To the Editor:

The editorial by Beitler and Cooper,¹ “Seduction by Induction,” raised both a question and a concern in regard to the treatment of patients entered on the docetaxel-containing (TPF) arm in the pivotal TAX 324 study and contained a factual error in regard to the nature of both the TAX 324² AND TAX 323³ pivotal studies in patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN). First, with regard to the latter, both TAX 323 and 324 are phase III registration trials, and not phase II trials as they were referred to throughout the editorial. These two studies led the US Food and Drug Administration to grant approval for the use of docetaxel in combination with cisplatin and fluorouracil (PF; the TPF triplet) as induction therapy before the application of curative-intent radiotherapy (RT; TAX 323) or carboplatin-based concomitant chemoradiotherapy (CRT; TAX 324) in 2006 and 2007, respectively, for LASCCHN. It is puzzling why Beitler and Cooper missed this widely known and important fact. As phase III trials, both studies definitively demonstrated an approximate 30% survival advantage to TPF compared with PF in the context of use of these regimens when an induction treatment plan is chosen for definitive therapy with curative intent in patients with LASCCHN.

More importantly, Beitler and Cooper¹ raised and rapidly answered on their own question, “Can induction therapy possibly interfere with the benefit of subsequent therapy? Yes.” Many in the radiation oncology community have assumed, in keeping with this statement by Beitler and Cooper and others in this community, that the 21% of the patients on TAX 324 who went off study did not receive definitive RT. This is incorrect. These patients received treatment according to local institution standards, as mandated in the TAX 324 study protocol. Patients went off protocol for local, regional, or distant progression; lack of response; or preference, as well as for emergent toxicity. Such patients were all included in the final analysis for survival, and progression reported.² Due to space limitations, we were not able to provide data on the nature of subsequent therapy for these patients. In fact, as seen in Table 1, 59% (29 of 49) of the patients in the TPF arm who went off study proceeded to receive definitive CRT or RT. Of the 255 patients in the TPF arm, 206 received per-protocol carboplatin-based CRT therapy and 29 patients received further off-protocol CRT or RT. Therefore, a total of 235 (92%) of 255 patients in the TPF arm received either per-protocol carboplatin-based CRT or off-protocol definitive RT or CRT based on local institutional preference. As a result only 20 (8%) of 255 patients in the TPF arm did not receive definitive radiation-based treatment. Some of the patients did not receive additional therapy because they received chemotherapy (3%) or no therapy (4%). In sum, for the vast majority of the patients under consideration, not receiving per-protocol CRT does not equal not receiving any definitive local therapy.

In discussing this issue further, the above numbers compare quite favorably to the Intergroup trial of unresectable head and neck cancer, in which 15% of the patients on the upfront CRT arm did not receive the intended (per protocol) definitive RT.⁴ It appears, based on a review of the current literature, that 5% to 15% of patients do not receive protocol-defined definitive RT on CRT protocols, as per data either published or presented in recent major meetings.^5,6 Furthermore, treatment breaks in the RT plan are often not reported. Treatment breaks have clear implications on both acute and chronic toxicity, as well as on outcome. Many trials only report a range of dates and compliance rather than define acceptable therapeutic limits for the study. We encourage reporting on this data in future trials.

In contrast to radiation-based trials, induction chemotherapy–containing sequential treatment plan trials in LASCHHN require an intermediate assessment of response that can lead per-protocol treatment to adjustment of treatment and/or removal of some patients from study. This is not the case in upfront RT- or CRT-based trials, where the patients are generally not assessed for response during therapy, and their treatment is simply prolonged or terminated early in the face of toxicity. This is an inherent, and admittedly crucial, difference in the nature of the therapies, and the trials themselves. In fact, it has been problematic to extract robust compliance data from upfront RT-/CRT-based trials.

We believe that in addition to the obvious efficacy of TPF in these trials, the intermediate assessment of response that occurs during and after the completion of the induction chemotherapy in the sequential schema is extremely valuable in managing LASCCHN, and can lead to risk-based improvements in subsequent surgery or CRT. Therefore, we strongly disagree with the statement by Beitler and Cooper¹ that these patients are disadvantaged and did not receive definitive treatment. As shown in Table 1, the data from TAX 324 do not support this notion.

It is also puzzling that lung cancer is often cited here¹ and in other commentary⁹ when discussing the failures of induction chemotherapy¹ in LASCCHN. This comparison is not appropriate, given the significant differences in the efficacy of therapy and the clinical and biologic behavior between these two malignancies. Recently, we have also seen repeatedly comparisons of therapy for anal cancer as another example of a group of cancers where induction chemotherapy has seemingly failed as a treatment option, often citing RTOG (Radiation Therapy Oncology Group) 98-11.⁷ It is important to note that RTOG 98-11 included a patient population that had low-stage (mostly stage 1 and 2) disease and chose to give the same induction therapy during radiation. One would not expect induction chemotherapy to be beneficial to or be utilized in this fashion for comparable stage populations of patients in head and neck cancer, whatever the intention might be in anal cancer. We would argue against such comparisons as being biologically inappropriate. We believe, based on the published data in the head and neck literature, that induction or sequential chemotherapy can be offered for patients with locally advanced disease in head and neck carcinoma, as manifested by advanced T and N stages⁸ and that the above comparisons of induction chemotherapy efficacy in LASCCHN to either lung or anal cancers are not warranted and are potentially misleading.

Finally, we encourage the academic medical and radiation oncology community, some members of whom have consistently rejected even the approved use of induction and sequential treatment plans,⁹ and who have been more focused on whether patients received definitive RT/CRT in the context of a sequential or induction plans, after the completion of the chemotherapy, to take another look at the complete therapy given in TAX 323 and 324 for toxicity, survival and progression outcomes. These outcomes clearly support TPF over PF and indirectly suggest a potential improvement in survival compared to CRT alone.^10,11 We believe the latter outcomes, survival and toxicity for the whole population over the whole treatment package, are the important outcomes. We encourage and truly welcome a respectful and scholarly scientific dialogue based on evaluating all of the published phase III data, and the continued collaborative and multidisciplinary optimal management of patients with head and neck cancer.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Robert I. Haddad, Bristol-Myers Squibb (C), sanofi-aventis (C); Marshall R. Posner, Bristol-Myers Squibb (C), Merck (C), sanofi-aventis (C), GlaxoSmithKline (C), Amgen (C), EMD Serono (C), Imclone (C) Stock Ownership: None Honoraria: Robert I. Haddad, Bristol-Myers Squibb, sanofi-aventis; Marshall R. Posner, sanofi-aventis, EMD Serono Research Funding: Marshall R. Posner, sanofi-aventis, Imclone, Bristol Myers Squibb Expert Testimony: None Other Remuneration: None