Authors: Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M
Source: N Engl J Med. 2004 May 6;350(19):1945-52.
Laryngeal cancer trials have foreshadowed these two papers with respect to the role of combined chemoradiation treatment. Prior to 1990, laryngeal cancer was commonly managed with total laryngectomy, however, the Veterans Affairs (VA) trial (NEJM, 1991) compared total laryngectomy with induction chemotherapy and radiation therapy. The chemotherapy regiment consisted of Cisplatin and fluorouracil, and responders received definitive radiation therapy after three cycles of chemotherapy. Two thirds of those treated with combined chemoradiation benefited from organ preservation and showed equivalent survival to those patients treated with total laryngectomy. This trial provided the basis for routine use of neoadjuvant chemotherapy in hopes of organ preservation. In 1991, the Radiation Therapy Oncology Group (RTOG) initiated a randomized study that built on this foundation of neoadjuvant chemotherapy for laryngeal cancer. Results show that the highest rate of organ preservation was in patients treated with concomitant RT and chemotherapy with no significant difference in overall survival. With this understanding of the background for the presumption that combined chemotherapy and radiation may be more effective in head and neck cancers, in 1991, a European and an American trial were undertaken to evaluate if concomitant Cisplatin and radiation were beneficial in locally advanced head and neck cancers.
Prior to the publication of the results of these studies, another study (Intergroup study 0099 [Al-Sarraf et al., JCO 1998]) showed an improvement in combined therapy for advanced nasopharyngeal carcinomas. Intergroup study 0099 results argued for a change in the standard of care, however due to poor results in the radiotherapy alone arm and the small size of the trial (150 patients analyzed), many questioned the strength of these data.
The preliminary report from the American study (RTOG 95-01) showed an improvement in local regional control but there was no statistically significant difference in 2 year disease-free survival or overall survival. An interim report of the this paper (EORTC 22931, Ann Oncol 2002) showed statistically significant improvements in local regional control, disease-free survival and overall survival. Thus the uncertainty created by the divergent results from the interim analyses of RTOG 95-01 and EORTC 22931 left doubt as the role of combined chemoradiation.
An update to the American study (RTOG 95-01, NEJM, 2004) was published back to back with this European study (EORTC 22931) and both suggest a paradigm shift is in order. The issues raised by the interim analysis results seem to be resolved after longer follow-up. Now, both groups find a statistically significant survival improvement with the addition of chemotherapy to definitive radiation.
Many argued that the EORTC results initially showed statistically significant improvement with combined therapy due to the different nature of the patients enrolled in that study as compared to those of the RTOG 95-01 study. In generally, the EORTC study patients has worse prognostic indicators such as margin status, degree of differentiation, and percent of patients with poorer prognosis (e.g. hypopharynx cancer). Those in opposition to changing patterns of care argued that chemotherapy was thus only significant for high risk patients with locally advanced disease. Now, however, results seem to suggest the addition of chemotherapy may benefit selected patients with head and neck locally advanced squamous cell carcinomas.
In this study, only 49% of patients receiving the planned three courses of chemotherapy without any delay or dose reduction, and thus the benefit of combined chemoradiation may be understated in this study.
Caution must however be exercised before undertaking such a regimen. The extent of benefit from combined therapy at particular head and neck sites cannot be reliably assessed in these studies. Furthermore, many find combined chemoradiation with cisplatin is difficult to tolerate, often requiring delays or interruptions in radiation therapy. The unconfirmed assumption is often made that treating with carboplatin may show similar benefits while being better tolerated by patients. With either chemo-therapeutic regimen, the increased toxicity of a combined chemoradiation therapy is more difficult for the patient to tolerate. With head and neck cancers, delays in treatment are thought to have adverse affects on outcome, and thus risks and benefits must be weighed. It thus becomes an important clinical decision to determine if the patient can tolerate a combined chemoradiation regiment, and whether or not the toxicity profile is acceptable.
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