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© 2001 American Society for Clinical Oncology
Commentary: Phase III Trial to Preserve the Larynx: Induction Chemotherapy and Radiotherapy Versus Concurrent Chemotherapy and Radiotherapy Versus Radiotherapy—Intergroup Trial R91-11ByFrom the Department of Otolaryngology–Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI. Address reprint requests to University of Michigan Health System, 1904 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0312.
THIS MULTI-INSTITUTIONAL phase II randomized trial to preserve the larynx in patients with advanced laryngeal cancer (RT 91-11) represents yet another milestone in clinical trial efforts in head and neck cancer. This study, conducted over a 9-year period and involving participation of over 90 institutions, is a credit to the tenacity and perseverance of the investigators. It will certainly assume a place of distinction among the several key randomized trials in head and neck cancer performed during the last 20 years.1-5 With the introduction of effective multiagent chemotherapy regimens as induction therapy for head and neck cancer in the mid-1970s, extensive efforts to define a role for chemotherapy in the routine management of patients with advanced, resectable cancer were undertaken. The rationale for these trials was based on using multiple cycles of neoadjuvant chemotherapy in an attempt to reduce tumor size, potentially reduce the magnitude of subsequent treatment (especially surgery), and provide rationale for the use of adjuvant chemotherapy in responders to induction therapy. Unfortunately, this theoretical potential has not been fulfilled. However, the ensuing enthusiasm and extensive subsequent experience with induction chemotherapy spawned many small, randomized trials. Several consistent positive observations were derived from clinical experiences in what were generally negative trials. These included the high rates (> 80%) of tumor responses in previously untreated patients, the strong association of favorable prognosis with tumor response, and demonstrations of acceptable toxicity when combined with standard treatments. Unfavorable findings included the inability to reduce the extent of subsequent surgical resection and difficulties in administering multiple cycles of adjuvant chemotherapy to a generally debilitated and unreliable patient population. Further, the overwhelming majority of trials demonstrated no significant improvement in survival with the addition of chemotherapy. Thus, a role for chemotherapy as routine management in patients with potentially curable disease has remained unclear. Multiple reasons for such slow progress in integrating potent chemotherapy regimens into routine management exist. They include the difficulty in conducting large randomized trials in patients with head and neck cancer, the complexity of multidisciplinary treatment, and the low disease prevalence of head and neck cancer (with an estimated incidence of less than 50,000 patients per year, of whom less than 12,000 will have larynx cancer). The heterogeneity of tumor sites with varying biologic behavior in the head and neck, the high rate of second primary cancers, and the presence of significant comorbidities may also contribute to the difficulty in demonstrating improvements in overall survival with the addition of chemotherapy to standard treatment approaches. In an attempt to overcome this conundrum, a large meta-analysis of 63 randomized trials consisting of more than 10,000 patients was recently performed to determine the benefit of chemotherapy added to locoregional treatment.6 The findings suggested a small (4%) but statistically significant benefit in overall 5-year survival with the addition of chemotherapy. Subset analysis according to timing of chemotherapy administration indicated that the majority of this benefit was derived from the trials of chemotherapy added to radiation therapy in an alternating or concomitant fashion with no significant benefit from trials of adjuvant or neoadjuvant chemotherapy. These findings have encouraged further development of treatment approaches that incorporate concomitant chemotherapy with radiation and are supported by positive results from several recent randomized trials.7-9 The R91-11 trial is particularly important in this regard because it directly compares concomitant chemoradiation in a randomized fashion with induction chemotherapy followed by radiation for chemo-responders and with radiation-alone treatment regimens, each of which can be an acceptable alternative to initial laryngectomy for patients with selected stage III or limited stage IV laryngeal cancer. The primary end points in the R91-11 trial were survival with preservation of laryngeal function, disease-free survival, tumor response, patterns of relapse, morbidity, rates of complication of salvage surgery, and quality-of-life outcomes. So how did the trial measure up? To interpret the results, the goals and rationale for organ preservation treatment approaches must be understood. In the development of organ-preserving strategies, improved survival is always the primary goal, with preservation of structure and function a secondary objective. The physician’s perception of benefit and the acceptance of trade-offs in terms of survival and function are not always the same as the patient’s.10 For laryngeal cancer in particular, the important priorities of function preservation are airway (ie, avoiding permanent tracheostomy), swallowing (ie, no aspiration or feeding tube), and finally, voice (ie, no electrolarynx). Failure to achieve preservation of these functions cannot be considered an organ preservation success even if the anatomic structure of the larynx is preserved. Thus, results of organ-preserving strategies must include assessments of function and quality of life, in addition to survival. The favorable prognosis of patients whose tumors respond to induction chemotherapy and the effectiveness of radiation therapy in eradicating small volume head and neck cancer led investigators in the 1980s to use the response to three cycles of induction chemotherapy to select patients for definitive radiation as an alternative to radical surgery. This approach was pioneered in patients with advanced laryngeal cancer by the Department of Veterans Affairs (VA) Laryngeal Cancer Study Group.3 That landmark study, however, failed to demonstrate any improvement in overall survival. In fact, at 5 and 10 years, the survival of the chemotherapy-treated group was 5% less than the surgical arm (difference not statistically significant). The study did prove the feasibility of such an approach as an alternative to initial laryngectomy because two thirds of surviving patients were able to avoid laryngectomy and the chemotherapy treatment group enjoyed a significant improvement in quality of life.11,12 In the VA trial, nonresponders to induction chemotherapy went to immediate planned laryngectomy. Thus, salvage surgery was an integral part of the initial treatment regimen and most patients who required laryngectomy had this surgery performed because of persistence of disease after chemotherapy or at the conclusion of radiation rather than for a later subsequent recurrence. Significant quality-of-life benefits were demonstrated for the chemotherapy treatment group.11,12 Unfortunately, the VA trial was criticized because some critics felt that many of the patients may have been cured with radiation alone, and the trial was not designed to prove the benefit of chemotherapy because it did not include a radiation-alone treatment arm. Thus, the three-arm trial (R91-11) was needed to compare the VA trial regimen of induction therapy plus surgical salvage treatment with radiation alone and with concomitant chemoradiation to determine whether the addition of chemotherapy (either induction or concomitant) was better than conventional radiation alone. A major significance of R91-11 trial is derived from its large size, homogenous treatment group, and large number of investigators. Because of this, the results should certainly be valid and widely applicable. Unfortunately, the trial results are disappointing in that they fail to demonstrate any survival benefit with the addition of chemotherapy over treatment with radiation alone. This is particularly disappointing for the concurrent chemoradiation arm because the promise of the Pignon et al6 meta-analysis was not fulfilled. Nonetheless, the R91-11 results extend encouraging findings from several recent randomized trials of concurrent chemoradiation7-9 because the disease-free interval was improved with the addition of chemotherapy. This was true for both induction and concurrent chemotherapy treatment groups. Is this favorable impact of chemotherapy the result of a true reduction in recurrences or merely delay in relapse? If overall survival is not improved, an analysis of causes of death is important to determine if patients are dying of complications, second primaries, or other unrelated causes. Until these data are known and analyzed, the use of concomitant chemoradiation must remain an alternative to primary surgery and/or primary radiation and certainly not be substituted as a new standard of treatment. If overall survival with these various treatment approaches is similar, how does one decide which approach is better? In this regard, R91-11 data suggest that laryngectomy-free survival is significantly longer with concomitant chemoradiation compared with radiation alone but not significantly different from the induction arm. The percent of patients with larynx preservation at 2 years was significantly higher with concomitant treatment. Thus, if preservation of anatomic structure is the secondary goal of importance, the concomitant approach is better. Treatment decisions are then based on other factors of toxicity, cost, experience of the investigator, logistics, risk of salvage surgery, and patient preferences. In R91-11, the stated goal was preservation of laryngeal function. Thus, assessment of success in terms of larynx preservation must consider functional status of the larynx, including presence of tracheostomy, swallowing status, morbidity of late salvage surgery, and quality of life. These data are not provided or, perhaps, are not yet available. Longer follow-up and further analysis should be helpful in this regard. Surgery is an integral part of the primary treatment for approximately 30% of patients on these organ-preservation protocols. It should be noted that the induction chemotherapy arm on R91-11 differs significantly in overall treatment strategy from the other two treatment arms with respect to the role of salvage surgery. In the induction approach, chemotherapy response is used to select patients for planned early surgery with the hope of maximizing cure rates. In the VA larynx study,3 this strategy was highly effective, and the survival of the poor prognostic group (nonresponders) was equal to that of the chemo-responders and also to the primary surgery cohort. However, this approach to therapy is complex and, to be successful, requires close teamwork and experience in assessing tumor response and surgical timing. The other two treatment arms of R91-11 rely on timely detection of late, recurrent, local disease and subsequent, successful, salvage surgery to ensure optimal survival rates. The success of this late salvage surgery is critical to an evaluation of these treatments and has not yet been reported for R91-11. It does seem that less than the expected number of patients had salvage surgery after chemotherapy on the induction arm. This could negatively bias the survival results of that treatment arm if persistent (nonresponders) disease was not recognized. Likewise, it may be that longer laryngectomy-free survival and higher larynx preservation rates with concurrent chemotherapy may simply be caused by delayed appearance of local recurrence. Delaying total laryngectomy in patients with radioresistant cancer may be a false measure of treatment success if salvage surgery cannot be performed in a successful fashion. The R91-11 results suggest an impact on distant metastases, although this could also be interpreted as a delay in the appearance of disseminated disease. Both chemotherapy arms show this effect. Full analysis of all sites of failure, causes of death, and disease status at death are necessary to interpret if the addition of chemotherapy actually reduces the absolute incidence of distant metastases. Pattern of failure information is particularly pertinent for neck failure because many patients in the trial had supraglottic cancers, which have a high propensity to regional metastases and for whom appropriate management of the neck is the single most important treatment factor related to prognosis. What important lessons are learned from this initial report of R91-11? First, advanced laryngeal cancer remains a deadly disease. Estimated 5-year survival rates are less than 60%. The addition of chemotherapy to radiation treatment incurs additional significant toxicity and is associated with a 2% to 3% morbidity. Preliminary larynx preservation rates are highest for concomitant chemoradiation, and laryngectomy-free survival is better among both chemotherapy-treated groups compared with radiation alone. Concern remains that neither concurrent or neoadjuvant chemoradiation added survival benefit over radiation alone, although disease-free survival seemed significantly better for both chemotherapy arms. More detailed analysis of causes of death, larynx function, quality of life, and success of salvage surgery are needed before we adopt concurrent chemoradiation as a new standard. The future holds great promise for further development of combined treatment approaches that maximize quality of life, minimize morbidity, and maintain or enhance survival in patients with advanced laryngeal cancer. Many caveats exist for concurrent chemoradiation approaches, including potential reductions in radiation dose caused by chemotherapy toxicity, delay in identifying persistent disease, and the need for accurate data regarding long-term quality of life and late laryngectomy rates. Until these concerns are addressed, concurrent approaches must remain investigational alternatives to radiation alone. Careful counseling and thorough discussion of the complex treatment, survival, and toxicity issues is mandatory for patients considering radiation alone or chemoradiation treatment as an alternative to total laryngectomy. The best organ preservation approach has yet to be defined. Whether concurrent chemoradiation offers the same survival rates as primary surgery can only be answered in direct randomized comparisons. As of yet, none of these approaches with combined chemotherapy provide better survival than surgery. However, it is clear that the most suitable candidates for organ preservation approaches combining chemotherapy and radiation are those patients who face total laryngectomy. With advances in conservation laryngeal surgery, particularly supracricoid laryngectomy,13 fewer patients now require total laryngectomy. Finally, the most effective approach to organ preservation in laryngeal cancer remains prevention and early detection at a time when these cancers are exquisitely curable with function-preserving single-modality treatment.
1. Head and Neck Contracts Program: Adjuvant chemotherapy for advanced head and neck squamous carcinoma: Final report of the Head and Neck Contracts Program. Cancer 60: 301-305, 1987[Medline] 2. Kramer S, Gleber RD, Snow JB, et al: Combined radiation therapy and surgery in the management of advanced head and neck cancer: Final report study of the 73-03 of the Radiation Therapy Oncology Group. Head and Neck Surg 10: 19-24, 1987 3. VA Laryngeal 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, 1991[Abstract]
4.
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. J Natl Cancer Inst 88: 890-899, 1996 5. Laramore GE, Scott CB, al-Sarraf M, et al: Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 23: 705-713, 1992[Medline] 6. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment of head and neck squamous carcinoma: Three meta-analyses of updated individual data. Lancet 355: 949-955, 2000[Medline] 7. Merlano M, Vitale V, Rosso R, et al: Treatment of advanced squamous cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 327: 1115-1121, 1992[Abstract]
8.
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
9.
Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced stage oropharynx carcinoma. J Natl Cancer Inst 91: 2081-2086, 1999 10. List MA, Stracks J, Havaf K, et al: HNC patient priorities: Do preference for potential outcomes change with experience of treatment and residual impairments. Proc Am Soc Clin Oncol 20: 228a, 2001 (abstr 908) 11. Terrell JE, Fisher SG, Wolf GT, The VA Laryngeal Cancer Study Group: Long-term quality of life after treatment for laryngeal cancer. Arch Oto-HNS 124: 964-974, 1998 12. Hillman RE, Walsh M, Wolf GT, et al: Functional outcomes following treatment for advanced laryngeal cancer: Part I. Voice preservation in advanced laryngeal cancer. Ann Otol Rhinol Laryngol 107: 1-20, 1998 (suppl 172)[Medline] 13. Laccourreye H, Laccourreye O, Weinstein G, et al: Supracroid laryngectomy with cricohyoidopexy: A partial laryngeal procedure for selected supraglottic and transglottic carcinomas. Laryngoscope 100: 735-741, 1990[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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