Early Morbidity after Radiotherapy with or without Chemotherapy in Advanced Head and Neck Cancer

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1 Strahlentherapie und Onkologie Short Communication Early Morbidity after Radiotherapy with or without Chemotherapy in Advanced Head and Neck Cancer Experience from Four Nonrandomized Studies Sabine Bieri 1, Soeren M. Bentzen 2, Pia Huguenin 3, Abdelkarim S. Allal 4, Luca Cozzi 5, Christine Landmann 6, May Monney 7, Jacques Bernier 5 Background: Data on early treatment-related morbidity after radiotherapy alone (RT; 217 patients) or combined with chemotherapy (RT + CT; 182 patients) of head and neck squamous cell carcinoma are analyzed. Patients and Methods: The patients were treated between November 1985 and November 1996 in four Swiss centers that independently introduced combined-modality therapy in selected cases of head and neck cancer. RT schedules varied among the four centers, but within each institution all patients received the same dose-fractionation schedule irrespective of whether they had CT or not. The following early morbidity items were evaluated: skin, mucosa, larynx, salivary glands, dysphagia, weight loss, and toxic death. Toxicity was scored using the EORTC/RTOG scale. Results: Although considerable variation was noted among the treatment schedules/centers, the main findings are as follows: (1) early morbidity was significantly enhanced after all five RT + CT schedules compared with RT alone; (2) typically, a third of the patients lost > 10% of their body weight during concurrent RT + CT as compared with 10% of the patients receiving RT alone; (3) at 12 weeks, the prevalence of grade 2 morbidity was 25 60% after RT + CT as compared with 4 20% after RT alone. Conclusion: A number of early morbidity items were found to be more prevalent and/or more severe after RT + CT than after RT alone. Key Words: Head and neck cancer Chemotherapy Radiotherapy Adverse effects Strahlenther Onkol 2003;179:390 5 DOI /s Akute Morbidität nach Strahlentherapie mit oder ohne Chemotherapie in 399 fortgeschrittenen Hals-Nasen-Ohren- Karzinomen. Ergebnisse von vier nicht randomisierten Studien Hintergrund: Vorstellung der akuten Nebenwirkungen nach alleiniger Radiotherapie (RT; 217 Patienten) oder kombinierter Radiochemotherapie (RT + CT; 182 Patienten) bei Patienten mit Hals-Nasen-Ohren-Tumoren. Patienten und Methodik: Die Patienten wurden zwischen November 1985 und November 1996 in vier schweizerischen Spitälern behandelt. Dabei kamen verschiedene unabhängige, kombinierte Behandlungen für fortgeschrittene Hals-Nasen-Ohren-Karzinome zur Anwendung. CT- und RT-Protokolle waren unterschiedlich, innerhalb jedes einzelnen Zentrums wurden jedoch alle Patienten nach dem gleichen Bestrahlungsschema behandelt (mit oder ohne CT). Folgende akute Nebenwirkungen wurden erfasst: Haut, Schleimhaut, Larynx, Speichelfluss, Dysphagie, Gewichtsverlust und Tod durch Komplikationen. Die Beschreibung der akuten Toxizität erfolgte nach der EORTC/RTOG-Skala. Ergebnisse: Trotz erheblicher Unterschiede in der Bestrahlungstechnik zwischen den Spitälern sind die wichtigsten Ergebnisse folgende: 1. Die akuten Nebenwirkungen waren bei kombinierter RT + CT signifikant stärker als bei alleiniger RT; 2. ein Drittel der Patienten verlor > 10% ihres Körpergewichts während der kombinierten RT + CTC; Wochen nach Abschluss der Behandlung stand eine Grad-2-Toxizität in 25 60% nach kombinierter RT + CT und in 4 20% nach alleiniger RT im Vordergrund. Schlussfolgerung: Die akuten Nebenwirkungen waren nach kombinierter RT + CT stärker und häufiger als nach alleiniger Bestrahlung. Schlüsselwörter: Hals-Nasen-Ohren-Karzinome Radiotherapie Chemotherapie Nebenwirkungen 1 Department of Radiation Oncology, Regional Hospital of Sion, Switzerland, 2 Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, United Kingdom, 3 Department of Radiation Oncology, University Hospital of Zurich, Switzerland, 4 Department of Radiation Oncology, University Hospital of Geneva, Switzerland, 5 Department of Radiation Oncology, Institute of Oncology of Southern Switzerland, Bellinzona, 6 Department of Radiation Oncology, University Hospital of Basel, Switzerland, 7 Department of Radiation Oncology, University Hospital of Lausanne, Switzerland. Received: July 23, 2002; accepted: February 21, Strahlenther Onkol 2003 No. 6 Urban & Vogel

2 Introduction Combined chemotherapy (CT) and radiotherapy (RT) has been introduced in the treatment of advanced head and neck cancer in many departments over the last 2 decades [4, 19]. A meta-analysis of 63 trials including a total of more than 10,000 patients showed a relatively modest gain from combinedmodality therapy. The advantage of CT added to locoregional therapy (RT and/or surgery) was statistically significant (p < ), but the absolute survival benefit was just 4% at 5 years [18]. This benefit was shown to depend on the scheduling of RT and CT, and induction CT was not associated with a statistically significant therapeutic gain. Nevertheless, a mailed questionnaire among 300 community cancer specialists in the USA showed that RT with induction CT was the most common treatment approach in locally advanced head and neck cancer [12]. This option was selected by 61% of the respondents, and 96% of these indicated that RT + CT was given outside of a controlled clinical trial. The situation in many European centers seems to be similar, and this state of affairs is reflected in the literature where quite a few papers are being published reporting combined-modality experience from nonrandomized series. In the meta-analysis from Paris [18], concurrent RT and CT, so-called chemoradiotherapy, showed a relatively larger gain, the absolute benefit in 2-year and 5-year survival being 7% and 8%, respectively. This result was statistically highly significant (p < ). It was noteworthy, however, that the statistical test for heterogeneity among these trials was also highly significant (p < ). Also, it is not clear whether certain subgroups of patients might benefit more than other groups. The estimated benefit from chemoradiation is in line with the data from some recent phase III studies showing quite substantial improvements in local tumor control after concurrent RT + CT relative to RT alone [3, 8, 16]. No toxicity data were available from the meta-analysis, and it is remarkable that, with a few notable exceptions, many of the individual studies have contained rather scarce data on early morbidity [20]. The conclusions regarding the therapeutic potential of RT + CT in four Swiss centers were very cautiously formulated allowing for the nonrandomized nature of the studies [1, 2, 11, 13]. All centers agreed to bring their databases into a common format to facilitate a joint analysis in order to synthesize the experience from the four series. Due to the absence of randomized controls and the differences in patient selection for RT + CT among the Swiss centers, it was decided to focus on early morbidity. Patients and Methods From November 1985 to November 1996, 399 patients with histologically verified squamous cell carcinoma of the head and neck were treated with RT with or without CT in four Swiss radiation oncology centers: Basel, Zurich, Geneva, and Vaud. The patients notes were reviewed retrospectively, except for Basel where the patients analyzed were enrolled in a prospective phase I II protocol of concomitant RT + CT. In the three other centers, patients were considered for CT according to individual characteristics, like performance status, the extent of the disease, and the patient s consent to receive chemotherapy. Overall, CT was administered to 182 of 399 patients (46%). Radiotherapy (RT) The radiation dose-fractionation schedules are summarized in Table 1. In Basel, the tumor response was assessed after 46.8 Table 1. Treatment schedules. CDDP: cisplatin; Carbo: carboplatin; 5-FU: 5-fluorouracil; GE: Geneva; VD: Vaud; ZH: Zurich; BS: Basel. Tabelle 1. Behandlungsschemata. CDDP: Cisplatin; Carbo: Carboplatin; 5-FU: 5-Fluorouracil; GE: Genf; VD: Vaud; ZH: Zürich; BS: Basel. Schedule Radiotherapy Chemotherapy BS 18 Gy in 10 fractions (1 fraction per day) Gy in Concomitant continuous infusion of CDDP 20 mg/m 2 on day 1 4 and 24 fractions, 2 fractions daily a ± surgery (gap of 12 days) For the last consecutive 12 days Carbo 25 mg/m Gy in 24 fractions, 2 fractions daily a. Nominal total dose 75.6 Gy. Field size reduced after 50.4 Gy ZH Nominal total dose 74.4 Gy in 62 fractions, 2 fractions Concomitant continuous infusion of CDDP 20 mg/m 2 on day 1 5 and daily a. Field size reduced after 50.4 Gy GE-concomitant 50.4 Gy in 28 daily fractions. Concomitant boost: Concomitant (day 1 4 and 22 25) bolus injection of CDDP 100 mg/m Gy in 13 fractions delivered as a second daily alone or combined with 5-FU 1,000 mg/m 2 in continuous infusion fraction a. Nominal total dose 69.9 Gy GE-neoadjuvant 50.4 Gy in 28 daily fractions. Concomitant boost: Induction of bolus injection of CDDP 100 mg/m 2 alone or combined with 19.5 Gy in 13 fractions delivered as a second daily 5-FU 1,000 mg/m 2 in continuous infusion fraction a. Nominal total dose 69.9 Gy VD 20 Gy in 10 daily fractions Gy in 31 fractions, Induction bolus injection of CDDP 100 mg/m 2 alone or combined with 2 fractions dailya. Nominal total dose 69.6 Gy. Field size 5-FU 1,000 mg/m 2 in continuous infusion reduced after 49.6 Gy a with a minimum interval of 6 h Strahlenther Onkol 2003 No. 6 Urban & Vogel 391

3 Gy, and those with a clinical complete response continued RT + CT. Patients without a complete remission had surgical excision of the residual tumor mass before finishing the planned Table 2. Treatment schedules according to center: number and percentage of patients receiving a given schedule within a center. CT: chemotherapy; RT: radiotherapy; other abbreviations see Table 1. Tabelle 2. Behandlungsschemata nach Spital: Häufigkeitsverteilung der Protokolle innerhalb desselben Spitals. CT: Chemotherapie; RT: Radiotherapie; übrige Abkürzungen s. Tabelle 1. RT alone BS CT ZH GE-con GE-neo VD Other CT Total BS % 100% ZH % 54% 100% GE % 11% 10% 5% 100% VD % 38% 1% 100% RT + CT [11]. Five patients did not continue RT beyond a dose of 46.8 Gy. They decided to stop RT. All centers used a cone-down technique with all anatomic regions of possible microscopic spread included in the large volume and a boost volume covering the initial sites of macroscopic tumor involvement including the primary lesion and palpable lymph nodes. No specific technical modifications were used in the group of patients receiving CT. Chemotherapy (CT) Five standardized CT schedules were used in the majority of all cases receiving combined therapy (Table 1). In Zurich, patients had concomitant CT from the 1st treatment day. In Vaud, all but one patient receiving RT + CT had neoadjuvant CT. In Geneva, the sequence of CT changed with time. Initially, CT was delivered before the start of RT (GE-neo). A good early tolerance led to a gradual shift in policy toward a concomitant schedule (GE-con). The patients treated in this transitional phase (policy shift) were classified as having other CT (Table 2); the type of drugs was the same. Table 2 shows the allocation of patients to the various types of therapy in the four centers. RT + CT was used in all cases in Basel, and was used in a larger proportion of cases in Zurich than in Vaud and Geneva. Drug dose modifications were done according to the severity of the acute mucosal reactions, hematologic and renal toxicity. Nutritional support (a PEG or nasogastric feeding tube) was placed in patients with 10% weight loss during the course of treatment. Statistical Methods The statistical analyses were performed using SPSS version (SPPS Inc., Chicago, IL, USA, 1999). Independence of variable in a cross-table was tested using the χ 2 -test, or, in the case of 2 2 tables, Fisher s exact test. A continuous variable in two groups was compared using the Mann-Whitney test. Spearman s rank correlation coefficient was used to test for an association between two continuous variables. All p-values are from two-sided tests, with 2p < 0.05 considered being statistically significant. Figure 1. Incidence of six types of early treatment-related morbidity as a function of treatment schedule. The schedules are identified in Table 1. Abbildung 1. Inzidenz von sechs Arten von Frühnebenwirkungen in Abhängigkeit vom Behandlungsschema. Die verschiedenen Behandlungsschema sind in Tabelle 1 beschrieben. Results Treatment-Related Early Morbidity The proportion of patients who developed clinically significant toxicity in various tissues are shown in Figure 1. Three 392 Strahlenther Onkol 2003 No. 6 Urban & Vogel

4 centers, Zurich, Vaud and Geneva, had RT-alone patients as controls and the proportion of these with toxicity were estimated for each center. In Zurich (2p = ) and Geneva (2p = 0.02), the rate of hospitalization for hydration, nutritional and supportive care was significantly higher in the RT + CT groups. In Vaud, where induction CT was used, there was no statistically significant difference. Also, nonoral alimentation was required more often after RT + CT than after RT alone in Zurich (2p < ) and Geneva (2p = ), whereas the difference was not significant in Vaud (2p = 0.22). The difference between the two schedules used in Geneva was not significant (2p = 0.28). The proportion of patients with grade 3 4 mucositis were significantly higher after RT + CT than after RT alone in Vaud (2p = 0.011) and Geneva (2p = ) but not in Zurich (2p = 0.15). The distribution of maximum grades of dysphagia was shifted toward significantly higher values after RT + CT than after RT alone in Zurich (2p = ) and Geneva (2p = 0.011) but not in Vaud (2p = 0.71). Again, the difference between GE-con and GE-neo was not significant (2p = 0.15). Salivary problems were more severe after RT + CT than after RT in Zurich (2p = 0.014) but once again not in Vaud (2p = 0.22) and not in Geneva (2p = 0.13). Grade 3 skin toxicity was relatively rare, except in the RT + CT groups in Geneva. In none of the three studies including RT control patients did the difference in skin toxicity reach statistical significance. Table 3. Weight loss versus treatment schedule. Abbreviations see Tables 1 and 2. Tabelle 3. Gewichtsverlust je nach Behandlungsschema. Abkürzungen s. Tabellen 1 und 2. Weight loss RT BS ZH GE-con GE-neo VD alone a Number of patients < 10% % 82% 63% 65% 93% 65% 10% % 18% 38% 35% 7% 35% Average loss (kg) b 4.1 ± ± ± ± ± ± 0.7 2p c a no significant difference among centers in patients receiving RT alone (p = 0.26) b ±1 standard error of the mean c two-tailed p-value for rejecting the hypothesis that the median weight loss after RT + CT is the same as after RT alone Weight Loss during Treatment Weight loss during RT was given additional attention as this was felt to be an easily quantifiable endpoint. Table 4 shows the proportion of patients who lost > 10% of their body weight at the start of RT. This proportion varied from just < 10% after RT alone to more than a third of the patients treated with the ZH, GE-con and VD schedules. Average weight loss was around 7 kg after these three schedules compared with 4.1 kg after RT alone. These differences were very highly significant in case of the ZH and VD schedules and just significant in case of GE-con (Table 3). If instead the significance test had been based on RT controls within each center, the two-tailed p-values become , 0.11, and for the ZH, GE-con and VD schedules, respectively. There was no strong correlation between weight loss after RT + CT and patient-related factors or toxicity scores on the EORTC/RTOG scale if the analysis was restricted to oropharyngeal carcinoma (the most frequent subsite within the head and neck in this material, n = 104). Only age came close: the correlation coefficient was for weight loss versus increasing age (2p = 0.08, 95% confidence limits on the correlation coefficient 0.02 and 0.35). For mucositis and dysphagia, the correlation coefficients were estimated at 0.10 and 0.02, respectively. The upper 95% confidence limit on the correlation coefficient was 0.29 for maximum grade of mucositis and 0.21 for maximum grade of dysphagia. There was no significant correlation between age and mucositis or dysphagia. Performance status got worse with increasing age with a correlation coefficient of 0.30 (2p = 0.002). Delayed Healing of Early Morbidity A 12-week follow-up was available in 49 of 217 patients (23%) in the RT group and 31 of 182 patients (17%) in the RT + CT group. These follow-ups were planned according to institutional practice or individual arrangement. Table 4 shows the prevalence of grade 2 early reactions at 12 weeks in the two groups. There was a highly significant increase in the prevalence of mucosal reactions and dryness of the mouth in the RT + CT compared with the RT group. A similar trend was seen for dysphagia, whereas laryngeal and cutaneous reactions were not statistically significantly different in the two groups. In order to test whether patients with a 12-week follow-up were representative for the whole population, we compared the disease status and the maximum grade and the score at week 5 of early toxicity in patients who were (80 patients) or Table 4. Prevalence of early reactions (RTOG grade 2) at week 12. Abbrevations see Table 2. Tabelle 4. Prävalenz der akuten Nebenwirkungen (RTOG-Grad 2) Woche 12. Abkürzungen s. Tabelle 2. RT + CT RT p-value Larynx 8/29 (27%) 10/49 (20%) 0.58 Mucosa 9/31 (29%) 2/49 (4%) Salivary gland 19/31 (61%) 9/49 (18%) Dysphagia 9/31 (29%) 6/49 (12%) 0.08 Skin 4/31 (13%) 4/49 (8%) 0.7 Strahlenther Onkol 2003 No. 6 Urban & Vogel 393

5 were not (311 patients) seen at week 12. Not surprisingly, patients seen at week 12 tended to have less advanced disease than those who were not. In terms of early toxicity, there was no general trend; patients seen at week 12 had early reactions at week 5 that were comparable to the reactions seen at that time in patients who did not have a follow-up at week 12. Toxic Deaths There were nine deaths probably related to treatment toxicity, four of these had RT + CT and five had RT alone. Zurich and Basel reported one toxic death each, both receiving RT + CT. In Zurich, one patient died of malnutrition, refusing supportive care. In Basel, one patient died of unclear reasons. Vaud had two toxic deaths, one after RT and the other after RT + CT. Geneva had one toxic death after RT + CT and four after RT alone. One patient died of malnutrition, refusing supportive care; one malnourished died from candida septicemia; one patient died from pneumonia as a consequence of a severe laryngeal edema; one patient died from a massive oropharyngeal hemorrage in a setting of post-chemotherapy thrombopenia. Another patient died of unclear reasons. These patients died during the 3 months following RT. Unplanned Gaps Early toxicity might potentially affect treatment compliance, especially with respect to prescribed overall treatment time and treatment discontinuation [21]. Among all patients, 14 did not complete the planned therapy, yielding an overall compliance of 93.5%. Except for BS, where a treatment-free interval of 12 days was planned, 71 patients had a gap during their treatment. Table 5 presents treatment time and treatment gaps for the four studies. GE and VD showed a significantly higher rate of RT gaps in the RT + CT groups. Mean gap length was significantly longer in the RT + CT than in the RT group in the GE study. GE and VD showed a significantly longer overall treatment time (RT + CT) due to the use of induction CT. Discussion Depending of the dose of CT and radiation schedules, the early toxicity of RT + CT is often severe [1, 2, 8, 10, 14, 21]. However, as pointed out by Trotti [20], early toxicity is poorly documented in many studies. The present study was undertaken to focus attention on a number of the toxicity items that are clinically relevant when considering the effects of combined RT + CT. The four studies analyzed here leave little doubt that early toxicity is enhanced after RT + CT relative to the same schedule of RT alone. This is true both in the case of morphologic endpoints like the pattern of mucositis, as well as functional endpoints like dysphagia, weight loss and the need Table 5. Gaps and overall treatment time. Abbreviations see Tables 1 and 2. Tabelle 5. Unterbrechungen und Gesamtbehandlungsdauer. Abkürzungen s. Tabellen 1 und 2. Proportion of Mean gap duration Mean RT Mean overall patients with RT gaps (days) duration (days) time of (scheduled gap RT + CT included) (days) RT CT + RT RT CT + RT RT CT + RT BS 86% ZH 13% 13% GE 1% 8% VD 9% 33% to hospitalize the patient for supportive care. The prevalence of grade 3 skin reactions was generally low, but showed a trend toward being more pronounced in the RT + CT groups. A particular concern is the observation that 29% of the patients had grade 2 mucosal reactions at week 12 after RT + CT as compared with just 4% after RT alone. It remains to be seen whether some of these patients will develop consequential late reactions [15 17]. It was not the aim of this study to compare the relative merits of the different treatment schedules analyzed here. Such a comparison would have required a more standardized scoring of morbidity between the centers. However, the general impression is that concurrent chemoradiation was associated with more pronounced early morbidity than sequential administration of the two modalities. Yet, it is also clear, that induction CT leads to very long overall treatment times from the first cytotoxic insult until the end of active primary therapy. It is not clear whether this is associated with a loss of therapeutic efficacy due to accelerated repopulation of tumor cells. However, there is strong clinical evidence that protracting RT leads to a loss of locoregional control, and experimental studies seem to indicate that the same is the case after cytotoxic drug therapy [9]. Evidence-based medical care is largely based on the outcome of randomized controlled trials [5, 7]. However, we believe that useful knowledge can be derived from nonrandomized studies. Studies of treatment-related morbidity have largely been nonrandomized [6], and one may argue that estimates of the prevalence of morbidity are less prone to the selection bias that affects most comparisons of efficacy of various treatments. Early morbidity is often relatively well documented in the patient s case notes. The patients are often followed in a standard schedule during therapy and adverse events are scored using an established scoring system. Also late treatment-related morbidity can be subject to nonrandomized studies [12 14]. However, the prerequisite is that standardized, structured follow-up is actually performed. This may require a prospectively planned retrospective study. In the present database, the quality of late morbidity data was too poor to allow any meaningful analysis to be carried out. Only one of the studies analyzed here, namely Basel, followed 394 Strahlenther Onkol 2003 No. 6 Urban & Vogel

6 a formal phase II protocol. Obviously, the experience from the introduction of new or modified treatments would be much more valuable if a formal prospective protocol were followed. Conclusion The incidence of multiple early morbidity signs and symptoms was significantly higher after combined RT + CT than after RT alone. References 1. Allal AS, Bieri S, Miralbell R, et al. Combined concomitant boost radiotherapy and chemotherapy in stage III IV head and neck carcinomas: a comparison of toxicity and treatment results with those observed after radiotherapy alone. Ann Oncol 1997;8: Allal AS, Miralbell R, Pipard G, et al. Early and long-term results of an original accelerated radiation therapy schedule in head and neck carcinoma. Acta Oncol 1997;36: Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study J Clin Oncol 1998;16: Baumann M, Klages HT. Comparison of various fractionation schedules in curative radiotherapy alone of locally advanced head and neck tumors. Strahlenther Onkol 2001;177: Bentzen SM. Towards evidence based radiation oncology: improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. Radiother Oncol 1998;46: Bentzen SM, Overgaard J. Clinical normal-tissue radiobiology. In: Tobias JS, Thomas PRM, eds. Current radiation oncology. London: Arnold, 1996: Bentzen SM, Saunders MI, Dische S, et al. Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001;60: 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 1998;338: Coppin C. The description of chemotherapy delivery: options and pitfalls. Semin Oncol 1987;14: Dobrowsky W, Naude J. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers (1). Radiother Oncol 2000;57: Glicksman AS, Wanebo HJ, Slotman G, et al. Concurrent platinum-based chemotherapy and hyperfractionated radiotherapy with late intensification in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1997; 39: Harari PM. Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 1997;15: Huguenin P, Glanzmann C, Taussky D, et al. Hyperfractionated radiotherapy and simultaneous cisplatin for stage-iii and -IV carcinomas of the head and neck. Long-term results including functional outcome. Strahlenther Onkol 1998;174: Leyvraz S, Pasche P, Bauer J, et al. Rapidly alternating chemotherapy and hyperfractionated radiotherapy in the management of locally advanced head and neck carcinoma: four-year results of a phase I/II study. J Clin Oncol 1994;12: Maciejewski B, Skladowski K, Pilecki B, et al. Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity. Radiother Oncol 1996; 40: 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 1992;327: Peters LJ, Ang KK, Thames HD. Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies. Acta Oncol 1988;27: Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three metaanalyses of updated individual data. MACH-NC Collaborative Group. Meta- Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355: Tobias JS. Chemotherapy-radiotherapy combinations for advanced head and neck cancer. In: Tobias JS, Thomas PRM, eds. Current radiation oncology, vol 1. London: Arnold: 1994: Trotti A. Toxicity in head and neck cancer: a review of trends and issues. Int J Radiat Oncol Biol Phys 2000;47: Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16: Address for Correspondence Dr. Sabine Bieri Service de radio-oncologie Hôpital de Sion-Hérens-Conthey 1951 Sion Switzerland Phone (+41/27) , Fax sabine.bieri@chr.ch Strahlenther Onkol 2003 No. 6 Urban & Vogel 395