The results of this study challenge the use of the platinum, 5-FU and cetuximab combination for the first-line treatment of recurrent and/or metastatic HNSCC. Indeed, we showed here that the sequential use of all efficient chemotherapy regimens led to an OS of 9.8 months among a non-sorted patient population. In addition, the OS reached 13.1 months among patients without classical major exclusion criteria for clinical trials.
Today, the first-line standard treatment for recurrent and/or metastatic HNSCC is the combination of platinum, 5-FU and cetuximab, which is continued as maintenance therapy since the EXTREME trial demonstrated an overall response rate of 36%, a median PFS of 5.6 months, and a median OS of 10.1 months vs. 20%, 3.3 and 7.4 months without cetuximab, respectively. However, there were more severe adverse events in the arm of patients treated with cetuximab. The EXTREME trial only included patients in good general condition (with a Karnofsky > =70%), with adequate organ function, and with a relapse-free interval of at least six months since the last chemotherapy for the treatment of the local disease
. Because of the high toxicity, many patients with impaired nutritional or functional status are not eligible for this regimen, and other therapeutic strategies should be offered to these patients.
In our series, platinum-based combination was the favored first line when patients were fit enough, to avoid subsequent platinum-ineligibility related to disease progression. Patient ineligible for cisplatin and for the platinum, 5-FU and cetuximab combination were treated with a carboplatin-based front line therapy. The combination of carboplatin and weekly paclitaxel showed response rates of 48 to 53% and median survival rates of 8 to 12.8 months in Phase II trials
[14, 15]. In addition, the tolerability was better than with a traditional three-weekly administration
[14, 16]. This combination could then be proposed to patients with an impaired general condition (with a performance status of 2 or >2). For these reasons, carboplatin and weekly paclitaxel was the standard carboplatin-based regimen in this series. For patients ineligible or resistant to a platinum therapy, less toxic first line regimens have been offered to patients. The efficacy of taxanes as monotherapy
[9, 10] or in combination with cetuximab
[7, 8, 17] after failure of platinum-based chemotherapy has been shown in several studies, with a response rate of 30% as monotherapy and a response rate of 38 to 54% for the combination. The tolerability profiles were good for both monotherapy and the combination. Thus, platinum, taxanes and cetuximab appear to be drugs of choice for the treatment of recurrent and/or metastatic HNSCC, and could be used either in combination or as successive therapies.
Since the approval of cetuximab for the treatment of recurrent and/or metastatic HNSCC, the comparison between several lines of single agent vs. combination chemotherapy regimens has never been performed in a clinical trial. In 1992, in a trial comparing cisplatin and 5FU as single agents and in combination, the response rate to the combination was higher but survival did not improve. In other cancer subtype, it appears more important for patients to receive all the active agents at some point during the course of treatment rather than the order or combination in which the drugs are received
[18–20]. Considering the high rate of comorbidities, impaired nutritional status, and impaired functional status of patients with recurrent and/or metastatic HNSCC, they should be treated with less toxic strategies. Thus, successive chemotherapy lines could be an effective treatment option. The higher response rate observed with combination strategy
 has been shown to improve the functional status of patients
. Moreover some patients in this series never received cetuximab. It appears that some patients would never receive any second line treatment given a rapid disease progression after failure of the first line regimen. The successive chemotherapy lines strategy might then be more suited for patients with low cancer-related symptoms, and with low tumor burden.
In this series, only 6% of the patients were treated in first line with the combination of platinum, 5-FU and cetuximab. First line therapy was adapted to patients’ general status and comorbidities. A major objective pursued by treating oncologists was to give all the active agents to a maximum of patients, explaining the high rate of patients receiving platinum, taxanes, cetuximab, methotrexate and 5-FU at least once. The estimation of patient’s outcomes in this series might be biased, given the retrospective nature of the study, the high heterogeneity of the patients and of the treatments.
Supportive care performed during and after the chemotherapy could have increased patients outcomes, as early integration of supportive care has been associated with survival benefit in another cancer setting (lung cancer)
, but teoretically could be transposed to head and neck cancer and deserve further studies. However because all consecutive patients treated in our institution have been included in this series, it might be a relevant estimation of “real life” patient outcomes. Even if a formal comparison is not possible between our retrospective study and the results of clinical trials, the OS in our study was higher than those obtained with a combination of platinum, 5-FU and cetuximab in first line
. The high number of successive chemotherapy line (39% of patients received 3 lines or more) might explain patients good outcomes. Because of the heterogeneity of the treatment described in this study, and because of the limitations of a retrospective study, we did not assess the adverse events rates of the successive chemotherapy lines strategy. However, the tolerability of multiple successive chemotherapy regimens should compare favorably with multiple-drugs combinations
. In this series, deaths related to chemotherapy toxicities were uncommon (3%) despite the high number of chemotherapy lines administered to patients. The two first lines were involved in all of these deaths.
The short PFS observed with single-agent regimens
[9–11, 23, 24] in first line does not necessarily indicate a failure of the global treatment strategy, if the progression can be identified before the occurrence of severe cancer-related symptoms, and if a switch to another chemotherapy is possible at progression. Therefore, a treatment strategy, including several lines of chemotherapy, should be formally compared with first-line combinations of multiple drugs in randomized controlled trials. Overall survival and a symptom scale should be the two major endpoints in such trials
, since progression-free survival should systematically favored the combination arm. With the increased number of innovative and active agents, strategy trials should become more and more important. The administration of successive chemotherapy lines could spare patients from severe toxic effects, but might not be as efficient as combination strategy in controlling symptoms for patients with severe cancer-related symptoms or with rapidly progressive disease. The combination of cisplatin-5FU plus cetuximab might then be preferred in first-line given its higher response rate. The eligibility criteria for a treatment strategy with successive chemotherapy lines were not investigated in this retrospective series, but only patients without severe cancer-related symptoms, with low tumor burden and who are eligible for a close follow-up were treated with this strategy. Given the increasing number of efficient drugs for the treatment of recurrent and/or metastatic HNSCC, the design of future clinical trials in this setting should define the successive lines to be used after failure of the first line therapy (when the investigational drug is evaluated in first line). The primary endpoint might then be the time to strategy failure, defined as the sum of PFS of the two or three planned treatment course. In conclusion, our results are very encouraging, but subsequent efficient drugs are now strongly needed.