A comparative evaluation of neoadjuvant chemotherapy followed by concomitant chemoradiation versus accelerated radiation therapy versus conventional radiation therapy in a locally advanced head and neck carcinoma

Introduction

Globally, newly diagnosed head and neck cancer (HNC) cases are 686,328 annually which is 4.8% of all cancers and deaths due to HNC are 375,665 which is 4.6% of all cancers. Newly diagnosed HNC cases in India are 145,087 annually, which are 14.3% of all cancers and deaths are 105,247, which are 15.4% of all cancer deaths.¹ Malignancies of oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses, and major and minor salivary glands constitute HNCs, and majority of them arise from the surface epithelium and are squamous cell carcinoma (SCC).² The dominant risk factors for the development of HNCs are tobacco and alcohol use.^3,4 The most important determinant of prognosis is stage at diagnosis. The 5-year survival for Stage I patients exceeds 80% but is <40% in locally advanced head and neck carcinoma (LAHNC).⁵

In general, either surgery or radiation is effective as single-modality therapy for patients with early-stage disease (Stage I or II) for most sites.⁵ LAHNC are usually treated with combination therapy including surgery, radiation, and chemotherapy (CT).^5,6

Neoadjuvant CT (NACT) is aimed at both the disseminated disease and the primary tumor. It may reduce the number of clonogenic cells and cause the reoxygenation of the surviving hypoxic cells, both of which render tumors more controllable by radiation. NACT followed by definitive radiation therapy (RT) has been studied for organ preservation in patients with locally advanced cancers of the larynx and of the hypopharynx. NACT may also be used as a method to predict tumor response to chemoradiation.⁷

Radiation may be more effective for controlling the localized primary tumor, because it can be aimed and large doses given, but it is ineffective against disseminated disease. CT, on the other hand, may be able to cope with micro-metastases, whereas it could not control the larger primary tumor.⁸ In LAHNC, carboplatin and cisplatin both have been found to produce a survival benefit when added to RT. Although it appears that cisplatin may be more active, carboplatin is better tolerated.⁹

The rationale for accelerating radiation schedules is predicated on tumor cells undergoing accelerated repopulation during the treatment course after a lag time. Shortening of overall treatment time, lessen the total dose of radiation wasted in compensating for accelerated tumor cell repopulation during treatment.¹⁰

NACT with docetaxel, carboplatin, and 5-fluorouracil (TPF) regimen is known to decrease tumor size and improve survival in LAHNC. Following NACT, patients are usually treated by concomitant platinum-based chemoradiation which is better than conventional RT alone. However, some of the patients may develop a compromised bone marrow, after NACT, where further CT may not be possible. Accelerated RT with 6-fractions a week has shown better response rates than conventional 5-fractions a week. In light of the above factual matrix, the present study was planned to evaluate the efficacy, tolerability, and toxicity of NACT with TPF followed by concomitant chemoradiation in one group, accelerated RT in second group, and conventional RT in third group, in patients of LAHNC.

Subjects and Methods

The present prospective, randomized, comparative, open label, parallel study was conducted on 75 previously untreated, histopathologically proven patients of SCC of head and neck. Patients included in the study were those having AJCC Stage III/IV and a positive biopsy for SCC of head and neck, Karnofsky Performance Status (KPS) >70, normal blood biochemistry, liver and kidney function test. The patients having distant metastases; prior radiation, surgery or CT for the disease; KPS <60; pregnant or lactating patient; associated medical conditions were excluded from the study.

Results

Discussion

The main objective of the study was to evaluate and compare the efficacy, tolerability, and toxicity of NACT with TPF followed by concomitant chemoradiation and their comparison with other two groups. Accordingly, we have explored the International Medical Literature and compared the results of our study to conclude the feasibility of the present study.

Majority of head and neck malignant neoplasms arise from the surface epithelium and are SCC or one of its variants, such as lymphoepithelioma, spindle cell carcinoma, verrucous carcinoma, and undifferentiated carcinoma.¹¹ People who use tobacco (including cigarettes, cigars, pipes, etc.,) or drink alcohol excessively are at much greater risk for developing HNCs.^3,4 Approximately, 70–80% of these patients are diagnosed with locally advanced disease and 30–50% with lymph node involvement.¹² Stage at diagnosis is the single most important determinant of prognosis. The 5-year survival for Stage I patients exceeds 80% but is <40% in LAHNC. NACT with TPF is better than PF only schedule in LAHNC; hence, we used this schedule in our study. Various famous trials are in support of this like Posner et al., conducted a randomized phase III trial for the treatment of head and neck SCC to compare induction CT with TPF with PF, followed by chemoradiation. There was a better locoregional control in the TPF group, but the incidence of distant metastases in the two groups did not differ significantly. Rates of neutropenia and febrile neutropenia were higher in the TPF group; CT was more frequently delayed because of hematologic adverse events in the PF group.¹³ Similarly, in a phase II comparative study of TPF versus PF as induction CT in 358-patients of LAHNC. At a median follow-up of 32.5 months, the median progression-free survival (PFS) was 11.0 months in the TPF group and 8.2 months in the PF group. Treatment with TPF resulted in a reduction in the risk of death of 27%, with a median overall survival (OS) of 18.8 months, as compared with 14.5 months in the PF group.¹⁴

In a further study, the effectiveness of induction CT with TPF followed by radiation was compared with that of concurrent chemoradiation with TPF in LAHNC patients and concluded that the effectiveness of concurrent chemoradiation with TPF was better than that of induction CT with TPF followed by radiation.¹⁵

Haddad et al. conducted a series of four Phase I-II trials of high-dose and intermediate-dose TPF-based induction CT on 101 LAHNC patients. After a median follow-up of 49 months, 64% remain alive with NED, and 3 patients remain alive with disease, for an OS rate of 67%. Twenty-six patients had locoregional recurrences, and 5 patients had both LRR and distant metastasis. Out of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil.¹⁶

The importance of even small amount of acceleration was emphasized by the results from the Danish Head and Neck Cancer Study Group 6 and 7 trial. In the Danish trial, Overgaard et al. aimed to find out whether shortening of treatment time by the use of six instead of five radiotherapy fractions per week improves the tumor response in SCC. Overall 5-year locoregional control rates improved (70% vs. 60%; P = 0.0005). The benefit of shortening treatment time was seen for primary tumor control (76% vs. 64%; P = 0.0001), but not for neck-node control. Acceleration from 7 to 6 weeks improved voice preservation in laryngeal cancer (80% vs. 68%; P = 0.007) and improved disease-specific survival (73% vs. 66%; P = 0.01) but not OS. Acute morbidity was significantly more frequent with six than with five fractions, but was transient.¹⁷

Bourhis et al. did an analysis of two randomized trials of the French Head and Neck Cancer Group to compare concomitant chemoradiation and accelerated radiotherapy comparing conventional RT (70 Gy in 35 fractions) either with concomitant RT-CT (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and 5-fluorouracil) or with very accelerated RT delivering 64 Gy in 3 weeks. The 5-year OS, specific DFS, and local-regional control rates were improved in favor of simultaneous RT-CT, whereas local-regional control was significantly improved with accelerated RT, along with a marginal effect on OS and DFS. They concluded that both concomitant chemoradiation and accelerated RT improved tumor control rates, as compared to conventional RT, along with increased but manageable toxicity.¹⁸ In a further Phase III randomized trial on LAHNC with an Eastern Cooperative Oncology Group performance status of 0–2, accelerated radiotherapy- CT offered no PFS benefit compared with conventional chemoradiation or very accelerated radiotherapy; conventional chemoradiation improved PFS compared with very accelerated radiotherapy. Three-year PFS was 37·6% after conventional chemoradiation, 34·1% after accelerated radiotherapy-CT, and 32·2% after very accelerated radiotherapy. They concluded that CT has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of CT.¹⁹

Conclusion

The present study was a feasibility study and have shown better complete response in Group II (Accelerated RT) than group III but was associated with severe acute radiation toxicity especially mucosal which was statistically significant too. Group III (Conventional RT) treatment schedule was tolerated by all the patients without significant problems however it yielded the least local control out of the three groups. Group I (Concomitant chemoradiation) showed better complete response than other two groups with toxicity profile more acceptable than group II. It is concluded that following neoadjuvant chemotherapy, concomitant chemoradiation is better schedule as compared to accelerated radiation therapy or conventional radiotherapy.