Induction Chemotherapy: Hope or Hype in Head & Neck Cancer - An Audit from Institute of National Importance in Western Rajasthan & Review of Literature

Head and Neck Cancers (HNCs) are malignant tumours of the upper aerodigestive tract which includes subsites as the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. Squamous cell carcinoma (SCC) constitutes for >90% of HNCs. 

The primary risk factors which contribute to incidence of head and neck carcinoma include use of tobacco, alcohol consumption, human papillomavirus (HPV) infection (mainly causes oropharyngeal cancer), and Epstein-Barr virus (EBV) infection (for nasopharyngeal cancer). When the upper aerodigestive tract is chronically exposed to these carcinogenic factors, it can result in premalignant changes in the oropharyngeal mucosa and ultimately result in the development of cancer. 

Worldwide, head and neck cancer accounts for approximately 0.9 million cases and over 0.4 million deaths on a yearly basis. In the U.S., head and neck cancer accounts for approximately 3 percent of all cancers, with approximately 60 thousand cases annually and 15 thousand deaths [1]. 

In India, it constitutes 25-30% of all cancers as opposed to 3-4% in the Western World [2]. 

Management of head and neck cancer includes a multimodality treatment approach which includes chemotherapy, radiotherapy, and surgery, the sequence of which depends on various factors like patient-related factors, stage of disease, and some logistic factors. 

As induction chemotherapy is considered an integral part of head and neck cancer management, this study focuses on its association with survival outcomes.

The records of head and neck cancer patients who received definitive or adjuvant radiotherapy in our department from 2018 to 2020 were compiled, and various factors associated with outcomes were assessed. The effect of induction chemotherapy on survival outcomes in various subsites was assessed using the Kaplan Meier Curve and Log Rank Test with hazard ratios estimated using Cox proportional hazards regression.

A total of 130 patients with proper records were taken into consideration. The mean age of presentation was 52 years (95% C.I. ranging from 50.07 to 54.87 years), Male predominant, 85 patients (65%) were oral cavity, 20 (10%) were pharyngeal subsites, 25(15%) were laryngeal subsite, 15 (11%) presented with Stage I, 20 (15%) presented with stage II, 19 (14%) presented with stage III, 74 (56%) presented with stage IVA, 2 (2%) presented with stage IVB. 

Out of 130 patients, 36(28%) patients received induction chemotherapy, out of which 25 received doublet chemotherapy while 11 received triplet chemotherapy. 

In surgically resectable oral cavity tumors, 12 patients received neo-adjuvant chemotherapy out of which 10(83%) patients received it for downstaging while 2 (17%) received it due to logistic issues (Table 1). 

Table 1: Baseline Characteristics. 

Survival Analysis of the patients with operable oral cavity cancer who received NACT or who underwent upfront surgery was done using Kaplan Meier analysis and median OS was found to be 40.9 months in the NACT arm vs 25.7 months in the upfront surgery arm (p=0.015, HR:0.412, 95% CI:019-0.86) (Figure 1).

Figure 1: Legends- Kaplan Meier Curve showing overall survival analysis in oral cavity cancer patients who underwent surgical management.

Survival analysis showed that among those patients with operable head and neck cancer [3-9], the median overall survival of those patients who received NACT compared to those that did not was 29.3 months vs 42.9 months (p=0.086, HR:1.29, 95% CI:0.57-2.91) (Figure 2).

Figure 2: Legends- Kaplan Meyer Curve showing overall survival analysis in head and neck cancer patients who underwent surgical management.

In Patients receiving definitive RT/CTRT, the median OS was found to be 32.1 months in the NACT arm vs 18.1 months in the non-NACT arm (p=0.11, HR:1.93, 95% CI:0.86-4.34) (Figure 3) [10,11]. 

Figure 3: Legends- Kaplan Meyer Curve showing overall survival analysis in patients who received definitive CTRT.

Overall, In all HNC subsites, the median OS was found to be 32.1 months in the NACT arm vs 34.5 months in the non-NACT arm (p=0.76, HR:0.91, 95% CI:0.49-1.68) (Figure 4).

Figure 4: Legends- Kaplan Meyer Curve showing overall survival analysis in all head and neck cancer subsites. 

Head and neck cancers are more prevalent in the Indian subcontinent due to multiple etiological factors as addiction-related, socio-economic factors, and other viral factors also. Gross variation in the incidence is predominantly due to the use of tobacco and areca nuts in India. While epidemiological data suggest a steady decline of tobacco-related cancers in the West with a concomitant rise in human papillomavirus (HPV) related oropharyngeal malignancies this trend has not been observed in India; HPV-related head and neck cancers being a relative rarity. 

Management of head and neck cancers includes the use of systemic agents such as chemotherapy, immunotherapy, targeted therapy, and local treatment options including surgery and radiotherapy. In our study, we tried to establish the role of induction chemotherapy in the management of head and neck cancer which is considered to be a hot and debatable topic. 

The role of induction chemotherapy (IC) in head and neck squamous cell carcinomas is still a hotly debated clinical problem with no consensus among existing literature about the same (Table 1). 

This retrospective review emphasizes the possible benefits and limitations associated with IC in this patient population, notably in terms of organ preservation, response rates, and survival outcomes. 

Our findings are almost consistent with the current literature, demonstrating that IC is effective at obtaining high response rates, particularly in locally advanced HNSCC of the oral cavity. This highlights its possible involvement in tumor downstaging, thereby allowing for more definite treatments like chemoradiotherapy or surgery. Furthermore, IC may improve locoregional control while decreasing distant metastases, which are a significant cause of failure in advanced HNSCC. 

However, the data also highlight the limitations and hazards of IC. Toxicity profiles, including hematologic and gastrointestinal side events, had a substantial impact on treatment discontinuation or delay in subsequent therapy. This underscores the importance of carefully selecting patients so that IC is reserved for those who will benefit the most. 

The diversity of patient groups and treatment methods is an important factor to consider in our research. The variability of IC regimens, dosages, and intervals makes it difficult to draw broad generalizations. The retrospective design of this study further restricts the ability to demonstrate causality or control for confounding factors such as comorbidities or performance level. 

Emerging biomarkers and precision oncology approaches hold the potential to improve the use of IC by identifying patients who are most likely to benefit. Prospective investigations and randomized controlled trials are critical for validating these findings and refining treatment approaches. 

To summarize, while IC remains a crucial tool in the multidisciplinary care of HNSCC, its use must be tailored to the individual patient, combining efficacy with potential harm. More research is needed to fully understand its role and successfully incorporate it into modern therapeutic procedures.

In a country like India where head and neck cancers are quite common and mostly present in the locally advanced stage, induction chemotherapy seems to be a valid option for helping in downstaging the disease and filling the gap between patient presentation and its definitive management in terms of either surgery or definitive radiotherapy. However, its effect on survival outcomes is still debatable and needs to be confirmed in further large-scale trials, NACT can be offered to patients with locally advanced disease with quite favorable outcomes.

1. Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72: 7-33.
2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, et al. (2020) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71: 209-249.
3. Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, et al. (2005) Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol 23: 8636-8645.
4. Posner MR, Colevas AD, Tishler RB (2000) The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck. Semin Oncol 27: 13-24.
5. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, et al. (2007) Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357: 1695-1704.
6. Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, et al. (2014) A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol Off J Eur Soc Med Oncol 25: 216-225.
7. Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, et al. (2009) Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 101: 498-506.
8. Cohen EEW, Karrison TG, Kocherginsky M, Mueller J, Egan R, et al. (2014) Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol 32: 2735-2743.
9. Haddad R, Colevas AD, Tishler R, Busse P, Goguen L, et al. (2003) Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck: the Dana Farber Cancer Institute experience. Cancer 97: 412-418.
10. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, et al. (2013) 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 Off J Am Soc Clin Oncol 31: 845-852.
11. De Figueiredo BH, Fortpied C, Menis J, Lefebvre JL, Barzan L, et al. (2016) Long-term update of the 24954 EORTC phase III trial on larynx preservation. Eur J Cancer Oxf Engl 65: 109-112.