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Originally published as JCO Early Release 10.1200/JCO.2005.04.1954 on December 27 2005 © 2006 American Society of Clinical Oncology.
Induction Chemotherapy for Larynx Preservation: Patient Selection or Therapeutic Effect?1 Section of Head and Neck Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
2 Head and Neck Surgery Section, Department of Surgical Oncology, Fox-Chase Cancer Center, Philadelphia, PA The role of chemotherapy as part of a larynx sparing treatment strategy for advanced laryngeal cancer has evolved considerably over the last 20 years. During the 1980s, no sort of chemotherapy—induction/neoadjuvant, concurrent, adjuvant, or any combination of these approaches—could be considered part of standard treatment. Partial laryngectomy and primary radiation were the recommended therapeutic options for patients hoping to avoid total laryngectomy. These approaches are still used in selected patients today. However, standard therapy for an advanced primary cancer of the larynx commonly entailed surgical removal of the voice box. The landmark Veterans Affairs’ (VA) laryngeal cancer study,1 initially published in 1991, provided the best initial evidence to support cisplatin-based, induction chemotherapy as part of a larynx preserving treatment approach. The VA investigators randomized patients with stage III or IV laryngeal cancer to primary surgery and postoperative radiation versus three cycles of induction chemotherapy followed by radiation. Laryngectomy was reserved for patients with a less than major response after two cycles of chemotherapy, suspected disease persistence after radiation, or relapse. The chemotherapy/radiation arm yielded survival rates comparable to those achieved with primary surgical management. Two thirds of surviving patients retained their larynx. The similarly designed European Organisation for Research and Treatment of Cancer (EORTC) larynx preservation study, which focused on patients with advanced cancer of the hypopharynx, further supported the principles of the VA trial.2 Induction chemotherapy followed by radiation with surgery reserved for salvage came to be considered a new standard treatment for patients with locally advanced cancer of the larynx. Subsequent studies, most prominently the Radiation Therapy Oncology Group (RTOG) study 91-11, which was undertaken in collaboration with the Head and Neck Intergroup and published in 2003,3 established the use of concurrent chemotherapy with radiation as the superior nonsurgical, larynx preservation strategy. The RTOG study demonstrated that patients with advanced laryngeal cancer receiving concurrent cisplatin and radiation had a better larynx preservation rate (84%) at a median follow-up of 3.8 years compared to that afforded either by radiation alone or by induction cisplatin/fluorouracil followed radiation (rates of 67% and 72%, respectively). Nonetheless, there have been strong and persistent undercurrents of interest in induction chemotherapy for patients with locoregionally advanced head and neck cancer.4,5 It should come as no surprise then that at least three randomized studies designed to determine whether the sequential integration of induction chemotherapy followed by concurrent chemotherapy improves outcome when compared to concurrent chemotherapy alone in such patients, are now in progress. These studies are not limited to larynx cancer, but the implications of their results for nonsurgical approaches to larynx and other head and neck tumors are obvious. The article reported by Urba et al in this issue of the Journal of Clinical Oncology6 also describes a sequential induction followed by concurrent chemotherapy strategy. However, it elaborates a different paradigm from that being evaluated in the aforementioned randomized trials. The VA larynx preservation study reported that a complete response after up to three cycles of induction chemotherapy, particularly when histologically confirmed, was a significant predictor of subsequent disease control.7 The investigators from the University of Michigan (Ann Arbor, MI) built on this observation with a related thesis —that the speed of tumor response to induction chemotherapy was an important prognostic factor and a predictor of successful organ preservation. In contrast to the VA study, wherein a decision regarding which locoregional treatment to pursue was made after two cycles of induction cisplatin/fluorouracil, in the current report, this decision was made after only one cycle of therapy. If there was a greater than 50% reduction, the patient proceeded to definitive chemoradiotherapy and two planned cycles of adjuvant chemotherapy; otherwise, laryngectomy followed by postoperative radiation was recommended. With this approach at a median follow-up of 41.9 months, the overall survival rate at three years was 85% and the cause-specific survival at the same time point was 87%. Seventy percent of patients retained their larynx. These results are noteworthy, because one third (32 of 97) of the patients had high volume or deeply invasive T4 disease, and 41% (13 of 32) of those had penetration of tumor through cartilage to involve the strap muscles and soft tissues of the neck. Patients with such massive primary tumors were excluded from RTOG 91-11 trial, as there were concerns regarding the adequacy of therapy with radiation alone—one of the three potential treatment randomizations in that study—in these patients with more deeply invasive disease. Additional trials evaluating this therapeutic approach seem warranted, but these encouraging results should be interpreted cautiously. This is a single-institution phase II trial, undertaken by an experienced multidisciplinary team thoroughly familiar with the protocol's requirements. In addition, the availability of increasingly sensitive diagnostic tests, with related stage migration, may frustrate comparison to results from other larger, multicenter randomized studies. Organ preservation therapy, of which larynx preservation represents a specific application, seeks to enhance simultaneously disease control, function, and appearance. Although conservation surgical procedures such as variants of partial laryngectomy are done with similar goals, more commonly, organ preservation refers to nonsurgical approaches. One of the challenges facing the developers of organ preservation protocols for advanced larynx cancer is how to balance optimally disease control while retaining the patient's voice box, with important quality of life priorities such as preservation of good speech and swallowing function, and avoidance of a permanent stoma. Total laryngectomy is one of the surgical procedures most feared by patients.8 Seminal work by McNeil et al showed that when healthy volunteers were queried, some were willing to accept a decrease in cure rate in hopes of avoiding a laryngectomy.9 However, more recent research from List et al demonstrates that cure and survival remain the highest priorities for the majority of patients.10 Reflecting the contribution of salvage laryngectomy to disease control, the estimated overall survival rates at five years were approximately 55% for all arms of RTOG 91-11. Certainly there is room for considerable improvement in survival. When larynx preservation therapy is successful there are few critics, but when nonsurgical management proves unsuccessful, as it does in a significant minority of patients, the morbidity and costs of treatment significantly increase, with a potential for compromise in survival. Arguably, proceeding directly to total laryngectomy for such patients would be preferable. Indeed, the postsurgical adjuvant chemoradiotherapy trials reported by the RTOG and EORTC provide support for surgery followed by concurrent cisplatin/radiation in appropriately selected patients with high risk tumors.11,12 The problem confronting head and neck oncologists is thus the selection of patients most likely to require laryngectomy anyway, despite the best intentions of organ preservation therapy. Considered in this context, the program from the University of Michigan assigns highest priority to the timely selection of treatment for either (1) concurrent chemotherapy and radiation, or (2) surgery. The anticipated result is to preserve or enhance survival rates and to decrease the morbidity and costs associated with unsuccessful efforts to avoid a laryngectomy. Implicit in the decision to limit induction therapy to a single cycle is the judgement that induction chemotherapy offers little therapeutic advantage beyond identifying tumors that will likely prove refractory to nonsurgical management. Can it be that induction chemotherapy serves only to identify tumors that are difficult to control? Indeed, the foundations of this philosophical approach suggest that induction chemotherapy may even represent a liability. Proper definitive treatment may be delayed, its intensity compromised, or its efficacy decreased due to the inappropriate continuation of an ineffective but potentially toxic induction regimen, that may change the biologic characteristics of the tumor and its sensitivity to therapy. If a reliable chemopredictive assay were available, which according to a recent American Society of Clinical Oncology technology assessment does not appear to be the case,13 then arguably even the single cycle of induction chemotherapy could be eliminated altogether with little or no ill effect. However, the trade-off is that for some patients the potential benefits of effective induction therapy (on distant metastases, for example), may be compromised. This concern is certainly germane because in the University of Michigan study the initial site of recurrence was below the clavicles 40% (8 of 20) of the time. Indeed, it has been recognized that distant metastases (particularly in patients with initially advanced nodal disease), and second primaries, increasingly define survival in head and neck cancer patients as locoregional control rates improve.4,14 Other data suggest that induction chemotherapy administered before radiation-based treatment may more predictably improve outcome, in comparison to its use before planned surgery and radiation.15 Adjuvant administration of systemic therapy provided an imperfect solution in the University of Michigan study. It was delayed until eight weeks after the completion of radiation, and only 19 (28%) of 68 eligible patients received the two planned cycles, as might be expected in view of the residual toxicity from aggressive locoregional treatment. Data reported by other investigators have similarly demonstrated that compliance with planned adjuvant chemotherapy after radiation-based treatment is often incomplete.16-18 In general, induction/neoadjuvant chemotherapy is better tolerated and complied with than adjuvant chemotherapy in patients with head and neck cancer. Another important concern is the mandate for an irrevocable decision regarding laryngectomy after a single cycle of induction chemotherapy. Clinical response assessment, especially for more extensive tumors, can vary between observers. It is not always clear-cut after just one cycle of induction chemotherapy. Evaluation of this protocol in a multicenter setting would provide important insights as to how easily and reproducibly the required response distinctions are made by teams less experienced with this treatment approach. Sometimes the true extent and trajectory of response becomes apparent only after the second cycle. With the University of Michigan approach, some patients who could potentially do well with radiation-based treatment may be faced with an unnecessary total laryngectomy. Recalling that the patient populations may not be comparable, in both the VA and RTOG 91-11 studies, the major response rate to induction chemotherapy after two cycles was 85%, which is consistent with an additional 10% of patients beyond the University of Michigan experience directed to nonsurgical management. The long-term larynx preservation rate in the concurrent chemoradiotherapy arm of the RTOG 91-11 trial was 84%, in comparison to the 70% seen in the Michigan series. The early selection of patients may risk increasing the percentage of patients undergoing laryngectomy. Many may view this trade-off in a negative light, although in fairness, others may argue that the trade-off is warranted because of the potential for better survival and lower morbidity. It should also be emphasized that lack of response to induction chemotherapy is not a perfect predictor of poor outcome with nonsurgical management. Data from RTOG 91-11 highlighted that among 24 patients who had total laryngectomy recommended because of less than a partial response at the primary site, 17 did not proceed with surgery. Eleven of these 17 patients received additional chemotherapy or radiotherapy instead. All 11 achieved a complete response, and 10 (91%) of these 11 patients obtained durable disease control without total laryngectomy. Furthermore, the data supporting the predictive role of response to chemotherapy with regard to subsequent responsiveness to radiation is largely derived from an era when radiation was given without concurrent chemotherapy. How subsequent concomitant therapy affects the predictive value of response to induction chemotherapy is less well studied. The University of Michigan approach, building on the foundations of important randomized trials such as the VA, EORTC, and Intergroup studies, illustrates the current generation of organ preservation trials. Investigators seek to further refine nonsurgical treatment with the intent of improving outcomes. Several approaches are under investigation as ways to improve the efficacy of nonsurgical, organ preservation treatment. These include, but are not limited to, altered radiation fractionation schedules; changes in radiation targeting to accelerate dose to tumor while reducing normal tissue toxicity (intensity modulated radiation therapy); amelioration of radiation toxicity through pharmacologic means; and the use of molecularly targeted therapies. Improving patient selection for nonsurgical management by identifying markers for response cannot be ignored. The use of induction chemotherapy either as a surrogate biomarker or to improve efficacy in this setting figures prominently among these initiatives. Though time-consuming and expensive to execute, well-designed, adequately powered, randomized trials will play a central role in determining which of these interventions will prove valuable, and for which groups of patients. Until more data become available, what can we say now? Larynx preservation with concurrent chemotherapy and radiation is feasible in patients with advanced larynx cancer. With appropriately selected patients and timely integration of surgical salvage, such an approach yields survival comparable to that obtained from primary surgical management. Depending on both the patient and the tumor, partial laryngectomy and radiation therapy alone also warrant consideration as larynx preservation treatment options. Patients having laryngeal tumors demonstrating gross cartilage destruction and invasion into soft tissues have more limited prospects for successful larynx preservation, and a recommendation for primary total laryngectomy is particularly appropriate to consider under these circumstances. For sufficiently robust patients, when chemotherapy in conjunction with radiation is pursued, concurrent cisplatin with radiation, as documented in the Intergroup study, is the best established standard treatment program. The American Society of Clinical Oncology has convened a multidisciplinary expert panel to develop clinical practice guidelines for the use of larynx preservation strategies in the treatment of laryngeal cancer. We anticipate these guidelines and related recommendations will assist head and neck oncologists and be an important resource with regard to therapeutic decision making in this setting. The potential for induction chemotherapy before concurrent treatment to improve survival, through patient selection or better disease control such as by reducing distant metastases, as well as to enhance larynx preservation while decreasing the morbidity of treatment, is of great interest. However, more data are needed before such sequential approaches can be promulgated as new treatment standards. Successful combined modality, chemotherapy-radiation programs require multidisciplinary expertise, enthusiastic cooperation and communication among team members, as well as experienced supportive care and rehabilitative services. Even then, patients must be carefully chosen if optimal results are to be achieved. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES 1. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685-1690, 1991 2. Lefebvre JL, 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. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996 3. Forastiere AA, 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 4. Brockstein B, Haraf DJ, Rademaker AW, et al: Patterns of failure, prognostic factors, and survival in locoregionally head and neck cancer treated with concomitant chemoradiotherapy: A 9 year, 337 patient, multi-institutional experience. Ann Oncol 15:1179-1186, 2004 5. Posner MR, Haddad RI, Wirth L, et al: Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: Evolution of the sequential treatment approach. Semin Oncol 31:778-785, 2004[CrossRef][Medline] 6. Urba S, Wolf G, Eisbruch A, et al: Single-cycle induction chemotherapy select patients with advanced laryngeal cancer for combined chemoradiation: A new treatment paradigm. J Clin Oncol 24:593-598, 2006 7. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12:1592-1599, 1994 8. Dropkin MJ: Body image and quality of life after head and neck cancer surgery. Cancer Pract 7:309-313, 1999[CrossRef][Medline] 9. McNeil BJ, Weichselbaum R, Pauker SG: Speech and survival: Tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 305:982-987, 1981[Abstract] 10. List MA, Stracks J, Colangelo L, et al: How do head and neck cancer patients prioritize treatment outcomes before initiating treatment? J Clin Oncol 18:877-884, 2000 11. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945-1952, 2004 12. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004 13. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004 14. Hanna E, Alexiou M, Morgan J, et al: Intensive chemoradiotherapy as a primary treatment for organ preservation in patients with advanced cancer of the head and neck: Efficacy, toxic effects, and limitations. Arch Otolaryngol Head Neck Surg 130:861-867, 2004 15. Paccagnella A, Orlando A, Marchiori, et al: Phase III trial of initial chemotherapy in stage III or IV head and neck cancer: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 86:265-272, 1994 16. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60:301-311, 1987[CrossRef][Medline] 17. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 18. Al-Sarraf M, LeBlanc M, Girl PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998 Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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