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  Table of Contents  
Year : 2017  |  Volume : 54  |  Issue : 2  |  Page : 394-396

Neoadjuvant chemotherapy for unresectable oral cancers: Optimizing outcomes?

Senior Medical Advisor - Oncology, Eli Lilly and Company, Gurgaon, Haryana, India

Date of Web Publication21-Feb-2018

Correspondence Address:
Dr. T Puri
Senior Medical Advisor - Oncology, Eli Lilly and Company, Gurgaon, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_257_17

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How to cite this article:
Puri T. Neoadjuvant chemotherapy for unresectable oral cancers: Optimizing outcomes?. Indian J Cancer 2017;54:394-6

How to cite this URL:
Puri T. Neoadjuvant chemotherapy for unresectable oral cancers: Optimizing outcomes?. Indian J Cancer [serial online] 2017 [cited 2022 Jul 6];54:394-6. Available from:

Oral cavity cancer comprises a majority of cancers in India.[1] Most cases are locally advanced and have a poor prognosis. Treatment strategies are designed according to disease stage, site of primary tumor site, operability, patient's age, and performance status. Management approaches include surgery, radiation therapy (RT) as external beam or brachytherapy, systemic therapy, or various combinations thereof. However, the optimal sequence of these therapies remains to be defined, especially for organ preservation strategies or for unresectable tumors.[2] Surgery is the preferred treatment for resectable disease although radical radiotherapy may be used in some cases; however, primary RT with or without systemic therapy is the standard approach for patients whose tumors are unresectable or those unwilling to undergo surgery.[3]

Chemotherapy combinations such as cisplatin and 5-fluorouracil (5-FU) (PF) produce response rates of 60%–90% in patients with locoregionally advanced head and neck cancer (LAHNC), with half of the patients achieving complete response.[4] Although these responses are often short lived, the use of induction/neoadjuvant chemotherapy (IC) before definitive surgery or RT has emerged as an attractive strategy in the past two to three decades, particularly with the advent of taxanes.[4] IC has several theoretical advantages, including enabling tumor shrinkage, optimizing delivery of drugs through intact vasculature, reducing distant metastases, and assessing tumor responsiveness.[2] The earlier studies of IC in head and neck cancers used the two-drug PF regimen. The veterans affairs laryngeal cancer study compared IC with PF followed by RT to surgery followed by RT. Although the survival outcomes in the two arms were similar, patients receiving IC were able to achieve a 64% organ preservation rate.[5] The EORTC 24891 study compared surgery and RT versus PF-IC with RT in patients with operable, locally advanced pyriform sinus cancer. Organ preservation was achieved in 42% cases with IC.[6] The 10-year overall survival (OS) was similar between the 2 arms (13.8% vs. 13.1%), whereas progression-free survival (PFS) was slightly better in the IC arm (8.5% vs. 10.8%).[7]

The meta-analysis of chemotherapy in head and neck cancer showed a 4.5% higher 5-year survival rate with PF chemotherapy (given as concurrent, induction, or adjuvant) with locoregional treatment compared to locoregional treatment alone in LAHNC (all sites).[8] The hazard ratio (HR) for death was 0.81 in favor of concomitant chemotherapy (95% confidence interval [CI]: 0.78–0.86; P < 0.0001) with an absolute benefit of 6.5% at 5 years. The HR for death was 0.96 (95% CI: 0.90–1.02; P = 0.18) in favor of IC with an absolute benefit of 2.4% at 5 years. Indirect comparison showed that there was a more pronounced effect on reduction of distant metastases with IC (HR: 0.73; 95% CI: 0.61–0.88; P = 0.001) compared to concomitant chemotherapy (HR: 0.88; 95% CI: 0.77–1; P = 0.04). However, IC did not decrease locoregional failures. Therefore, IC with PF is not considered standard in LAHNC, except in larynx preservation where both PF induction and concomitant chemoradiation (CRT) are standard.[9],[10]

Several recent Phase III studies have evaluated the role of taxanes as IC in head and neck cancer. The TAX 323 study compared three-drug induction with TPF (docetaxel, cisplatin, and 5-FU) to standard two-drug induction with PF for up to four cycles followed by RT in both arms in patients with unresectable head and neck cancer.[11] The PFS was significantly longer with TPF induction (11 vs. 8.2 months; P = 0.007).[11] The TAX 324 study compared three cycles of TPF versus PF-IC followed by CRT in locally advanced resectable and unresectable head and neck cancer.[12] Long-term follow-up showed that the median OS was significantly longer in the TPF arm (71 vs. 35 months, P = 0.013).[12] A recently published meta-analysis of five trials by the MACH-NC group comparing induction Tax (paclitaxel or docetaxel) PF versus PF in LAHNC yielded a HR for death of 0.79 (95% CI: 0.70–0.89; P < 0.001) and an absolute benefit of 7.4% at 5 years in favor of Tax-PF.[13] Tax-PF was also associated with significant reductions of progression, locoregional failure, and distant failure compared with PF. The authors concluded that although Tax-PF induction must be considered one of the standards for larynx preservation, further testing in patients at high risk of metastases is warranted and its precise role compared with upfront CRT in the management of LAHNC needs to be defined.[13]

Two recent trials have evaluated IC followed by CRT in head and neck cancer. The PARADIGM trial compared 3 cycles of TPF-IC followed by cisplatin-based CRT versus CRT.[14] The trial was stopped early due to slow enrollment. The 3-year OS was similar, 73% versus 78% for IC versus CRT alone, respectively (P = 0.77).[14] The DECIDE study compared CRT alone to two cycles of IC followed by CRT with docetaxel-based regimens in LAHNC.[15] Although OS was similar in both arms (HR: 0.91; 95% CI: 0.59–1.41), the IC arm had a lower incidence of distant failure (P = 0.043).[15] Like the PARADIGM study, the DECIDE study also did not meet its accrual target. As anticipated, both studies had higher incidence of toxicity, especially febrile neutropenia, in the IC arm.

Patil et al.[16] reported their experience on a hitherto unexplored strategy of neoadjuvant chemotherapy followed by surgery in locally advanced unresectable oral cavity cancers. The authors hypothesize that neoadjuvant chemotherapy could achieve tumor shrinkage in technically unresectable tumors, thereby enabling surgical resection and improved outcomes, based on the principle that feasibility of resection is an important prognostic factor in oral cavity cancers. The characteristics used to define tumors as technically unresectable include tumor extension up to or above the zygoma, extension of the tumor up to the hyoid level, extension of the tumor from the anterior two-thirds of the tongue to the vallecula, involvement of the infratemporal fossa, or extensive skin infiltration. The authors previously reported their preliminary experience using the same treatment protocol.[17] The chemotherapy protocol was a two- or three-drug regimen with a taxane and platinum (cisplatin or carboplatin) with or without 5-FU, which was decided based on patient's performance status, creatinine clearance, financial constraints, and patient preference. The patients were assessed after two cycles of chemotherapy and if deemed operable by the surgeon, underwent surgery followed by appropriate adjuvant therapy. The remainder underwent radical CRT, radical radiation, palliative chemotherapy, or best supportive care.[16] [Table 1] summarizes the baseline patient characteristics and outcomes with neoadjuvant chemotherapy and surgery in the reports by Patil et al.[16],[17] of a retrospective series of consecutive patients at their center. In the two reported studies, close to 40% patients receiving the doublet regimen achieved the aim of resectability.[16],[17] This not only confirms the efficacy of these regimens but also addresses an unmet need in patients with oral cavity cancers, a majority of whom present with advanced unresectable disease.
Table 1: Summary of baseline characteristics and outcomes with neoadjuvant chemotherapy and surgery in oral cancers

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Despite encouraging outcomes in the study by Patil et al.,[16] comparison of reported results with historical studies is fraught with challenges. Previously reported large studies of neoadjuvant chemotherapy have been conducted in heterogenous populations regarding tumor site and presentation.[11],[13] The proportion of oral cavity cancers is low in these largely Western studies, based on geographic epidemiology. In addition, the definition of unresectability is also contentious, involving disease status, site of involvement, surgical skills, quality of life issues, and ability to achieve negative surgical margins.[18] Although the MACH-NC analysis has established that three-drug neoadjuvant chemotherapy is superior to two-drug regimens, this regimen is often not feasible in the Indian context due to resource constraints.[13] Patil et al.[19] have previously reported concerns with using RECIST in assessing resectability and found that there is a significant discordance between pathologic response and radiologic response. The number of cycles of neoadjuvant chemotherapy is also not standard (ranging from two in the study by Patil et al.[16] to up to four in historical studies),[11],[12] which makes comparisons difficult. In addition, oral cavity cancers are less chemosensitive than oropharyngeal cancers. The retrospective nature of the study, absence of internal control, and variable neoadjuvant and adjuvant treatment are some of the lacunae of the study. Nonetheless, an important issue of addressing technical unresectability has been raised.

Despite encouraging results from the MACH-NC analyses and the studies reporting neoadjuvant chemotherapy followed by surgery in unresectable oral cancers, several issues about neoadjuvant chemotherapy still remain unresolved. These include the optimum number of cycles; appropriate response assessment; incorporation of targeted therapy into induction treatment protocols; indications of IC, including organ preservation, unresectable disease, high metastatic risk, and bulky primary or nodal disease; biomarker-based chemotherapy selection; and optimizing treatment of human papillomavirus associated head and neck cancer.[2]

Thus, neoadjuvant chemotherapy does remain an option for treating patients with locoregionally advanced disease with a high risk of distant failure.[20] However, there are more questions than answers at this time, and well-designed prospective studies will be required to best answer these questions.

  References Top

Coelho KR. Challenges of the oral cancer burden in India. J Cancer Epidemiol 2012;2012:701932.  Back to cited text no. 1
Pointreau Y, Atean I, Fayette J, Calais G, Lefebvre JL. Induction chemotherapy in head and neck cancer: A new paradigm. Anticancer Drugs 2011;22:613-20.  Back to cited text no. 2
Huang SH, O'Sullivan B. Oral cancer: Current role of radiotherapy and chemotherapy. Med Oral Patol Oral Cir Bucal 2013;18:e233-40.  Back to cited text no. 3
Forastiere AA, Adelstein DJ, Manola J. Induction chemotherapy meta-analysis in head and neck cancer: Right answer, wrong question. J Clin Oncol 2013;31:2844-6.  Back to cited text no. 4
Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685-90.  Back to cited text no. 5
Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890-9.  Back to cited text no. 6
Lefebvre JL, Andry G, Chevalier D, Luboinski B, Collette L, Traissac L, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 2012;23:2708-14.  Back to cited text no. 7
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.  Back to cited text no. 8
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949-55.  Back to cited text no. 9
Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. Long-term results of RTOG 91-11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-52.  Back to cited text no. 10
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.  Back to cited text no. 11
Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: Long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.  Back to cited text no. 12
Blanchard P, Bourhis J, Lacas B, Posner MR, Vermorken JB, Cruz Hernandez JJ, et al. Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: An individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 2013;31:2854-60.  Back to cited text no. 13
Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet Oncol 2013;14:257-64.  Back to cited text no. 14
Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735-43.  Back to cited text no. 15
Patil VM, Prabhash K, Noronha V, Joshi A, Muddu V, Dhumal S, et al. Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers. Oral Oncol 2014;50:1000-4.  Back to cited text no. 16
Patil VM, Noronha V, Joshi A, Muddu VK, Gulia S, Bhosale B, et al. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference? Indian J Cancer 2013;50:1-8.  Back to cited text no. 17
Pradhan SA. Surgery for cancer of the buccal mucosa. Semin Surg Oncol 1989;5:318-21.  Back to cited text no. 18
Patil V, Noronha V, Joshi A, Muddu Krishna V, Juvekar S, Pantvaidya G, et al. Is there a limitation of RECIST criteria in prediction of pathological response, in head and neck cancers, to postinduction chemotherapy? ISRN Oncol 2013;2013, p. 6. doi:10.1155/2013/259154.  Back to cited text no. 19
Hanna GJ, Haddad RI, Lorch JH. Induction chemotherapy for locoregionally advanced head and neck cancer: Past, present, future? Oncologist 2013;18:288-93.  Back to cited text no. 20


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