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© 2000 American Society for Clinical Oncology Hyperfractionated Radiation Therapy With or Without Concurrent Low-Dose Daily Cisplatin in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Prospective Randomized TrialFrom the Departments of Oncology, and Otorhynolaryngology, University Hospital, Kragujevac, Yugoslavia, and Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Address reprint requests to Branislav Jeremic, MD, PhD, Department of Radiotherapy, University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen, Germany; email bjeremic{at}med.uni-tuebingen.de
PURPOSE: To investigate whether the addition of cisplatin (CDDP) to hyperfractionation (Hfx) radiation therapy (RT) offers an advantage over the same Hfx RT given alone in locally advanced (stages III and IV) squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: One hundred thirty patients were randomized to receive either Hfx RT alone to a tumor dose of 77 Gy in 70 fractions in 35 treatment days over 7 weeks (group I, n = 65) or the same Hfx RT and concurrent low-dose (6 mg/m2) daily CDDP (group II, n = 65). RESULTS: Hfx RT/chemotherapy offered significantly higher survival rates than Hfx RT alone (68% v 49% at 2 years and 46% v 25% at 5 years; P = .0075). It also offered higher progression-free survival (46% v 25% at 5 years; P = .0068), higher locoregional progression-free survival (LRPFS) (50% v 36% at 5 years; P = .041), and higher distant metastasis-free survival (DMFS) (86% v 57% at 5 years; P = .0013). However, there was no difference between the two treatment groups in the incidence of either acute or late high-grade RT-induced toxicity. Hematologic high-grade toxicity was more frequent in group II patients. CONCLUSION: As compared with Hfx RT alone, Hfx RT and concurrent low-dose daily CDDP offered a survival advantage, as well as improved LRPFS and DMFS.
RADIATION THERAPY (RT) has been considered the standard treatment for locally advanced, unresectable squamous cell carcinoma of the head and neck (SCC H&N). However, with standard-fractionation RT using tumor doses of 60 to 75 Gy, response rates are relatively low and the majority of the patients die of locoregional disease. As a result, 2-year survival rates are less than 30%.1 To overcome the poor locoregional control rates, many approaches have been tested, such as altered fractionated regimens2-5 and combined RT and chemotherapy (CHT), with or without surgery.6-8 One of the former methods is hyperfractionation (Hfx), whose radiobiologic premises include differences in repair capacity between early-reacting normal tissues/tumors and late-reacting normal tissues, differences in "self-sensitization" between the tumors and late-reacting normal tissues, a less profound oxygen effect at lower doses, and inherent acceleration of the biologic tumor dose-rate.9-11 Hfx RT has been increasingly used in SCC H&N. Randomized studies that compared standard RT and Hfx RT obtained conflicting results. With an increase in severe complication in the Hfx arm, Marcial et al12 found no significant improvement in local control, which was not surprising with the total dose (60 Gy) used in this Radiation Therapy Oncology Group study. Datta et al13 found that 79.2 Gy via 1.2 Gy bid offered an advantage over standard-fractionation RT to a tumor dose of 66 Gy. A significant increase in 2-year disease-free survival from 33% to 63% was observed in the Hfx RT arm. A significant advantage for Hfx RT was also found by Sanchiz et al14 and Pinto et al.15 European Organization for Research and Treatment of Cancer study 2279116 clearly showed improved 5-year locoregional tumor control by Hfx RT (P = .02) and a trend (P = .08) toward an improved overall survival in T2/T3 oropharyngeal SCC. Another therapeutic option in locally advanced SCC H&N is the use of combined RT and CHT. The main rationale for this combination is that CHT would improve locoregional tumor control while offering a theoretical possibility of controlling distant metastases, with the likelihood of efficacy depending upon how drugs are given and in what combination and dose. While studies on the use of adjuvant17 and neoadjuvant CHT and RT18 failed to show a survival benefit of such treatment over surgery and/or RT alone, numerous studies using concurrent RT and CHT have shown promising results. Concurrent RT and CHT may be instituted in several ways, including bolus administration of CHT19 with or without adjuvant CHT,20 continuous-infusion CHT,8 and low-dose daily CHT during the RT course.21 Among the drugs used concurrently with RT, cisplatin (CDDP) has been frequently tested because its toxicities do not overlap with those of RT.19-21 Although the primary mechanisms of the RT/CDDP interaction are thought to be inhibition of potentially lethal damage repair,22 inhibition of sublethal damage repair, selective radiosensitization of hypoxic cells, and reduction of tumor burden leading to an improved blood supply, reoxygenation and redistribution toward a more sensitive cell-cycle phase may also play important roles in its action.23 It was shown that increased exposure to active platinum species occurs with its prolonged administration, such as continuous infusion (which may be regarded as the ultimate low-dose CHT) as opposed to bolus administration.24 Finally, laboratory data showed that the CDDP-enhanced RT effect is most profound when the drug is present in target cells at the moment of irradiation,25 especially when fractionated schedules are used.26 On the basis of these premises, we conducted a prospective randomized trial of Hfx RT with or without concurrent CHT in locally advanced (stages III and IV) nonmetastatic SCC H&N.
To be eligible for this study, adult patients (  18 years) had to have histologically confirmed, locally advanced, nonmetastatic (stages III or IV, M0) SCC of the nasopharynx, oropharynx, hypopharynx, oral cavity, or larynx, a Karnofsky performance status score 50%, adequate hematologic (leukocyte count 4,000/mm3 and platelet count 100,000/mm3), renal (serum creatinine level < 1.5 mg/dL), and hepatic (serum bilirubin level < 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 that of skin nonmelanoma), unless the patient had shown no evidence of disease for more than 5 years. Patients with tumors of the nasal cavity and paranasal sinuses and those with salivary gland tumors were deemed ineligible for this study. The initial examination included a medical history, a physical examination with special emphasis on the head and neck region, endoscopy, a complete blood count with differentials, a biochemical analysis, an electrocardiogram, chest x-rays, an abdominal ultrasound, a bone scan, and a computed tomography scan of the head and neck. Patients were randomized to receive either Hfx RT (group I) or the same Hfx RT regimen in combination with concurrent low-dose daily CDDP (group II). Hfx RT was given mostly with 6-MV photons from linear accelerators; only 13 patients (group I, six patients; group II, seven patients) were treated with 10-MV photons. The target volume included the primary tumor and the lymph nodes of the neck and supraclavicular fossa. Two daily fractions of 1.1 Gy were used with aninterfraction interval of 4.5 to 6 hours. The primary tumor and upper neck nodes were treated with two lateral opposed fields with 50.6 Gy in 46 fractions in 23 treatment days over 4.5 weeks, after which reduced lateral fields were used to boost the dose to the primary tumor 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 single anterior field, starting 0.5 cm below the lateral fields, and with a total dose of 50.6 Gy at a 3- to 3.5-cm depth in 4.5 weeks using the same fractionation and apical lung shield. A 0.5-cm gap was applied uniformly to all patients. This was enough to avoid a hot spot in the spinal cord but not too much to cause cold spots in the tumor. All fields were treated every day. 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 change from the shorter interval to the longer interval and vice versa.
CDDP was administered as an intravenous 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 ( Patients were examined at the end of treatment, every month for 6 months after the completion of the treatment, every 2 months for 2 years thereafter, and every 4 months thereafter. Complete blood counts (with differentials), biochemical analyses, endoscopy, chest radiographs, and abdominal ultrasounds were performed at each visit. Bone scans were performed at 3- to 6-months intervals. Restaging at the time of any disease progression was performed with the procedures mentioned above together with a head and neck computed tomography scan. Toxicities were mostly evaluated using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria.27 Late toxicity was defined as that persisting after 90 days from the beginning of RT or appearing after 90 days from the beginning of RT. Toxicities attributed to CHT were assessed using World Health Organization criteria.28 End points of this study were survival and complete response rates. Differences between pairs of groups in complete response rates and incidence of toxicity were evaluated using the Fisher’s exact test. Survival and progression-free survival rates were calculated from the start of treatment with the Kaplan-Meier method, and the differences between pairs of groups in survival curves were examined using the log-rank test. In calculating locoregional progression-free survival (LRPFS) and distant metastasis-free survival (DMFS) rates, patients who developed either type of failure were considered at risk for the other end point and censored at the time of the last evaluation. All of these statistical analyses were conducted by one of the authors (Y.S.) using the Halwin computer program (Gendaisuugakusha, Kyoto, Japan). Statistical tests were based on a two-sided significance level. A total of 128 patients in the two treatment groups were thought to be required to detect a difference in the 2-year survival rate of 25% with a significance level of P < .05 and a power of 0.829 assuming a baseline survival rate of 45%.3
Between January 1991 and March 1993, a total of 154 patients were evaluated for enrollment onto this trial, and 130 patients were randomized into the two treatment groups and treated thereafter at the Department of Oncology, University Hospital, Kragujevac, Yugoslavia. All patients were from Yugoslavia. They were all assessable for toxicity, response, and survival, and no patient was lost to follow-up. Pretreatment patient characteristics are listed in Table 1. There was no difference in these characteristics between the two treatment groups. The median follow-up period for the living patients was 79 months.
The complete response rate was significantly in favor Hfx RT/CHT when compared with Hfx RT alone (49 of 65 v 31 of 65; P = .002). Patients treated with Hfx RT/CHT had significantly higher survival rates than those treated with Hfx RT alone (68% v 49% at 2 years and 46% v 25% at 5 years; P = .0075) (Fig 1). Progression-free survival was also significantly better in the Hfx RT/CDDP group (5-year PFS, 46% v 25%; P = .0068) (Fig 2). There were also higher LRPFS rates in patients treated with combined Hfx RT/CHT and the difference was significant (5-year LRPFS, 50% v 36%; P = .041) (Fig 3). Patients treated with Hfx RT/CHT had higher 5-year DMFS rates than those treated with Hfx RT alone (86% v 57%; P = .0013) (Fig 4).
The numbers of locoregional recurrences and distant metastases were 41 and 16, respectively, in group I and 32 and 5, respectively, in group II. Locoregional failures were the initial failure in 41 patients in group I and in 31 patients in group II, whereas distant metastases were the initial failure in eight patients in group I and in four patients in group II. Locoregional tumor progression was the cause of death in 37 and 30 patients in treatment groups I and II, respectively. Distant metastasis was the cause of death in 12 and five patients in groups I and II, respectively; death from intercurrent disease was observed in two and three patients in the two treatment groups.
Acute high-grade (
In European Organization for Research and Treatment of Cancer study 22791, Horiot et al16 confirmed previous observations13-15 that Hfx RT improves locoregional tumor control when compared with standard RT. Consistently, more acute reactions (mostly mucositis) and their earlier onset were reported for Hfx RT. Contrary to that, no significant increase in the late complication rate was found with the Hfx RT regimens. This was confirmed by the current study, in which patients treated with Hfx RT achieved a 5-year survival rate of 25%. However, 40% and 18% of the patients experienced high-grade stomatitis and esophagitis, respectively, and high-grade xerostomia was observed in 16%. The addition of concurrent low-dose daily CDDP did not cause a significant increase in these RT-induced toxicities, and it caused a significant increase only in high-grade leukopenia; the increase in high-grade thrombocytopenia was marginally insignificant. Furthermore, treatment interruptions because of toxicity, frequencies of weight loss of 10% during Hfx RT, and/or frequencies of hospitalization needed to manage acute toxicity were not different between the two treatment groups. Also, there was no difference in the incidence of late high-grade toxicity. Finally, the toxicities we encountered during our previous randomized study,21 in which one arm of concurrent RT (70 Gy) and CHT used the same daily dose of CDDP (ie, 6 mg/m2), were consistent with those observed during this study in the Hfx RT/CHT arm. Although CDDP-induced toxicities cannot be ignored, with this schedule of its administration they are predictable and are not troublesome, if appropriately managed. As in our former study, we tried to build on laboratory observations that this type of concurrent RT/CHT may have an impact on the local/regional level, not expecting that low-dose daily CHT has a direct influence on the distant level. Indeed, similar to our previous study, the addition of low-dose daily CDDP in this study led to improved survival over that obtained with Hfx RT alone (5-year survival, 46% v 25%; P = .0075). This improvement was achieved owing to the improvement in LRPFS (5-year LRPFS, 50% v 36%; P = .041), confirming again that the profound radiosensitizing effect of CHT may be obtained when it is administered concurrently with RT at a low-dose daily rate.21,30-32 This is in accordance with recent pharmacokinetic observations that increased exposure to the active CHT species occurs when continuous-infusion CHT (which may be regarded as an ultimate form of low-dose daily CHT), as opposed to bolus administration of CHT, is used.24 This observation was already confirmed in our previous randomized study, which enabled administration of high total cumulative CDDP doses (210 to 235 mg/m2), similar to that obtained in this study (210 mg/m2). As we have successfully shown before,21 the rigid criteria of not allowing either Hfx RT or CHT dose reductions but allowing temporary interruptions in the treatment allowed us to achieve a high total cumulative dose of CDDP in all our patients (100% compliance rate). This was achieved owing to the schedule of CDDP administration, although some factors, such as short interfraction intervals, may have had an unfavorable impact. An unexpected finding, possibly of major importance, was the increase in DMFS observed when low-dose daily CDDP was added to high-dose Hfx RT (5-year DMFS, 86% v 57%; P = .0013). This was especially so because this study design exclusively addressed the issue of local/regional tumor control and not the distant tumor control. Studies that used a few (mostly two to three) cycles of high-dose CDDP-based CHT according to the original RTOG 81-17 study19 mostly reported an improvement at the local/regional level but not at the distant level, showing unequivocally that the type of attempt to control distant metastasis still needs refinement.33,34 This leads us back to the well-known issue in head and neck oncology that local/regional tumor control dominates the outcome in this patient population, and with improvement in local/regional tumor control, improvement in survival is achievable, as extensively discussed over the last two decades by Herman Suit, MD.35-37 Results of the current study confirmed this premise as well as another one, that improved locoregional tumor control may lead to an improvement in distant metastasis control,38 since it is less likely that this type of CHT may have a direct effect on DMFS. This may be explained by the time sequence of the events seen in the Figs 3 and 4. While a significant difference in LRPFS was achieved at 8 months, a significant level of difference in DMFS was achieved at 17 months. It may be possible that significantly better locoregional control of tumors in group II (Hfx RT/CDDP) made them less prone to disseminate. Contrary to that, the pronounced effect on DMFS may have been achieved exclusively (or mostly) by eradicating micrometastases present from the outset. Finally, a third possibility exists, which is that an effect on DMFS is actually a combination of the aforementioned two possibilities. Whichever one of these hypotheses is true remains to be investigated in future clinical studies. With increasing evidence that altered-fractionation regimens offer an advantage over standard-fractionation RT,14-16 a number of studies used altered-fractionation regimens concurrently with CHT, adding new evidence that RT/CHT offers an advantage over RT alone. Sailer et al39 reported on a trial of accelerated Hfx RT (74 Gy via 1.5 Gy bid, given with two gaps) alone or concurrent with two cycles of fluorouracil/CDDP. RT/CHT significantly prolonged both overall survival and disease-free survival. Wendt et al40 reported on accelerated Hfx split-course RT given concurrent with three cycles of CDDP, fluorouracil, and leucovorin. Three cycles of RT (each 23.4 Gy via 1.8 Gy bid) were given with a 10-day gap between the cycles, for a total dose of 70.2 Gy in 51 days. An advantage for RT/CHT over the same RT given alone was observed in both local control (34% v 17%) and overall survival (48% v 24%). A randomized study from Duke University compared continuous-course accelerated Hfx RT to a dose of 74 Gy given via 1.25 Gy bid in 42 days with split-course accelerated Hfx RT with two cycles of concurrent CDDP/fluorouracil. The total RT dose of 70.5 Gy in the control arm was delivered with the same fraction size in 47 days, but with a 7- to 10-day gap after 40 Gy. The 4-year locoregional control rate was significantly better in the RT/CHT arm (70% v 44%; P = .01), but this did not translate into an improvement in disease-free survival (61% v 41%; P = .08) or overall survival (55% v 34%; P = .07).41 Also, Huguenin et al42 treated 64 patients with stage III/IV SCC H&N, excluding that of the nasopharynx, with a total RT dose of 74.4 Gy via 1.2 Gy bid and concurrent CDDP (20 mg/m2 daily for 5 days at weeks 1 and 5). Overall survival was 37% at 5 years, and disease-free survival was 59%. Local control without salvage surgery was 74% at 5 years and locoregional disease-free survival was 72%. In order to further increase therapeutic benefit, other CHT agents such as fluorouracil may be added, preferably by prolonged continuous infusion. It was shown that this mode of administration may enable high fluorouracil systemic exposure, which in turn may lead to better tumor response and survival,43 although the addition of fluorouracil to RT may cause a sharp increase in acute toxicity, especially mucositis. Also, a targeted supradose of CHT (eg, CDDP), achievable by intra-arterial administration, may enable high response rates and high locoregional tumor control, not just in patients at early stages but in those with advanced tumor stages too.44 Finally, salvage surgery may be offered to patients with a partial response, because it has been shown to offer an increase in complete and overall response rates.6,34 Unfortunately, as in our previous study, we did not offer it and this is a clear disadvantage of the current study. This study showed an improvement in survival when concurrent low-dose daily CDDP was added to the high-dose Hfx RT regimen to achieve local (primary) tumor control. An unexpected finding of this study was an improvement in DMFS, which seems to be a consequence of improved LRPFS in light of the time sequence of these events. However, more patients and new studies are needed before any definite conclusions can be made about the utility of CDDP/Hfx RT in clinical practice.
Supported in part by Grants-in-Aid for Scientific Research (B) 10557087, 11470190, and 11877152 from the Japanese Ministry of Education, Science, and Culture.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
