT EARLY STAGE

­ Bottom Line General Approach: o Primary surgery or radical radiation alone o No role for chemotherapy

­ Prognosis: o 5­yr OS 56­90% depending on location of the tumor

LOCALLY ADVANCED

­ Bottom Line General Approach: o Management depends on a number of factors including anatomical site, size, invasion,

co­morbidities, patient preference, etc: Consider discussion at a multi­disciplinary tumor board Often:

Oral cavity: primary surgery followed by radiation +/­ chemotherapy Oropharyngeal, laryngeal, hypopharyngeal: Radiation +/­ chemotherapy,

surgery for salvage therapy only ­

o If goes for primary radiation +/­ concurrent chemotherapy Radiation: 70Gy/35# Cisplatin 100mg/m2 d1, 22, 43 (5)

50% of patients do not get third dose Consider RT + weekly cisplatin 40mg/m2 for less well patients If cisplatin contraindicated consider RT + cetuximab 400mg/m2 load (one

week prior to RT) then 250mg/m2 weekly during radiation (6) No clear benefit for patients over 71 years of age – area of ongoing

research. Ongoing trials investigating whether less intense chemotherapy is effective for

patients with HPV+ HNSCC (7)

o If goes for primary surgery then post­operative management: No adjuvant treatment if low­risk (no intermediate or high­risk features) Intermediate risk: adjuvant RT alone 66Gy/33#

>T2 Close margins PNI LVI N2 or greater Level IV or V nodes

High­risk (8): adjuvant CRT with high­dose cisplatin 100mg/m2 d1, 22, 43 Positive margins Extracapsular spread

Note: Begin within 11 weeks of surgery

­ Prognosis: o Better with HPV+ non­smokers(9) o High­risk for secondary malignancy (usually due to life­style i.e. smoking)

­ ­ Follow­up:

o Imaging ~2 months after treatment ­ ­ Important Phase III Clinical Trials:

RTOG 91­11 Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal

cancer. Forastiere et al. NEJM. 2003. UPDATED: Long­Term Results of RTOG 91­11: A Comparison of Three Nonsurgical

Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer. Forastiere et al. JCO. 2013.

Regimen 1. Induction cisplatin 100mg/m2 d1 plus 5­FU 1000mg/m2/d d1­5 q3w x

3 cycles followed by RT 70Gy/35# 2. Concurrent cisplatin 100mg/m2 d1, 22, 43 and RT 3. RT alone

Primary Endpoint Laryngectomy­free survival Inclusion/Exclusion Criteria

Previously untreated stage III/IV HNSCC of the larynx T1 and T4 excluded Karnofsky PPS >= 60

Size (N) 518 Results Laryngectomy­Free Survival: Concurrent CRT significantly

improved LFS HR 0.58 (95% CI 0.37­0.89, p=0.005) Overall Survival: No difference although trend towards worse with

concurrent CRT HR 1.25 (95% CI 0.98 – 1.61, p=0.08) compared to induction chemotherapy

Toxicity Concurrent CRT more toxic: stomatitis (43% vs 20%), esophagitis (35% vs 19%), nausea/vomiting (20% vs 14%)

Conclusion Concurrent CRT improved laryngectomy­free survival with no improvement in OS

Other Comments 70% of patients in concurrent CRT arm received 3 cycles of cisplatin (more than real­world numbers)

Radiotherapy plus cetuximab for squamous­cell carcinoma of the head and neck. Bonner

et al. NEJM. 2006.

Regimen 1. RT alone, 70­76Gy 2. RT plus Cetuximab (400mg/m2 load 1 week prior to RT then

250mg/m2 weekly during RT) Primary Endpoint Locoregional control Inclusion/Exclusion Criteria

Previously untreated stage III/IV non­metastatic HNSCC of the oropharynx, hypopharynx or larynx

Karnofsky PPS >= 60 Normal hematopoietic, hepatic and renal function

Size (N) 424 Results Locoregional control: RT+cetux significantly improved locoregional

progression median 24.4mo vs 14.9mo, HR 0.68 (95% CI 0.52­0.89, p=0.005)

Overall Survival: RT+cetux significantly improved median survival 49.0 vs 29.3 mo (p=0.03), 3­y OS 55% vs 45% (p=0.05), HR 0.74 (95% CI 0.57­0.97)

Toxicity acneiform rash: 87% vs 10% all grades, 17% gr 3­5 infusion reaction: 15% vs 2% all grades, 3% vs 0% gr 3­5 other mild side effects of cetuximab: weight loss, headache, nausea

Conclusion RT+cetux improves locoregional control and overall survival compared to RT alone

­ Other Important Published Data for HNSCC:

Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Bernier et al. Head & Neck. 2005.

Methods: o Analysis of pooled data from EORTC 22931 (10) and RTOG 9501 (11,12). Both studies

compared post­surgery adjuvant radiation to adjuvant chemoradiation with high­dose cisplatin (100mg/m2 d1,22,43) in patients with high­risk features.

Results o Patients who benefit from addition of adjuvant high­dose cisplatin to radiation include those

with features of positive margins and/or extracapsular extension from lymph nodes Patients without these features had no survival advantage with addition of

chemotherapy Bottom­line

o Patients with positive margins and/or extracapsular extension have improved survival with addition of cisplatin to radiation.

Meta­analysis of chemotherapy in head and neck cancer (MACH­NC): An update on 93 randomised trials and 17,346 patients. Pignon et al. Radiotherapy and Oncology. 2009.

Methods: o Individual patient data from trials comparing loco­regional treatment of radiation with or

without chemotherapy Results

o 87 trials with 16,485 individual patients included o HR for death = 0.88 (p < 0.0001) for addition of any chemotherapy, 5­year absolute survival

benefit of 4.5% (p < 0.0001) o Concurrent CRT better than sequential (either induction or adjuvant)

HR for death = 0.81 for concurrent CRT, 5­year absolute survival benefit = 6.5% o Decreasing benefit with age, particularly >70yo

Bottom­line o Significant benefit of concurrent CRT o Consider RT alone for patients >70yo

Notes o Trials of NPC only were excluded

Meta­analysis of chemotherapy in head and neck cancer (MACH­NC): A comprehensive analysis by tumour site. Blanchard et al. Radiotherapy and Oncology. 2011.

Methods: o Individual patient data from trials comparing loco­regional treatment of radiation with or

without chemotherapy o Patients divided into 4 tumor locations: oral cavity, oropharynx, hypopharynx and larynx

Other tumor locations were excluded Results

o 87 trials with 16,192 individual patients included o Addition of chemotherapy beneficial for all sites o Concurrent CRT better than sequential statistically for oropharyngeal and laryngeal only.

5­year OS benefits of concurrent vs sequential: 8.9% oral cavity (p = 0.15) 8.1% oropharynx (p < 0.0001) 5.4% larynx (p = 0.05) 4% hypopharynx (p = 0.31)

Bottom­line

o Significant benefit of chemotherapy for all anatomical sites o Concurrent better for oropharyngeal and laryngeal and likely also for oral cavity and

hypopharynx although not statistically significant SUPPORTIVE MEASURES

­ Consults: o All patients should be referred to a dietitian and considered for a feeding tube

Assess weight prior to each chemo dose, >10% weight loss is concerning o SLP o Dentistry o Smoking cessation o Consider hearing test

­ Hydration o Patients on high­dose cisplatin require significant hydration at home or some centres

choose to admit patients to hospital METASTATIC

­ Bottom Line General Approach: o Consider salvage surgery or radiation o First­line is cisplatin 75mg/m2 d1 and 5­FU 1000mg/m2/d d1­4 q3­4w

Consider splitting cisplatin 25mg/m2/d d1­3 o Other first­line regimens: weekly cisplatin, carboplatin + paclitaxel o Cetuximab added to platinum + 5­FU in some places based on EXTREME trial(13) but not

funded in Ontario o No evidence for survival for second­line treatments but reasonable option is docetaxel

Evidence for nivolumab in second line will be available in 2016

­ Prognosis: o Median OS 6­9 months, better in HPV­related disease

­ Important Phase III Clinical Trials:

EXTREME Trial

Platinum­Based Chemotherapy plus Cetuximab in Head and Neck Cancer. Vermorken et al. NEJM. 2008.

Regimen Platinum (cis or carbo) plus 5­FU with or without cetuximab

(400mg/m2 load then 250mg/m2 weekly) MOA of Experimental Drug

EGFR inhibitor

Primary Endpoint OS Inclusion/Exclusion Criteria

Recurrent or metastatic HNSCC Karnofsky PS >=70

Size (N) 442 Results Survival: Cetuximab improved median OS by 2.5 months (10.1 vs

7.4, p=0.04), HR for death 0.80 PFS: Cetuximab improved median PFS (5.6 vs 3.3 months, p<0.001) Response Rate: Cetuximab improved RR (36% vs 20%, p<0.001)

Toxicity Cetuximab arm had 9% grade 3 rash, otherwise similar toxicity Conclusion Addition of cetuximab to first­line platinum based chemotherapy for

patients with metastatic HNSCC provides a small but significant increase in OS, PFS and RR.

Other Comments Similar study with panitumumab was negative(14)

Nasopharyngeal Carcinoma

A) PUBLIC HEALTH

EPIDEMIOLOGY(1) ­ Incidence:

o Rare: <1:100,000/yr in North America, up to 65:100,000 among patients in Northern Africa, Southern China and Southeast Asia.

o In 2010 250 Canadians were diagnosed with NPC o Male:Female = 2:1

­ Mortality: o In 2010 100 Canadians died from NPC

RISK FACTORS ­ NPC

o Most common in Southeast Asian and Chinese ancestry o Epstein­Barr virus o Salted fish and meat o Smoking

PREVENTION & SCREENING ­ Prevention:

o Smoking cessation o Reduce intake of salted fish and meat o Reduce occupational exposures

­ Screening: o No screening recommendations in Canada or United States.

B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS ­ Common Symptoms:

o Palpable mass or lymphadenopathy o Nasal symptoms: nose bleeds or bloody discharge from the nose, stuffiness or blockage in

the nose o Ear symptoms: pain or blockage in one ear, persistent infections in one ear, ringing in the

ear, or tinnitus, hearing difficulties or hearing loss o Eye symptoms: bulging eye, diplopia o trismus, sore throat, facial pain, headache, cranial nerve deficits o weight loss

INVESTIGATIONS

­ Physical exam ­ Laboratory:

o Routine BW, hepatitis screen o EBV level

­ Diagnostic Imaging: o CT head and neck o MRI neck o CT chest o PET scan if no obvious metastases o CT abdomen and bone scan are not routinely performed

­ Diagnostic Procedures: o Endoscopy o Biopsy/FNA, EBER on tumor

PATHOLOGY & MOLECULAR BIOLOGY ­ Common Histology:

o Keratinizing squamous­cell carcinoma (WHO type I) o Differentiated non­keratinizing carcinoma (WHO type II)

Strongest relationship with EBV o Undifferentiated carcinoma (WHO type III)

­ Common Metastatic Sites: o Local recurrence o Lung o Bone

­ Relevant Molecular Biology: STAGING

C) TREATMENT LOCALIZED / ADJUVANT / RESECTABLE

­ Bottom Line General Approach: o Stage I

Radiation to primary (70Gy/35#) o Stage II

Radiation plus high­dose cisplatin (100mg/m2) +/­ adjuvant chemotherapy ­ Prognosis:

o 5­yr OS 70­90%

­ Important Phase III Clinical Trials for NPC:

Concurrent Chemoradiotherapy vs Radiotherapy Alone in Stage II Nasopharyngeal Carcinoma: Phase III Randomized Trial. Chen et al. JNCI. 2011.

Regimen Radiotherapy alone

Radiotherapy plus cisplatin 30mg/m2 weekly Primary Endpoint OS Inclusion/Exclusion Criteria

Chinese 1992 stage II NPC

Size (N) 230 Results Survival: Chemotherapy HR for death = 0.3 (95%CI 0.12­0.76,

p=0.007), 5­yr OS absolute benefit of 8.7% (94.5% vs 85.8%) Toxicity Increased early toxicity (neutropenia, nausea/vomiting, mucositis)

No difference in late toxicity Conclusion Addition of weekly cisplatin concurrently with radiotherapy improves

overall survival in patients with stage II NPC Other Comments If reclassified to AJCC staging then about 85% stage II, 15% stage III,

slightly more stage III were in the CRT group LOCALLY ADVANCED / UNRESECTABLE

­ Bottom Line General Approach for NPC Stage III­IV: o Concurrent chemoradiation as per CCO guidelines(15)

Benefit of adjuvant chemo in addition to CRT is currently being investigated with multiple ongoing phase III studies

CRT and adjuvant chemo: Radiation: 70Gy/35#, cisplatin 100mg/m2 d1, 22, 43 then adjuvant chemo 4 weeks post­radiation cisplatin 80mg/m2 d1 plus 5­FU 1000mg/m2/d d1­4, q28d x 3 cycles

Consider CRT alone: Cisplatin 20mg/m2/d and 5­FU 400mg/m2/d continuous for 96hrs d1­4 and 43­46

­ Prognosis: o 5­yr OS: 45­62%

­ Follow­up: o Imaging ~2 months after treatment

Important phase III clinical trials for NPC:

Intergroup 0099 Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal

cancer: phase III randomized Intergroup study 0099. Al­Sarraf et al. J Clin Oncol. 1998.

Regimen RT 70Gy/35# +/­ cisplatin 100mg/m2 d1,22,43 then post­radiotherapy cisplatin 80mg/m2 d1 and 5­FU 1000mg/m2/d d1­4 q4w x 3 cycles

Primary Endpoint PFS Inclusion/Exclusion Criteria

Stage III­IV

Size (N) 193 Results 3­yr PFS: improved in chemotherapy arm (69% vs 24%, p<0.001)

3­yr OS: improved in chemotherapy arm (78% vs 47%, p=0.005) Conclusion Addition of chemotherapy to radiotherapy significantly prolonged PFS

and OS in patients with locally advanced NPC

­ Other Important Published Data for NPC: Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Chen et al. Lancet Oncol. 2012.

Methods: o Phase III RCT of concurrent radiation (66Gy/33#) plus weekly cisplatin (40mg/m2) with or

without adjuvant cisplatin (80mg/m2 d1) and 5­FU (800mg/m2/d d1­4) q4w x 3 cycles o Primary end­point was failure­free survival

Results o 508 patients enrolled o No difference in 2­yr failure­free survival (86% vs 84%, p=0.13) o No difference in toxicity

Bottom­line o No benefit of adding adjuvant cisplatin and 5­FU to CRT for locally advanced NPC

Note o Early results published, final results are pending

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC­NPC meta­analysis. Blanchard et al. Lancet Oncology. 2015.

Methods: o Individual patient data from trials comparing treatment of radiation with or without

chemotherapy for locally advanced NPC, updated from 2006 meta­analysis. o Included interaction testing for different schedules of chemotherapy

Results o 19 trials with 4806 individual patients included o Pooled HR for death 0.79 (95%CI 0.73­0.86, p<0.0001) o Absolute 5­yr OS benefit of chemotherapy is 6.3% o Concurrent chemotherapy with or without adjuvant chemotherapy is better than adjuvant

alone or induction alone (p=0.01) Bottom­line

o Concurrent chemoradiation significantly improves OS, PFS and local control in patients with locally advanced NPC.

o Addition of adjuvant chemotherapy to chemoradiation of unclear benefit, non­significant trend towards improvement with adjuvant chemotherapy.

o Minimal or no benefit with induction chemotherapy or adjuvant chemotherapy alone SUPPORTIVE MEASURES

o Refer to supportive measures for HNSCC METASTATIC

­ Bottom Line General Approach: o Consider salvage surgery or radiation o No randomized evidence, consider clinical trial o Cisplatin and gemcitabine typically given as first­line, one possible regimen is:

Cisplatin 70mg/m2 d1 and gemcitabine 1000mg/m2 d1 and 8 q21d o Other first­line regimens: carboplatin and gemcitabine, cisplatin and 5­FU, cisplatin and

paclitaxel, weekly cisplatin, capecitabine ­ Prognosis:

o 5­yr OS 20%

­ Other Important Published Data for NPC:

Comparison of five cisplatin­based regimens frequently used as the first­line protocols in metastatic nasopharyngeal carcinoma. Jin et al. J Cancer Res Clin Oncol. 2012.

Methods: o Retrospective review of 822 patients with metastatic or recurrent NPC

Results o Five common treatments: cisplatin plus gemcitabine, cisplatin plus 5­FU, cisplatin plus

paclitaxel, cisplatin plus paclitaxel plus 5­FU and cisplatin plus 5­FU plus bleomycin. o Highest RR with cis­gem (71.1%), statistically significant over cis­5­FU (60.2%), p=0.033. o No difference in PFS or OS. o More toxicity with three­drug regimens.

Bottom­line o Cis­gem, cis­5­FU and cis­paclitaxel are all active regimens for metastatic NPC o No benefit for three drugs over two.

D) REFERENCES

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