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Year : 2019  |  Volume : 56  |  Issue : 1  |  Page : 2--3

Testing alternate biochemotherapy combinations in recurrent/metastatic head and neck cancer - Putting the best foot forward

HS Darling 
 Consultant, Department of Medical Oncology and Hemato-oncology, Artemis Hospital, Gurugram, Haryana, India

Correspondence Address:
H S Darling
Consultant, Department of Medical Oncology and Hemato-oncology, Artemis Hospital, Gurugram, Haryana

How to cite this article:
Darling H S. Testing alternate biochemotherapy combinations in recurrent/metastatic head and neck cancer - Putting the best foot forward.Indian J Cancer 2019;56:2-3

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Darling H S. Testing alternate biochemotherapy combinations in recurrent/metastatic head and neck cancer - Putting the best foot forward. Indian J Cancer [serial online] 2019 [cited 2020 Oct 19 ];56:2-3
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Recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC) patients constitute a heterogeneous group. Apart from the history of previous treatment received, they differ by subsites, p16 status, disease load, etiology, age, and tumor aggressiveness. Moreover, in future, we may be looking at other molecular variables, viz programmed death receptor ligand-1 expression, microsatellite instability, or tumor mutational burden profiles, which may further subcategorize these patients. Despite the introduction of newer modalities, such as targeted therapy and immunotherapy in R/M HNSCC, the prognosis remains dismal. With the currently approved palliative drug regimens, while we are able to accomplish only limited clinically relevant difference in median progression-free survival (PFS) and overall survival (OS), the other drivers of treatment algorithm, for instance, quality of life, cost, and productivity, become equally important.

Possible racial and geographical differences in disease incidence, behaviour, and treatment responses are increasingly being implicated in various cancers, as already witnessed in lung adenocarcinoma. Epidemiologically, HNSCC is a mammoth problem in India, ranked first, with an annual incidence of 1,92,563 and death rate of 1,14,013 (59.2% mortality). It constitutes 18.32% of all malignancies, in contrast to 4%–5% in the West.[1] The annual incidence of HNSCC worldwide is 5,50,000 with 3,80,000 deaths (69% mortality).[2] The United States has annual incidence of 63,000, constituting only 3% of total cancer burden, and 13,000 deaths (20.6% mortality), whereas, the Europe has 250,000 new cases per annum (4% of all cancer cases) and 63,500 deaths (25.4% mortality).[3],[4] The Indian data, as a matter of fact, may be representing just a tip of the iceberg because of incomplete reporting and ineffective case registration system. Moreover, many patients never reach the medical facilities. This entails the need to embark upon planning and designing indigenous innovative clinical trials, which apart from representing the tumor microenvironment of Indian patients, will also showcase the drug regimens and dosages which best comply the Indian setting.

While awaiting newer molecules to prove their worth in the given arena, the available armamentarium must be utilized in the best cost-effective way, causing minimum collateral damage. This damage avoiding strategies may comprise, reducing the financial toxicity, using shorter infusion regimens, lesser number of drugs, lesser treatment cycles, lesser hospital visits, lesser cannulations, lesser sampling requirements, less frequent imaging, and strengthening the supportive care paraphrenelia. The current standard recommendation for first line treatment for R/M HNSCC is platinum and 5-fluorouracil (5-FU) doublet, 3 weekly, along with weekly cetuximab.[5] Owing to the equivalent overall survival and lesser toxicity, the conventional platinum and 5-FU regimen, used in EXTREME trial,[6] is largely replaced by the relatively easier regimen of 3 weekly platinum and paclitaxel.[7] Apart from better tolerability, another advantage of this regimen is its replaceability with an easier weekly regimen,[8] if and when required, as compared with relatively difficult regimen of 5-FU, hitherto. Biweekly Cetuximab has shown comparable pharmacokinetics and pharmacodynamics to weekly Cetuximab and is an off-label recommendation in colorectal cancer.[9] It has also been similarly studied and tested in HNSCC.

Against this background, the indigenous hypothesis generating study “Biweekly cetuximab in combination with platinum and 5-fluorouracil in metastatic head and neck carcinoma” attempts to carve a new niche, by introducing a modified by Surmeli et al, convenient regimen, which not only depicts a longer survival but also substantially reduces the cumulative drug doses, number of visits, cost, and possibly the incidence of infusion reactions.[10] Ironically, no study till now has shown a median PFSof 6.8 months and OS of 13.3 months, as shown by this study. Moreover, this becomes very vital in Indian scenario as R/M HNSCC is not only the most common cancer in India but also it occurs predominantly in rural India where the cancer treatment facilities are meagre and difficult to access as well as afford; and the levels of education and awareness are dismally low. As depicted in this study, 28.3% patients were upfront palliative as compared with 15% or less in EXTREME trial.[6] The innovative regimen modification by the authors of this study seems not only more efficacious and better tolerable but also requiring lesser cost, visits, and admissions. This study has performed better than another retrospective study with a similar design, by Hannah et al., of biweekly Docetaxel, Cisplatin, and Cetuximab, which has shown lesser survival and more toxicity.[11] The survival benefit shown in the present study looks inspiring, thought provoking, and may stand practice changing after confirmation in a large randomized trial.

Looking at the other side of the coin, the current most practical regimen of 3 weekly taxane and platinum combination, with weekly cetuximab, is easier to administer and less toxic than any regimen of 5-FU. Second, it is a retrospective, nonrandomized single-arm study. The conclusions brought out will have to stand the test of time. Also, the oropharynx was the least common site in this study, whereas it was the most common site in EXTREME trial, which may have impacted the results.

To conclude, the biggest HNSCC population “rocket,” propelled by poor access to healthcare, late detection, treatment unaffordability, and lack of awareness pushes India into the “space” of high number of R/M HNSCC cases. The treating oncologist is well versed with the plight of R/M HNSCC patients, as a merciless death sentence, which tantamounts to “slow strangulation,” where, despite extensive mutilation of head and neck area by the disease, there is relative sparing of, the otherwise preserved, rest of the body. The prognosis of R/M HNSCC has not changed much since ages. India being home to 17% of world's population, possesses more than one-third of HNSCC cases, majority having reached the advanced stage of the ailment. We need to pioneer the research in this field. Close on the heels of immunotherapy attempting to score the first-line treatment position in R/M HNSCC, we must not miss the bus to explore other potential options, such as metronomic therapy, targeted therapy, etc. Akin to innovative idea implemented in this study, there lies the scope of considering Capecitabine in place of 5-FU. Oral duo of Capecitabine and Lapatinib has been studied, with a remarkable OS of 10.7 months, in the first-line setting.[12] Cetuximab, by and large, being devoid of any life threatening dose-limiting toxicity, may be tested as a 3 weekly regimen and/or at a higher dose. Reducing the undesired load is as important to improve the efficiency of the engine, as is augmenting its power. Sometimes, removing the last single straw can save the back of the camel from breaking.


1Globocan 2018. Availabe from: [Last accessed on 2019 Jan 16].
2Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol 2017;3:524.
3Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7.
4Gatta G, Botta L, Sánchez MJ, Anderson LA, Pierannunzio D, Licitra L, et al. Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study. Eur J Cancer 2015;51:2130-43.
5NCCN Clinical Practice Guidelines in Oncology; Head and Neck Cancers. Version 2. 2018. Availabe from: [Last accessed on 2019 Jan 16].
6Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.
7Forastiere AA, Leong T, Rowinsky E, Murphy BA, Vlock DR, DeConti RC, et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel+cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001;19:1088-95.
8Guntinas-Lichius O, Appenrodt S, Veelken F, Krug B. Phase II study of weekly docetaxel and cisplatin in patients with advanced recurrent and metastatic head and neck cancer. Laryngoscope 2006;116:613-8.
9Fernandez-Plana J, Pericay C, Quintero G, Alonso V, Salud A, Mendez M, et al. Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: Final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). BMC Cancer 2014;14:865.
10Surmeli ZG, Ozveren A, Arslan C, Degirmenci M, Karaca B, Uslu R. Biweekly cetuximab in combination with platinum and 5-fluorouracil in metastatic head and neck carcinoma. Indian J Cancer 2019;56:4-8.
11Fuchs H, Pammer J, Minichsdorfer C, Posch D, Kornek G, Aretin MB, et al. Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer. Med Oncol 2018;35:32.
12Weiss JM, Bagley S, Hwang W-T, Bauml J, Olson JG, Cohen RB, et al. Capecitabine and Lapatinib for the first-line treatment of metastatic/recurrent head and neck squamous Cell Carcinoma. Cancer 2016;122:2350-5.