Patient selection characteristics of major trials which have evaluated neoadjuvant chemotherapy for larynx preservation

What Should Be The Ideal Regimen?

Although initial larynx preservation trials used the doublet regimen of cisplatin and 5-fluorouracil (5 FU) for induction, the later trials used a triplet regimen adding docetaxel to the doublet. The doublet regimen consisted of cisplatin 100 mg/m 2 on day 1 and 5 FU 1000 mg/m 2 day 1–5 as a 24 h infusion daily.[6],[7],[14] In triplet regimen, the cisplatin dose reduced to 75 mg/m 2 on day 1 plus 5 FU 75 mg/m 2 day 1–5 and docetaxel 75 mg/m 2.[10] The only trial that has compared head on between the two is the GORTEC 2000–01 trail which randomized 213 patients of laryngeal and hypopharyngeal cancer to receive three cycles induction chemotherapy with Taxol, Platinum, 5Fu (TPF) or Platinum, 5Fu (PF). Patients with >50% regression of tumor were then treated with CTRT or RT alone.[12] 3-year larynx preservation was significantly improved in the TPF arm compared to PF arm (70.3% vs. 57.5%, P = 0.03). 3 year OS was 60% in both the arm with 3-year disease-free survival (DFS) also not different (58% vs. 44%, P = 0.011). The TPF-treated patients had higher rate of neutropenia (31.5% vs. 17.6%) and more febrile neutropenia (10.9% vs. 5.8%). However, only 62.7% and patients in the TPF and 32% patients in the PF group completed the treatment without delay or dose reduction. Thus, the addition of one-third agent is associated with significant toxicity but improves laryngeal preservation rates. This can be seen in parallel to the trails comparing doublet versus triplet chemotherapy in head and neck cancer where significant survival benefit was seen with the triplet regimen but at the cost of increased toxicity.[15],[16],[17] Thus, in patients with good performance status, a triplet regimen should be preferred, keeping in mind the higher laryngeal preservation rates associated with it.

Some smaller series have also evaluated doublet regimens such as docetaxel plus cisplatin/carboplatin for organ preservation.[18] A small study by Rubio Suárez et al. had evaluated the combination of vinorelbine, cisplatin, and Tegafur/uracil. Had a good laryngeal preservation rate of 50% in laryngeal primaries.[19]

Pfreundner et al. evaluated paclitaxel + cisplatin as NACT for organ preservation in patients with advanced laryngeal and hypopharyngeal carcinomas and reported a larynx preservation rate of 84% at 25 months.[20]

Response assessment after NACT should be done after 2–3 cycles of chemotherapy. It would be more logical to go for response assessment after 2 cycles as followed by the Veterans affairs (VA) trial and then go for a third cycle in responders.[6] It gives enough time for RT planning and prevents gap in the treatment. Smaller series have also reported assessment after 1 cycle of chemotherapy and reported a high response rate of >70% with 1 cycle.[21] A maximum of 3 cycles must be given as giving >3 cycles may prolong the overall treatment time and may increase the accelerated repopulation of tumor cells. The response rate to triplet chemotherapy has been reported to be as high as 85%.[22]

Who Should Be Selected For Larynx Preservation Versus Surgery?

The patients after receiving 2–3 cycles of NACT must undergo a response assessment and should be properly selected for a further RT for organ preservation or surgery. The trials have varied in their approach of selection of patients for organ preservation. The European Organization for Research and Treatment of Cancer Head and Neck Cooperative Group (EORTC) 24891 selected only patients with a complete response (CR) after NACT for organ preservation approach while those without a CR went on to have a surgery.[11] However, the VA trial and the RTOG 91–11 trial took patients at least who had a partial response (PR) (≥50% reduction in size of the primary) for RT approach.[6],[7] However, when we analyze the results the rate of larynx preservation was higher in the VA and the RTOG trial than the EORTC trial. This may be because some of the patients who might have had larynx conservation underwent surgery due to strict cutoff for response in the EORTC trial. The trials that followed these three land mark trials also used the criteria of at least a PR to chemotherapy as a indication for RT over surgery. Thus, it is logical to evaluate the patient after 2–3 cycles of NACT and those patients who have at least a PR be selected for further RT.

A summary of various chemotherapy schedules and selection criteria for larynx preservation used in various trials is given in [Table 2].

Summary of various chemotherapy schedules and selection criteria for larynx preservation used in various trials

Expected Survival And Larynx Preservation Rates

When we analyze the larynx preservation in various trials, it is basically the anatomically intact larynx that we consider as preserved larynx. The various functions of larynx include phonation, prevent aspirations while deglutition. Provide a safe pathway for air into the lung. Ideally, these various functions of larynx must be intact reasonably to call the patient has a functionally preserved larynx. However, also to be careful is that the survival of the patient should not be compromised in an attempt to improve larynx preservation rates. A delicate balance of these various factors is the key to successful implementation of larynx preservation protocols.

One the earliest trial reported was the VA trial.[6] This trial randomized 332 patients of locally advanced, but resectable SCC of larynx to surgery followed by adjuvant radiation or induction chemotherapy followed by radiation for those achieving >50% response. 2-year survival was 68% in both the treatment arm. However, DFS was nonsignificantly inferior in the treatment arm. The most important finding was larynx preservation in 64