• 2/18/2005
  • Houston, TX
  • Adam S. Garden
  • Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1059-1060

Nasopharynx cancer is a disease known for chemosensitivity compared with its counterparts in the head and neck, and is also notorious for a greater incidence of systemic spread compared with squamous cancers arising from other head and neck sites. Thus, the appeal of systemic therapies to treat this disease is great. In the current issue of the Journal of Clinical Oncology, Chua et al1 report a form of meta-analysis evaluating cisplatin-based induction therapy for nasopharynx cancer. By pooling the data from the two largest trials exploring the role of induction chemotherapy, it was hoped that the combination of two independently negative trials would gain sufficient statistical power to result in a positive result. Alas, with respect to overall survival, the overall trial results remain negative.

The current analysis adds to the growing database of neoadjuvant chemotherapy trials in head and neck cancer that have not demonstrated a survival advantage for the use of induction therapy. These results are consistent with the Meta-Analysis of Chemotherapy in Head and Neck Cancer Collaborative Group’s finding, which revealed no significant survival benefit associated with the use of neoadjuvant chemotherapy.2

In the 1990s, induction chemotherapy was a critical component in the management of patients when organ preservation was the goal. Often, survival equivalence was a satisfactory end point. The Veterans Affairs and European Organization for Research and Treatment of Cancer larynx preservation studies demonstrated that not all patients with advanced larynx and hypopharynx cancers required surgery.3,4 However, both studies made a priori assumptions that induction therapy was required. Similar to other studies of concurrent chemoradiotherapy, the results of the Radiation Therapy Oncology Group and Head and Neck Intergroup Larynx Preservation Trial 91-11 demonstrated that a concurrent chemotherapy approach was superior to radiation alone in achieving larynx preservation.5 More importantly, it demonstrated that the concurrent approach achieved an improvement in larynx preservation compared with induction chemotherapy. Finally, patients receiving induction therapy did not have a significantly better larynx preservation rate than those receiving radiation alone, but they did have more treatment-related toxicity.

The results of the study by Chua et al1 leave us with the same questions we had at the initiation of the trials on which the analysis was based. It unfortunately reinforces the conclusion that induction therapy demonstrates some effect of neoadjuvant therapy on the disease, but ultimately not on the patient. We are left questioning whether the neoadjuvant approach is conceptually valid, when yet to be proven in the appropriate circumstances. Proponents argue that neoadjuvant therapy has failed to demonstrate efficacy for several reasons: inadequate study design, inadequate drug intensity, inadequate drug efficacy, or inadequacy of the local therapies allowing for the systemic component to demonstrate its effect. To address these issues, several groups have investigated taxane-based induction therapy6 or have advocated the combination of an induction regimen with concurrent chemoradiotherapy.7

Despite demonstrating a lack of efficacy (with an evidence-based approach) with respect to survival or organ preservation to date, induction therapy remains a component of many practices, and my editorial comments would be disingenuous if I did not admit that we still treat some of our patients with induction therapy, and continue to develop protocols that try to define a role for this therapy. One reason is the perception that neoadjuvant therapy remains an effective strategy for managing systemic micrometastases. For patients with low T stage (but high N stage) tumors, particularly if the disease is in the low neck, the probability of systemic failure can be greater than the local regional failure; the latter can be successfully managed with local therapies. Thus, a systemic treatment seems reasonable, though proof of efficacy is lacking.8 A second practical reason is that neoadjuvant therapy can be initiated quickly in the occasional patient with either very advanced disease (or rapidly progressive disease) who find themselves in a clinical setting in which radiation therapy can not be started expeditiously. Finally, induction therapy for some represents a predictive marker, as the clinician can choose the “appropriate” local therapy based on response to induction therapy.

To improve outcomes in head and neck cancer, a multidisciplinary approach is a key element. However, the integration of these approaches remains a challenge. The strongest evidence to date establishes concurrent chemoradiotherapy as the most effective approach in controlling advanced disease.2 This has been demonstrated for head and neck cancer in general, as well as for specific subsites, such as nasopharynx, oropharynx, and larynx. This has also been demonstrated in the nonsurgical and postoperative settings. The vast majority of studies have used radiation alone as the control, and improvements with a concurrent approach have been made by decreasing the rates of primary and nodal recurrence. These advances, however, have come at the cost of increased toxicity.

We are entering an era of “targeted” therapies for head and neck cancer, in which relatively nontoxic therapies can effect unique molecular changes in the cancer cell, leading to improvement in tumor control. One lesson early experiences are teaching us is that there are multiple targets, and one molecularly targeted therapy may be a success only in a subgroup of our patients. Betensky et al9 demonstrated that molecular heterogeneity may confer different risks to patients that, if unaccounted for, could result in an unsuccessful trial due to underpowering of the trial design. The same can be said for our experiences with neoadjuvant therapy in that it is a valid concept, but the appropriate population needs to be identified. Perhaps it is time to stop testing the approach for all patients with advanced disease, but rather design trials to identify which subgroups will truly benefit.

It is also an opportunity to think of radiation as another agent, rather than a competing therapy, thus developing optimal multiagent therapies for the appropriate scenarios. Each agent has its differing mechanisms of causing cell death, and each, a set of toxicities. Striking the appropriate balance with all therapies and taking advantage of their tumoricidal effects, while minimizing their acute and late sequelae, remains the ultimate challenge.

Author’s Affiliation:
The University of Texas M. D. Anderson Cancer Center, Houston, TX

REFERENCES
(1)Chua D, Ma J, Sham J, et al: Long-term survival after cisplatin-based chemotherapy and radiotherapy for nasopharyngeal carcinoma: A pooled data analysis of two phase III trials. J Clin Oncol 23:1118-1124, 2005

(2)Pignon J, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group—Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949-955, 2000

(3)The Department of Veteran Affairs Larynx Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 19921

(4)Lefebvre J, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. J Natl Cancer Inst 88:890-899, 1996

(5)Forastiere A, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003

(6)Shin D, Glisson B, Khuri F, et al: Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck. Cancer 95:322-330,

(6)Kies M, Haraf D, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16:2715-2721, 1998

(7)Johnson F, Garden A, Palmer J, et al: A phase II study of docetaxel and carboplatin as neoadjuvant therapy for nasopharyngeal carcinoma with early T status and advanced N status. Cancer 100:991-998, 2004

(8)Betensky R, Louis D, Cairncross J: Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol