Survival and toxicity outcomes of induction chemotherapy followed by concurrent chemoradiotherapy compared with concurrent chemoradiotherapy alone in inoperable stage III and IVA / B head and neck cancer

There are several areas within the head and neck where cancer can develop, including the mouth and lips, pharynx, larynx, nasopharynx, nose, sinuses and salivary glands. However, Thyroid cancer, brain cancer, ocular malignancy, and esophageal cancer are not categorized as head and neck cancer (HNC). Squamous cell carcinoma (SCC) and its variations are the most prevalent HNCs.1 In 2020, there were 9,31,931 new cases of HNC worldwide, with 4,67,125 fatalities.2 In Bangladesh, 32,337 new cases of HNC were diagnosed in 2020, with 18,145 deaths.3 Concurrent chemoradiotherapy (CCRT) is the recommended treatment for individuals with inoperable locally advanced HNC.4 Induction chemotherapy (ICT) is often utilized in clinical practice, although its significance is still debated. In HNC, a number of trials compared the survival advantages of ICT plus CCRT to CCRT alone. Article Info Abstract

Concurrent chemoradiotherapy with or without induction chemotherapy is widely practiced in inoperable stage III and IVA/B head and neck cancer. The aim of this study was to investigate the survival and toxicity outcomes of induction chemotherapy combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in inoperable stage III and IVA/B head and neck cancer patients. From June 2018 to July 2020, 86 patients participated in a quasi-experimental study. Patients were purposively assigned to one of the two arms (arm A or arm B). Arm A got induction chemotherapy and concurrent chemoradiotherapy, while arm B got only concurrent chemoradiotherapy. According to our findings, the 2-year progression-free survival rate in arm A was 48.8% vs 37.2 % in arm B (p-value=0.042), and the 2-year overall survival rate in arm A was 65.1 % versus 60.5 % in arm B (p-value= 0.416). There were no statistically significant variations in treatment-related toxicities between the two groups (p-value > 0.05). In conclusion, inoperable stage III and IVA/B head and neck cancer patients who got induction chemotherapy plus concurrent chemotherapy had a better progression-free survival rate than those who received concurrent chemoradiotherapy alone.
Some of them failed to show that ICT plus CCRT had a substantial survival benefit over the CCRT arm. [5][6][7] However, two earlier trials found that combining ICT with CCRT improved overall and progression-free survival significantly. Furthermore, they observed that the harmful effects of chemotherapy and radiation were nearly same between the two treatment arms. 8,9 In this study, we compared the survival and toxicity outcomes of ICT plus CCRT to CCRT alone in patients with inoperable Stage III and IVA/B HNC. The study was carried out in line with the Helsinki Declaration. Criteria for inclusion was patients with inoperable stage III and IVA/B squamous cell carcinoma of the Head and neck. Criteria for exclusion were age below 18 and above 70 years ; patients with an Eastern Co-operative Oncology Group (ECOG) performance status of three or above; prior head and neck chemotherapy or radiation or surgery; serious concurrent medical condition; and pregnancy or lactating patients. Following the application of inclusion and exclusion criteria, patients were purposively divided between two arms (Arm A and Arm B). Before each patient's involvement in the study, a signed informed consent was obtained from them. To gather information, a data collection sheet was employed. ICT was used with CCRT in Arm A, while CCRT was used alone in Arm B. ICT was administered in arm A with the injection cisplatin 100mg per m2 of body surface area (BSA) with normal saline on day one and injection 5-fluorouracil 1000 mg per m2 of BSA per day with normal saline continuous infusion on days one to five for three cycles. 10 Before and after chemotherapy, adequate hydration and pre and post chemotherapy medicines were maintained. CCRT was used in both arms of the study. Both arms received 66 Gray (33 fractions, 2 Gray/day, 5 days per week over 6.5 weeks) of radiation. During radiation, concurrent chemotherapy was administered weekly with injection cisplatin 30mg per m2 of BSA. 11 Patients were monitored for toxicity every three weeks during ICT and once a week during CCRT. The Radiation Therapy Oncology Group (RTOG) toxicity criteria were used to assess toxicity. 12 Following the end of treatment, patients were evaluated every three months for the treatment responses. RECIST (Response Evaluation Criteria in Solid Tumors) criteria were used to evaluate treatment responses. 13 Patients were evaluated by clinical examination and appropriate investigations during follow-up. The IBM SPSS software application for Windows was used to analyze the data. To compare the toxicity outcomes of the two arms, the Chi-square test was utilized. The log-rank test was performed to compare the two arms in terms of overall and progression-free survival. The Kaplan-Meier curve was generated to compare the survival rates of the two arms. A p-value of less than 0.05 was regarded as significant.

Results
The overall number of participants in the study was 86, with 43 in Arm A and 43 Table-II According to the survival analysis, 48.8 percent and 37.2 percent of patients in arms A and B, respectively, were progression-free after two years ( Figure -1).  Overall survival was 65.1 percent in arm A and 60.5 percent in arm B after two years ( Figure -2).

Discussion
In locally advanced head and neck cancer, CCRT was found to be the best therapeutic choice in a meta-analysis of chemotherapy in head and neck cancer (MACH-NC). 14 The effectiveness of induction chemotherapy is still debatable. Several investigations on the effect of ICT in locally advanced HNC have been conducted. Two of them found that combining ICT with CCRT improves overall and progression-free survival. 8,9 The goal of this study was to investigate the survival and toxicity of ICT plus CCRT against CCRT alone in inoperable stage III and IVA/B HNC patients.
In several clinical studies, TPF (docetaxel, cisplatin, and fluorouracil) outperformed PF (cisplatin plus fluorouracil) in terms of ICT scheduling. 15,16 Our study, on the other hand, was done in government institutions with low-income patients who couldn't afford TPF regimen with granulocyte-colony stimulating factor (G-CSF) assistance. As a result, instead of using the TPF schedule, we utilized a less expensive cisplatin plus fluorouracil regimen.  differences were not statistically significant (p > 0.05), which is consistent with the findings of Paccegnella et al. 9 Toxicities, on the other hand, were well tolerated and easily managed.
The results of all prior studies were either 3-year or 5-year survival rates. Only a 2-year survival rate was shown in our study. According to our data, the 2-year PFS rate in the IC plus CCRT arm was 48.8%, while it was 37.2 % in the CCRT alone arm. This difference between the two arms is statistically significant (p-value=0.042). Ghi et al also observed in their study that the ICT plus CCRT arm had a significantly higher PFS than the CCRT arm. 8

Conclusion
In terms of progression-free survival, ICT coupled with CCRT is more effective than CCRT alone in inoperable stage III and IVA/B HNC with comparable toxicity. At the same time, the overall survival is slightly higher in the ICT arm, but the difference is not statistically significant between the two treatment groups.