Revisiting Induction Chemotherapy
With the improvement in locoregional control and overall survival achieved with chemoradiotherapy, distant metastases emerged as a leading problem. As discussed previously, the vast majority of the earlier induction trials did not support this approach as the optimal treatment strategy, in part because of the inability to improve locoregional control. Induction chemotherapy followed by concurrent chemoradiotherapy is an alternative strategy being evaluated.
There are compelling theoretical advantages to induction chemotherapy, including high response rates and clear benefit with regard to organ preservation. It has also been shown that a response to induction chemotherapy predicts response to definitive therapy by RT or chemoradiation. Sequencing induction chemotherapy followed by chemoradiotherapy, addresses many of the issues arguing against induction chemotherapy.
Over the past decade, the addition of newer agents to known active regimens has been actively investigated. Much of the interest has focused on the incorporation of a taxane in various treatment settings. In the induction setting, several phase II trials have investigated the incorporation of a taxane to a variety of induction regimens, most commonly a cisplatin(Drug information on cisplatin)/5-FU (PF) backbone in the treatment of patients with locoregionally advanced SCCHN. Response rates greater than 90% have been reported with impressive survival rates.[27,44,45]
In an attempt to build on these encouraging results, the logical next step has been to incorporate induction chemotherapy into the chemoradiotherapy approach. The high response rates as well as an expected decrease in the development of distant metastases added to the previously noted gains in locoregional control and overall survival demonstrated with chemoradiotherapy could potentially lead to further improvements in outcomes. Although several phase II trials have investigated this approach, we will focus on three recent phase III trials (Table 3).
• EORTC 24971/TAX 323—The most recent results of the EORTC 24971 (TAX 323) trial comparing docetaxel(Drug information on docetaxel) (Taxotere), cisplatin, and 5-FU (TPF) and PF induction chemotherapy followed by RT in patients with locoregionally advanced, unresectable SCCHN were recently reported.. In this phase III trial, 358 patients were randomized to receive either PF or TPF every 3 weeks for four cycles. This was followed by RT within 4 to 7 weeks.
The primary endpoint of median progression-free survival (with a median follow-up of 32.5 months) was 11.0 months in the TPF group and 8.2 months in the PF group (P = .007). Median overall survival was 18.8 months and 14.5 months for the TPF and PF groups, respectively (P = .02). The investigators also noted an absolute increase in 3-year survival of 10.9% in the TPF group. TPF induced more leukopenia and neutropenia than PF, but with prophylactic antibiotics, did not lead to more frequent infections. There were fewer treatment delays in the TPF group as well as a lower incidence of grade 3/4 thrombocytopenia, nausea, vomiting, and stomatitis.
• Spanish Trial—In 2005, Hitt et al published the results of a Spanish phase III trial in which 382 patients with stage III/IV resectable and unresectable SCCHN were randomized to receive three cycles of induction chemotherapy with either cisplatin and 5-FU (CF) or cisplatin, 5-FU, and paclitaxel(Drug information on paclitaxel) (PCF). Following induction chemotherapy, patients were reevaluated and further assigned based on response. Patients who achieved a complete response (CR) or partial response greater than 80% in the primary tumor then received concurrent chemoradiotherapy consisting of cisplatin 100 mg/m2 on days 1, 22, and 43 with conventional radiotherapy to a total dose of 70 Gy.
The CR rate was 14% in the CF arm and 33% in the PCF arm (P < .001). The researchers found no differences between the two groups in a comparison of overall responses to induction and chemoradiotherapy treatment. A clear survival benefit was seen only in the subgroup of patients with unresectable disease, with a median survival of 36 months in the PCF group vs 26 months in the CF group (P = .04). There was no difference in grade 3/4 neutropenia between the two treatment groups. An increase in mucositis was seen in the CF group.
• TAX 324—The results of the TAX 324 trial were published simultaneously with the TAX 323 trial. In this phase III trial, 501 patients with SCCHN who were considered to have unresectable disease or to be a candidate for an organ-preservation approach were randomized to receive three cycles of either TPF or PF induction chemotherapy. This was followed by chemoradiotherapy utilizing weekly carboplatin(Drug information on carboplatin). The primary endpoint in the study was overall survival.
The estimated 3-year survival rate was 62% in the TPF group and 48% in the PF group (P = .002). The median survival was 71 and 30 months for the TPF and PF groups, respectively (P = .006). Locoregional failure was 30% in the TPF group and 38% in the PF group (P = .04). The investigators observed no statistically significant difference in the incidence of distant metastasis. The TPF arm was associated with a significant increase in grade 3/4 neutropenia and febrile neutropenia, compared to the PF group. Despite this finding, there were significantly fewer treatment delays in the TPF group.
• Further Reflections on Induction Chemotherapy—Based on the results of these phase III trials, it appears evident that TPF is superior to PF as an induction chemotherapy regimen in patients with locoregionally advanced SCCHN prior to either chemoradiotherapy or radiation alone. However, no completed trials have directly compared induction chemotherapy plus chemoradiotherapy to chemoradiotherapy alone. Until these data become available, the precise role of induction chemotherapy in this group of patients will remain unclear.
It is well understood that that there is a substantial increase in toxicity associated with chemoradiotherapy, compared to radiation alone. With the potential added toxicities of induction chemotherapy as well as a prolongation in the time it takes to complete therapy, an important concern is that a proportion of patients may not complete the chemoradiotherapy portion of treatment as planned. It is also critical not to compromise the previously noted gains achieved with chemoradiotherapy by choosing potentially less effective agents to be delivered during chemoradiotherapy. Another concern is that without further data, the routine incorporation of induction chemotherapy may result in overtreatment for a substantial number of patients. Thus, it is imperative that we are better able to define which subset of patients, if any, should routinely receive this intensive treatment approach.
Phase III Trial Design Considerations
Clinical trial design is critical in validating the induction chemotherapy hypothesis and should be based on the experience and data available from clinical trials that have addressed this issue. Emphasis should be placed on testing the induction chemotherapy hypothesis in a patient population most likely to benefit from induction chemotherapy. Conceptually, this would parallel “risk adaptive” strategies applied to other cancer sites.
For example, patient selection could be limited to patients with oropharynx T4 and N2 or greater nodal involvement. Given the increasing validity of the prognostic implications of human papillomavirus (HPV)-16 positivity, consideration should be given to either stratification for HPV status or exclusion of such patients from induction chemotherapy trials. Locally advanced hypopharyngeal cancer patients are known to be at higher risk of occult metastatic disease and distant recurrence after locoregional treatment, and they represent a different subset of patients.
Chemoradiotherapy is the “backbone” of treatment and efforts should be made to hold chemoradiotherapy constant in order to provide direct comparison of treatment with and without induction chemotherapy. One of the challenges is to determine which chemoradiotherapy regimen is optimum, particularly in consideration of radiation delivery, variations in chemotherapy, and increasing evidence supporting the contribution of EGFR in chemoradiotherapy regimens.
Selection of endpoints is another critical factor in the design of clinical trials. Most would agree that overall survival should be the primary endpoint with adequate power to be able to demonstrate a 10% to 15% advantage. Toxicity endpoints should be designed to capture acute toxicity, especially focusing on delivery of the intended chemoradiotherapy without compromise resulting from the induction chemotherapy. Emphasis needs to be placed on intermediate and long-term toxicities, which are generally thought to be underreported.
Current Phase III Studies
As this review is being written, we are aware of three ongoing phase III clinical trials that are testing the induction chemotherapy hypothesis. The Paradigm trial is a randomized phase III trial in patients with stage III/ IV SCCHN. Patients randomized to the induction arm will receive three cycles of TPF followed by chemoradiotherapy determined by the response to TPF. Patients with a “less than good response to induction” will receive 4 weeks of accelerated concomitant boost radiotherapy combined with weekly docetaxel. Patients with a “good response to induction chemotherapy” will receive 7 weeks of single-fraction radiation therapy combined with weekly carboplatin. The control arm is chemoradiotherapy of accelerated concomitant boost radiotherapy and cisplatin, 100 mg/m2, at 21-day intervals for two cycles.
The second trial is being conducted in Italy with a two-arm randomization of TPF for three cycles with a secondary randomization to chemoradiotherapy with cisplatin/5-FU or radiation therapy with cetuximab(Drug information on cetuximab). The control arm receives no induction chemotherapy with the same secondary radiation randomization. This design will permit a 2 × 2 factorial design with overall survival as the primary endpoint, comparing induction chemotherapy vs no induction chemotherapy and radiation with either cisplatin/5-FU or cetuximab.
The third trial is an international phase III trial for patients with nodal stage N2 or N3 locally advanced disease. Patients are randomized to receive either two cycles of induction TPF followed by chemoradiation using docetaxel, 5-FU, and hydroxyurea with twice-daily radiation on an alternating-week schedule or the same chemoradiation scheme alone.
It is important to keep in mind when evaluating the existing trials that there is considerable heterogeneity with respect to the patient populations included as well as in the chemotherapy regimens and radiation schedules used. Although cisplatin-based chemoradiotherapy can still be considered the standard of care, there remain many unanswered questions, and it is difficult to recommend a “one size fits all” approach. With each new report, although we are able to witness exciting developments, more questions emerge.
In an attempt to achieve the best outcome for our patients, several questions often arise in our daily treatment decisions. Chief among them are the following: Which patients should be considered for induction chemotherapy? Should cisplatin remain the standard agent for patients receiving chemoradiotherapy? What is the optimal radiation schedule when combined with chemotherapy? How can we best integrate the EGFR inhibitors and other targeted agents into our treatment strategies?
At the same time, we must keep in mind the substantial toxicities associated with all of these approaches and give a clear focus to the evaluation of long-term functional outcomes and quality-of-life issues. Only with carefully planned and completed trials will these questions be answered, so that we can best serve this challenging patient population.