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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3540-3548 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.076 Radiation Therapy With or Without Concurrent Low-Dose Daily Chemotherapy in Locally Advanced, Nonmetastatic Squamous Cell Carcinoma of the Head and NeckFrom the Departments of Oncology and Head and Neck Surgery, University Hospital, Kragujevac, Serbia Address reprint requests to Branislav Jeremic, MD, PhD, Applied Radiation Biology and Radiotherapy Section, Division of Human Health, Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Wagramer Strasse 5, P.O. Box 100, A-1400 Vienna, Austria; e-mail: b.jeremic{at}iaea.org
PURPOSE: To retrospectively investigate the difference between conventionally fractionated (CF) and hyperfractionated (Hfx) radiation therapy (RT), with and without either daily cisplatin (CDDP) or carboplatin (CBDCA), in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) enrolled onto two consecutive prospective randomized studies. PATIENTS AND METHODS: Treatment consisted of CF RT (70 Gy, group 1), CF RT and either daily CDDP (6 mg/m2) or daily CBDCA (25 mg/m2; group 2), Hfx RT (77 Gy, 1.1 Gy bid; group 3), or Hfx RT and daily CDDP (group 4). RESULTS: Hfx RT plus CDDP achieved better overall survival (OS) and local recurrence-free survival (LRFS) than any other group. There was an insignificant difference favoring Hfx RT over CF RT, either alone or in combination with CDDP or CBDCA, regarding both OS (P = .058 and P = .051, respectively) and LRFS (P = .088 and P = .091, respectively). No difference was seen between CF RT plus chemotherapy (CHT) and Hfx RT alone regarding either OS (P = .32) or LRFS (P = .48). Regional recurrence-free survival was similar in the four treatment groups. CF RT plus CHT and Hfx RT plus CDDP achieved better distant metastasis-free survival than CF RT and Hfx RT. High-grade toxicity was significantly more frequent in Hfx RT plus CDDP than in any other group, except in the Hfx RT group. Hfx RT led to significantly more acute toxicity and xerostomia than CF RT plus CHT. Hfx RT was more toxic than CF RT, either alone or with concurrent CHT. CONCLUSION: Results of this study show that there may be a therapeutic benefit for CF RT plus CHT over Hfx RT plus CDDP in patients with SCCHN, but this cannot be firmly established without a larger and well-planned controlled trial.
To overcome generally poor locoregional tumor control obtained with either surgery or radiation therapy (RT)1 in locally advanced (stages III and IV), nonmetastatic (M0), squamous cell carcinoma of the head and neck (SCCHN), altered fractionated regimens2-5 and combined RT and chemotherapy (CHT), with or without surgery,6-8 have been used. In the last several decades, several approaches in combined-modality treatment have been identified as feasible, particularly those using combined RT and CHT.9-13 Recent preliminary evidence that newer RT techniques14,15 and new drugs16 may further improve treatment outcome in this disease warrant identification of standard treatment regimens in this disease to be used in common clinical practice and also for future comparisons in randomized studies. Unfortunately, this task is almost impossible because of the extreme diversity of clinical studies published in the past regarding both RT (total doses and fractionation used)17-19 and CHT (choice of the drug or drugs and their timing relative to RT).9,10,20-27 As a consequence, no standard regimen was identified or even widely adopted worldwide, although several meta-analyses identified concurrent RT plus CHT as the most likely effective approach.28-31 In the most recent meta-analysis,31 no benefit was seen for either neoadjuvant (induction) or adjuvant CHT. Contrary to that, CHT administered concurrently with RT gave significant benefits, although heterogeneity of the results prohibited firm conclusions. Having a continuous interest in this disease, we have designed and performed two prospective randomized studies,9,10 both evaluating whether the addition of concurrent low-dose, daily, single-agent CHT would improve locoregional tumor control, ultimately leading to an improvement in overall survival (OS). The only difference was the type of RT administered. In the first study,9 we used conventionally fractionated (CF) RT, either alone or with low-dose cisplatin (CDDP) or carboplatin (CBDCA) administered daily during the RT course. These drugs were expected to influence locoregional tumor control. In the second study,10 the same treatment design was used (RT alone or with concurrent low-dose daily CDDP), but we used hyperfractionated (Hfx) RT, which originated from tendencies to apply altered fractionated regimens on the basis of prevailing radiobiologic premises at that time.32-34 It was expected that Hfx RT would enable successful dose escalation, while minimizing the effects on late-reacting tissues. Also, in the second study,10 we administered low-dose daily CDDP in between the two daily fractions, an approach we designed and applied in a number of other studies, including studies of non–small-cell lung cancer35-38 and small-cell lung cancer.39,40 This particular timing of the drug administration was based on the assumption that it would interfere with the cell repair process. Brief search of the literature and the trials used for the purpose of the meta-analyses and systematic reviews28-31 disclose that this was a unique treatment approach in the literature because of a particular administration and timing of CHT. The two studies in SCCHN enabled us to pool the data and to retrospectively investigate some important questions in the treatment of locally advanced (stages III and IV), nonmetastatic (M0) SCCHN.
During a 5  -year period (January 1988 to June 1993), two prospective randomized trials of patients with locally advanced, nonmetastatic (stages III and IV) SCCHN were performed at the University Hospital (Kragujevac, Serbia). Eligibility criteria in both studies included histologically confirmed, locally advanced, unresectable, nonmetastatic (stages III and IV; M0) SCCHN, Karnofsky performance status of  50%, age older than 18 years, adequate hematologic (WBC 4,000/µL and plateletes 100,000/µL), renal (serum creatinine < 1.5 mg/dL), and hepatic (serum bilirubin < 1.5 mg/dL) function, and no previous therapy. The tumor mass had to be measurable, and patients could not have any serious concomitant diseases or a history of any prior or concurrent cancer (except skin nonmelanoma), unless the patient had shown no evidence of disease for more than 5 years. Patients with tumors of nasal cavity and paranasal sinuses and those with salivary gland tumors were deemed ineligible for this study. For both studies, patients gave an informed consent. In the first study,9 patients were randomly assigned to receive either CF RT alone (group 1) or the same CF RT with concurrent low-dose daily CDDP (group 2) or CBDCA (group 3). RT was used with 6- to 10-MV photons from linear accelerators. The target volume included the primary tumor, the lymph nodes of the neck, and supraclavicular fossa. The tumor-bearing area received 70 Gy, and uninvolved neck and supraclavicular nodes received 45 Gy. Daily fractions of 1.8 to 2.0 Gy were used five times a week. The primary tumor and upper neck nodes were treated with two lateral opposed fields with 45 Gy in 5 weeks, after which reduced lateral fields were used to boost the primary and involved nodes to 70 Gy in 7 to 7.5 weeks. The uninvolved lower neck and supraclavicular nodes were treated with a single anterior field, starting 0.5 cm below the lateral fields and with a total dose of 45 Gy at 3 to 3.5 cm of depth in 5 weeks with an apical lung shield. CDDP was administered as intravenous (IV) bolus 30 minutes before the irradiation at a daily dose of 6 mg/m2 every day of the RT course. CBDCA was administered as IV bolus 45 to 60 minutes before the irradiation at a daily dose of 25 mg/m2 every day of the RT course. In the second study,10 patients were randomly assigned to receive either Hfx RT (group 1) or the same Hfx RT in combination with concurrent low-dose daily CDDP (group 2). Hfx RT was administered primarily with 6-MV photons from linear accelerators, and only 13 patients (group 1, n = 6; group 2, n = 7) were treated with 10-MV photons. The same target volumes in the first study were used. Two daily fractions of 1.1 Gy were used with an interfraction interval of 4.5 to 6 hours. The same treatment field design as in the first study was used to deliver an initial 50.6 Gy in 46 fractions in 23 treatment days over 4.5 weeks, followed by the boost to the primary and involved nodes to 77 Gy in 70 fractions in 35 treatment days over 7 weeks. The dose to the spinal cord was kept at 50.6 Gy. The uninvolved lower neck and supraclavicular nodes were treated with a total dose of 50.6 Gy at 3 to 3.5 cm of depth in 4.5 weeks using the same twice-a-day fractionation. Interfraction intervals of 4.5 to 5 hours or 5.5 to 6 hours were nonrandomly assigned to each patient, and under no circumstances was it allowed to be changed from the shorter interval to the longer interval and vice versa. Patients were equally distributed between the two treatment groups. CDDP was administered as IV bolus 3 to 4 hours after the first daily fraction (ie, 1 to 2 hours before the second fraction) at a dose of 6 mg/m2 on every treatment day of the Hfx RT course.
In case of acute high-grade ( For the purpose of this analysis, groups 2 and 3 in the first study9 were combined into a single group because of the identical nature of intervention (the only difference was administration of either CDDP or CBDCA), as well as the fact that there was no difference in any of the end points (outcome or toxicity) used throughout that study.9 After this intervention, as a summary, in the current study, group 1 was CF RT, group 2 was CF RT plus CHT, group 3 was Hfx RT, and group 4 was Hfx RT plus CDDP.
End points chosen for this study included OS, local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), and acute and late high-grade (
During these two prospective randomized studies,9,10 a total of 289 patients were enrolled, randomized, and subsequently treated with RT with or without CHT. The median follow-up for all patients in the first study9 was 12.5 months (range, 1 to 73 months); whereas in the second study,10 it was 34 months (range, 4 to 91 months). The median follow-up for the living patients in the first study9 was 55 months (range, 1 to 73 months); whereas in the second study,10 it was 79 months (range, 63 to 91 months). There was no difference between the four treatment groups regarding various pretreatment patient and tumor characteristics (Table 1). OS according to treatment group is given in Figure 1 and Table 2. CF RT alone was inferior to CF RT plus CHT (P = .003) and Hfx RT plus CDDP (P < .001), whereas Hfx RT plus CDDP appeared to be superior to all other groups but was only marginally superior to the CF RT plus CHT group (P = .051). Although CF RT plus CHT achieved better results than Hfx RT, the results did not significantly differ (P = .32). As shown before,10 Hfx RT plus CDDP was superior to Hfx RT alone (P = .007). Hfx RT alone achieved better results than CF RT alone, but the difference was only marginally insignificant (P = .058).
When LRFS was used as an end point, CF RT alone achieved inferior results to all other group results, whereas Hfx RT plus CDDP achieved superior results to all other group results (Fig 2, Table 3). There was no difference between CF RT plus CHT and Hfx RT alone (P = .48) Again, CF RT was inferior to Hfx RT, but the difference was only marginally insignificant (P = .088). The same was observed when CF RT plus CHT was compared with Hfx RT plus CDDP (P = .092). However, when RRFS was used as an end point (Fig 3, Table 4), no significant difference was found between the four treatment groups.
Finally, when DMFS was used as an end point (Fig 4, Table 5), the addition of low-dose, daily CHT had a more significant beneficial effect compared with RT alone (P = .001 for Hfx RT v Hfx RT plus CDDP, and P = .075 for the CF RT plus CHT v CF RT alone). Also, CF RT plus CHT was superior to Hfx RT (P = .001) and Hfx RT plus CDDP when compared with CF RT (P = .039). As expected, the CF RT and Hfx RT curves are not significantly different when either administered alone (P = .42) or combined with low-dose, daily CHT (P = .67).
Treatment-related acute high-grade ( grade 3) toxicity was evaluated next to provide additional data that might offer a better perspective for the observed difference between the four treatment groups (Table 6). There was no difference between CF RT alone and CF RT plus CHT and no difference between Hfx RT alone and Hfx RT plus CDDP regarding both stomatitis and esophagitis. With all other comparisons, it was observed that intensification of the treatment led to progressively higher incidence of acute high-grade toxicity, with the highest incidence observed in the Hfx RT plus CDDP group.
Treatment interruptions that were allowed to palliate acute toxicity during the treatment course occurred in two patients (4%) receiving CF RT (range, 4 to 7 days), in nine patients (8%) receiving CF RT plus CHT (range, 5 to 11 days), in six patients (9%) receiving Hfx RT (range, 6 to 14 days), and in seven patients (11%) receiving Hfx RT plus CDDP (range, 7 to 14 days). There was neither a significant difference across the four treatment groups (P = .57), nor a significant difference in any comparison of these treatment groups (data not shown). Regarding late high-grade toxicity (Table 7), patients treated with Hfx RT alone and with Hfx RT plus CDDP experienced a higher incidence of xerostomia than patients treated with CF RT alone and with CF RT plus CHT, but there was no significant difference between CF RT alone and CF RT plus CHT or Hfx RT alone and Hfx RT plus CDDP. Other late high-grade toxicities (subcutaneous, bone, and skin) were not observed with an increasing incidence in Hfx RT alone and Hfx RT plus CDDP, probably because of the small number of events observed; however, slightly more late high-grade skin toxicity was observed in Hfx RT plus CDDP, which was also the most effective treatment group.
Our two consecutive prospective randomized studies in stages III and IV (M0) SCCHN gave us an opportunity to evaluate the difference in the outcome and toxicity of two fractionation regimens with or without concurrent low-dose, daily CHT. Although one might criticize the small sample size, the homogenous patient cohorts, identical pre- and posttreatment evaluations, and follow-up are factors that strengthen our findings. Furthermore, these patients are those most often seen in the clinic; therefore, they are a good representation of our clinical practice. Results of our Hfx RT alone arm confirm the results of Hfx RT alone in the recent RTOG 9003 trial43 and the results of the EORTC 22791 trial.19 Indeed, RRFS, DMFS, and OS were similar between the RTOG 9003 study43 and our own study (2-year survivals: 72% v 67%; 83% v 89%; and 54.5% v 49%, respectively). The only striking difference was observed for LRFS (2-year LRFS: 62% in RTOG 9003 v 43% in our study), which, at least in a part, can be explained by more stage IV (M0) tumors observed in our study than in the RTOG 900343 (83% v 66%, respectively). The same holds true when comparison to EORTC 2279119 is made (5-year LRFS, 59%). However, the EORTC 22791 study included only oropharyngeal tumors and no N2 disease, and it used locoregional recurrence-free survival as an end point. Furthermore, the toxicity of the Hfx RT regimen in RTOG 9903,43 EORTC 22791,19 and our study was similar. Similar findings could be applied to the comparison of the CF RT regimen in our study and the RTOG 900343 study, as well as those in EORTC 2279119 and 2285144 (LRFS, 40% to 46% in the latter studies v 36% in our study). However, in the EORTC 22851 study,44 CF RT led to 5-year locoregional relapse-free survival of 46%, possibly because more N0-1 stages were observed in that study. CF RT regimens used in all these studies showed a similar incidence of toxicity, although RTOG 900343 experienced a somewhat higher incidence of acute high-grade toxicity. Our Hfx RT alone regimen offered only a nonsignificant benefit over that achieved with the CF RT alone regimen, although a strong trend favored Hfx RT. This was observed regarding both OS (P = .058) and LRFS (P = .088) when both CF RT and Hfx RT were given alone or combined with low-dose CHT (P = .051 and P = .091, respectively). Explanation for this may lie in the lack of numbers. Also, clinical EORTC data indicated a necessity of 15% higher total dose for the improvement in Hfx RT that they observed, whereas we have offered only a 10% increase in the Hfx RT dose. However, our shorter interfraction interval in Hfx RT alone may have favored a higher incidence of high-grade toxicity, as previously shown.45 When compared with the toxicity of CF RT alone, Hfx RT alone brought an increase in acute high-grade but not late high-grade toxicity. This may reflect a true sparing effect of the Hfx RT regimen, although small patient numbers and few late events observed may have obscured true results. Also, another clear disadvantage of our study is that late toxicity was presented as actual numbers and not actuarially. It is now a well-recognized fact that these toxicities should preferentially be scored prospectively on a prolonged basis, a good example being in the EORTC 2279119 and RTOG 9003 studies.43 It would be interesting to speculate about the marginally insignificant difference between CF RT and Hfx RT alone in terms of the dose per fraction used in the CF RT regimen. We allowed doses of 1.8 to 2.0 Gy per fraction for the CF RT regimen in the first study.9 It may be that the difference would have been significant if we had compared Hfx RT alone with CF RT alone when only 1.8 Gy was used because, presumably, more cell proliferation would occur during the extra time needed to execute the continuous RT course using 1.8 Gy per fraction, as was recently discussed.46 Small patient numbers in the CF group prevented us from making a meaningful analysis; it is a question for future studies. The most interesting finding of our study lies in the comparison of CF RT plus CHT and Hfx RT alone. Continuous observation during the current study indicated that CF RT plus CHT offered higher median times to event and both short- and long-term survival results (OS, LRFS, and RRFS), which, however, never reached statistical significance because of the lack of numbers. However, translated into the trade-off, it seems that low-dose daily CHT effectively compensated the –10% of the total dose used in CF RT alone and, furthermore, enabled more effective distant micrometastasis control, owing to the finding of better DMFS for that group, which was also similar to that achieved with Hfx RT plus CDDP. Finally, CF RT plus CHT led to significantly less acute high-grade stomatitis and esophagitis than Hfx RT, as well as less late high-grade xerostomia; other late toxicities were similar between the two groups. Therefore, the trade-off favored the addition of CHT to CF RT rather than using Hfx RT alone. Of additional importance is that more acute high-grade toxicity will inevitably lead to more treatment interruptions, which have been shown to have a profound adverse impact on treatment outcome in RT of this disease.47 In our study, intensification of treatment led to more acute high-grade toxicity, and consequently, more treatment interruptions were used to palliate these toxicities. Although there was no difference in the incidence of treatment interruptions for the four treatment groups, the approximate effect of treatment interruption on treatment outcome (given that, on average, 10 days of delay have happened, at least in all non–CF RT groups) would total 15% (assuming a relatively consistent finding of 1.5% reduction of LRFS per day over the years48-50) for the patients experiencing interruptions. However, this would have only minor impact on LRFS (approximately 0.3% for CF RT, 1.0% for CF RT plus CHT, 0.6% for Hfx RT, and 1.6% for Hfx RT plus CDDP), without changing the results. Taken together, these findings seem to favor CF RT and concurrent low-dose, daily CHT over Hfx RT alone, the former achieving a better therapeutic ratio. A similar trade-off was observed in the study of Brizel et al,12 in which 70 Gy of RT and concurrent CHT achieved better results than 75 Gy of RT alone; both RT regimens used the same twice-a-day scheme. Although improvement in LRFS in their study was significant (P = .01), in OS, it achieved only a strong trend (P = .07). Furthermore, the toxicity was not higher in their RT plus CHT group of patients. Another similar trade-off was observed in a German multi-institutional study that compared concurrent CHT and accelerated Hfx RT to 70.6 Gy with accelerated Hfx RT alone to 77.6 Gy.51 For concurrent CHT and accelerated Hfx RT compared with accelerated Hfx RT alone, the actuarial locoregional control (50.4% v 40.6%, respectively; P = .007) and OS rates (33.7% v 27.7%, respectively; P = .04) were significantly better. The median locoregional control and OS times were 49 versus 17 months and 23 versus 17 months, respectively. Although progression-free survival was also improved with concurrent CHT and accelerated Hfx RT (P = .02), no difference in the DMFS was seen (P = .91). Toxicity was similar in the two arms. Therefore, lowering total RT dose by approximately 10% with concurrent CHT offered a better therapeutic ratio when compared with RT alone to a higher dose using the same fractionation. Results on the regional level in our study mirror the results observed in the two original studies,9,10 with no difference between RT and RT plus CHT. The fact that primary tumors have a relatively greater benefit from accelerated fractionation than lymph nodes was already observed during accelerated RT studies.5,52 Our combined RT plus CHT regimens, regardless of fractionation pattern, should also be seen as a type of accelerated regimen because more intensive treatment was achieved with concurrent RT plus CHT, and it was indicated that concurrent CHT should be seen as a type of concomitant boost.46 No other rational explanation exists for the finding at the regional level, except that heterogeneity of tumor sites, tumor and node stages, and grades of differentiation altogether obscured possible differences that otherwise might have been observed. Small patient numbers and sometimes troublesome differentiation between true local and true regional failures, especially when occurring late in the treatment fields previously irradiated to a high-dose RT, should also be taken into consideration. The Hfx RT plus CDDP group achieved the best results at the expense of increased toxicity, both acute and late, confirming the findings of Browman et al.29 Although this may undermine further attempts for wider applicability of this approach, it should be remembered that high-dose RT regimens using high-dose CHT administered with more split lead to even more high-grade toxicity, both acute and late.53,54 In contrast to these studies, our low-dose daily CHT led to less toxicity, both acute and late, although it was higher than the toxicity observed in our CF RT and Hfx RT groups alone. That this type of concurrent RT plus CHT is less toxic and yet an effective treatment approach confirmed recent results obtained when continuous infusion of paclitaxel was administered during course of radical RT (70 Gy in 35 daily fractions).16 It was not only possible to produce the prolonged levels of paclitaxel indicated by in vitro studies as necessary for enhancement of RT response but also to enable the highest ever total cumulative doses of paclitaxel. It is expected that, with wider application of newer RT technologies,14,15 or with mucosal protectors, such as amifostine,55 or new and potent drugs,16,56,57 more effective treatment will be administered while acute (and likely consequential late) toxicity will be diminished and the therapeutic ratio further improved. However, without investigating formal quality of life, this would be hard to document clearly. Although one might criticize the retrospective nature of this study with all its associated caveats, such as stage migration from the first to second study, somewhat different follow-up, and small sample size, the homogenous patient cohorts and identical pre- and posttreatment evaluations are factors that strengthen our findings. Furthermore, these patients are those most often seen in clinic and, therefore, a good representation of our clinical practice. This study showed superior results of high-dose RT and concurrent CHT, confirming the results of the meta-analyses and systematic reviews.28-31 There was no significant difference between Hfx RT plus CDDP and CF RT plus CHT in the survival end points, although strong trends favored Hfx RT plus CDDP in OS and LRFS. However, these results were accompanied by significantly more acute and late high-grade toxicity with Hfx RT plus CDDP (except bone toxicity). This may imply a therapeutic benefit for CF RT plus CHT over Hfx RT plus CDDP, which cannot be firmly established outside a larger and well-planned controlled trial. CF RT plus CHT had similar activity to Hfx RT alone, but it had much less acute high-grade toxicity and xerostomia and, therefore, had a better therapeutic ratio. Finally, CF RT alone was the worst treatment option and should perhaps be considered less often for use in this disease, as already suggested.46 Thus, the results of our study may have an implication for the clinical practice and the design of clinical studies in this disease using RT (CF or Hfx) and CHT.
The authors indicated no potential conflicts of interest.
The authors thank Jack Fowler, PhD, and Paul Harari, MD, for their thoughtful comments and suggestions, which made the publication of this article possible.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Statistical analyses were carried out by one of the authors (B.M.) using the SPSS computer program (SPSS, Inc, Chicago, IL). Statistical tests were based on a two-sided significance level. Cutoff dates for this analysis were the dates each of the studies closed, before the results were analyzed and subsequently published. No update of follow-up was possible because the chief investigator in both studies (B.J.) left the institution in late 1998. 
