Originally published as JCO Early Release 10.1200/JCO.2004.12.193 on November 8 2004

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Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced Head and Neck Cancers Treated With Hyperfractionated Radiotherapy

From the Departments of Radiation Oncology, Medical Oncology, and Head and Neck Surgery, University Hospital Zürich, Zürich; University Hospital Berne; SIAK Coordinating Center, Berne; University Hospital Geneva, Geneva; University Hospital Lausanne, Lausanne; Ospedale San Giovanni, Bellinzona; Kantonsspital St Gallen, St Gallen; Kantonsspital Basel, Basel; Kantonsspital Winterthur, Winterthur; Kantonsspital Luzern, Luzern; Hôpital Cantonal de Sion; Kantonsspital Aarau, Aarau; Stadtspital Triemli, Zurich; and the Radiotherapy Quality Assurance Working Party, Switzerland.

Address reprint requests to Pia Huguenin, MD, Radiation Oncology, University Hospital Zurich, 8091 Zurich, Switzerland; e-mail: pia.huguenin{at}usz.ch

	ABSTRACT

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PURPOSE: To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone.

PATIENTS AND METHODS: From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m² on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity.

RESULTS: There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease–free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups.

CONCLUSION: The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.

	INTRODUCTION

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Squamous cell carcinomas of the head and neck (HNSCC) are the most common type of malignancies of the upper aerodigestive tract; they represent 5.3% and 1.2% of new malignancies in male and female Swiss residents,¹ respectively. Patients with resectable HNSCC can be treated with surgery, with radiotherapy, or with a combination of both. The best choice depends on several factors, including the extension and location of the tumor, the comorbidity, and the desires of the patient. For patients with unresectable tumors, radiotherapy represents the only chance of cure.

During the last 10 years, numerous studies have tested ways to increase the rate of locoregional control and survival in patients with HNSCC, and two ways seemed most promising: the use of altered fractionation and the combination of radiotherapy with chemotherapy.

Compared with conventional fractionation using 2 Gy per day and five fractions per week, application of altered fractionation, especially hyperfractionated or accelerated radiotherapy with concomitant boost, has increased locoregional tumor control^2-4 and survival⁴ in patients with HNSCC during the last 15 years. A second important change in treatment of these patients during the same period has been the implementation of chemotherapy in addition to radiotherapy. Because of large variability in the combination of the two modalities, a clear advantage of combined treatment was demonstrated only recently,^5,6 particularly for concurrent application of cisplatin-containing regimens. However, the most effective combination of radiotherapy and chemotherapy with acceptable toxicity remains to be defined.

Intensive cytotoxic combination chemotherapy plus simultaneous radiotherapy increases locoregional control while reducing the risk of distant metastatic disease.⁷ However, given the toxicity of chemotherapeutic compounds and the considerable comorbidity of patients with HNSSC, combinations of multidrug chemotherapy and radiotherapy require alternating application or treatment interruptions, and/or dose reductions, of both modalities.⁷ Mucositis is the major dose-limiting acute toxicity of concomitant chemotherapy and radiotherapy.⁸ However, single-agent chemotherapy incorporating cisplatin in moderate doses as a radiosensitizer has no effect on mucous membranes in combination with standard fractionation radiotherapy, as demonstrated by the Radiation Therapy Oncology Group.⁹ Several pilot studies have demonstrated favorable adverse effect profiles of cisplatin administered by various schedules in combination with hyperfractionated^10,11 or accelerated radiotherapy. ¹² On the basis of additional favorable results of a phase II trial performed in 64 patients with advanced HNSCC,¹³ the Swiss Group for Clinical Cancer Research (SAKK) has conducted a randomized trial comparing hyperfractionated radiotherapy alone with a combination of hyperfractionated radiotherapy and moderate-dose cisplatin. In this investigation we sought to determine whether two courses of cisplatin administered simultaneously with hyperfractionated radiotherapy are superior to radiotherapy alone in achieving tumor control in locally advanced and/or node-positive nonmetastatic HNSCC.

	PATIENTS AND METHODS

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Eligibility Criteria
All eligible patients had invasive squamous cell carcinoma of the oral cavity, oro- or hypopharynx, or larynx, at clinical stages summarized in Table 1. Tumors were classified according to the tumor-node-metastasis staging system (International Union Against Cancer, edition 4, 1987). Participants ranged in age from 20 to 75 years, and demonstrated WHO performance status 2. Those with primary tumor sites in the nasopharynx or paranasal sinuses were excluded from the trial. Each eligible participant underwent clinical evaluation by an interdisciplinary team. This evaluation included a chest radiograph, computed tomography of the head and neck, and examination of the head and neck under general anesthesia, with esophagoscopy and bronchoscopy. The judgment of operability was left to the treating surgeon.

Radiotherapy
Patients were treated with radiotherapy up to a median total dose of 74.4 Gy (72 to 76.8 Gy). Treatments were administered during 7 weeks, with 1.2 Gy given twice daily with an interfraction interval of 6 hours. Volume definition and dose calculation were based on computed tomography findings determined with patients’ heads immobilized. The radiation dose was prescribed according to the International Commission on Radiation Units and Measurements.¹⁴ Shielding of the spinal cord after administration of 36 to 40 Gy limited the total radiation dose to this region to a maximum of 45 Gy from all fields. Spinal accessory lymph nodes were irradiated with electrons. For all locations, the planning target volume included the gross tumor with a margin of at least 2.5 cm up to 50 Gy; thereafter, the margin was 1.5 cm. Smaller margins were recommended if the gross tumor was close to organs at risk. The planning target volume was reduced twice; the recommended dose to involved areas was 74.4 Gy (72 Gy for volumes larger than 10 x 10 cm, 79.2 Gy maximum for smaller boost volumes excluding the larynx), whereas electively irradiated areas received 62 or 50.4 to 54 Gy, depending on the location relative to involved areas. There were no planned treatment interruptions with the exception of weekends. All radiotherapy toxicities were assessed weekly and maximal toxicity was graded according to the Radiation Therapy Oncology Group.¹⁵

Chemotherapy
Cisplatin 20 mg/m² was administered with intravenous hydration on 5 consecutive days during weeks 1 and 5 or 6 of radiotherapy, 1.5 hours before the afternoon radiotherapy session. During the first course of cisplatin, chemotherapy was discontinued in the event of grade 3 allergic reaction, serum creatinine increase of more than 160 µg/L, grade 3 neurotoxicity, treatment-refractory vomiting, hearing problems, or persistent tinnitus. The second course of cisplatin could be omitted because of grade 3 granulocytopenia complicated by infection, thrombocytopenia requiring transfusion of platelets, grade 3 neurotoxicity, grade 3 allergic reaction, treatment-refractory vomiting, or persistent tinnitus or hearing loss. This second course was begun only after patients’ examination findings met the following criteria: granulocytes 1,000/µL, thrombocytes 100,000/µL, and creatinine clearance 60 mL/min. All chemotherapy toxicities were graded according to WHO classification.¹⁶

Follow-Up
All patients were seen by head and neck specialists weekly if grade 3 mucositis occurred, and otherwise at 6 weeks after radiotherapy and every 3 months for the first 3 years, then at 6-month intervals up to 5 years, and yearly thereafter.

Management of the Neck
Macroscopically involved neck nodes were included in the boost volume up to the total dose. In addition, participating institutions were asked to describe their policy of either conservative management of the neck node area or elective neck dissection for presumed residual disease after radiotherapy, and were required to adhere to this policy throughout the trial. Only one institution routinely performed elective neck dissections for patients with initially positive nodes.

Randomization Procedure
Randomization was performed using the minimization method at the Swiss Institute for Applied Cancer Research Coordinating Center, and stratified by institution, site of the primary tumor (hypopharynx v other), and nodal status (N2c or N3 v other).

End Points and Statistics
The main end point was time to treatment failure as a result of any cause. Secondary end points were time to local or nodal treatment failure, time to distant relapse, overall survival, and toxicity.

All time-to-event end points were calculated using the date of random assignment as the starting point and were tested for differences using the log-rank test. Treatment failure was defined as the occurrence of any of the following events: tumor recurrence at any site, salvage surgery, second primary tumor, or death as a result of any cause. Locoregional relapse was defined as any local or nodal progression or recurrence and/or death as a result of tumor, irrespective of autopsy findings. Diagnosis of distant metastases and death as a result of tumor were considered as events in the calculation of time to distant metastatic relapse, whereas deaths as a result of toxicity or other causes, diagnosis of second primary tumors, and patient survival were censored. To take effects of other explanatory variables into account in the analysis of time to any treatment failure and to locoregional failure, we first performed bivariate Cox regression analyses including treatment plus successively one of the following known explanatory variables: site of primary tumor, nodal status, sex, performance status, T stage, weight change in the last 6 months, age, and operability, with the respective treatment interaction term if appropriate. The significant variables (together with their respective treatment interactions) in this process were then selected by a stepwise selection procedure with entry criterion P = .10 and staying criterion P = .05 in a multivariate Cox regression, whereas treatment was forced to stay in the model.

Originally, a group sequential design using spending functions^17,18 with O’Brien-Fleming boundary shape¹⁹ was adopted under the assumption of a treatment failure rate of 40% to 50% at 2.5 years and a 15% improvement by combined-modality treatment. Interim evaluations were planned when the number of events reached 50 and 100, with a type I error of 5% and a type II error of 20% (power of 80%) for a two-sided test. Early termination of the trial was possible when the null hypothesis of no difference between the randomized arms or the alternative hypothesis of a 15% difference could be rejected. For an accrual rate of 70 to 100 patients per year, the planned number of patients was 250 to 400. Considering the lower but constant actual accrual rate of 35 patients per year, and following the first interim analysis in October 1997, which suggested continuation of the trial, the SAKK Scientific Committee decided to recalculate the sample size based on the actual accrual rate. Using the same type of group sequential design with the same significance level and power, the revised sample size was 210 to reach a total of 170 events in 10 years (the maximum duration of the trial). This calculation assumed a 45% failure-free rate at 2.5 years (corresponding to a median time to any event of 2.17 years, based on an exponential survival distribution) in the radiotherapy arm, a 15% improvement of failure-free survival in the radiotherapy plus chemotherapy treatment arm (median time to any event, 3.39 years), and an accrual rate of 35 patients per year.

The second interim analysis was performed on August 3, 2000, when the number of treatment failures reached 115. Results of this analysis supported continuation of the trial. In fact, the trial was closed on July 31, 2000 because the revised sample size was reached, with a total of 224 patients. Data used for this final analysis reflect follow-up until October 15, 2002, with 154 events for the primary end point and 104 patients still alive. Assuming an exponential distribution existed for the time to treatment failure, the investigators noted it would take longer than 10 years to observe the required number of events because preliminary results (especially as demonstrated by a both-arms pooled overall survival curve) suggested that the failure rate was lower than anticipated. To publish the results within a reasonable timeframe and during a time of high scientific interest, the SAKK decided to carry out the final analysis even though the required number of events was not reached. Analysis was done according to the intention-to-treat principle and included all patients, irrespective of their received treatment.

Quality Assurance
Three quality assurance rounds were held during the trial. During the trial, 12 radiation oncologists from all participating institutions reviewed all original documents and case report forms of patients randomly selected by the SAKK Coordinating Center and reported their findings to the trial chair and the SAKK Scientific Committee.

	RESULTS

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From July 1994 to July 2000, 224 patients were randomly assigned to hyperfractionated radiotherapy plus simultaneous cisplatin (experimental arm, chemotherapy plus radiotherapy, n = 112) or to hyperfractionated radiotherapy administered alone (standard arm, n = 112). Eleven Swiss institutions and one in northern Italy participated in the trial. The number of patients enrolled by individual institutions ranged from two (1% of total accrual) to 62 (28%). One patient in the radiotherapy arm was ineligible (T2N0 supraglottic larynx carcinoma). Another patient in the radiotherapy arm died early as a result of a nontumor-related cause; this patient was only included in the overall survival analysis. A diagram according to the Consolidated Standards of Reporting Trials is shown in Fig 1.

View larger version (34K): [in this window] [in a new window]   Fig 1. Consolidated Standards of Reporting Trials patient flow diagram.

Four patients randomly assigned to the combined-treatment arm did not receive chemotherapy (patient refusal, n = 2; administrative problems, n = 1; tumor progression, n = 1). The full dose of cisplatin was administered to 104 patients (93%) in the first cycle and to 80 patients (71%) in the second cycle; two patients received the second cycle in week 6. Reasons for dose reduction were toxicity (n = 14), patient refusal (n = 5), other (n = 5), or unreported (n = 8).

Acute Toxicity
None of the patients with low creatinine clearance (ie, < 60 mL/min) required reduced chemotherapy doses in cycle 2. Among 16 patients with low platelet counts (ie, < 100 x 10⁹/L) in cycle 1, the second treatment cycle was omitted because of hematologic toxicity (n = 6), renal dysfunction (n = 1), or distant metastasis (n = 1). Table 3 shows that maximal grade 3 to 4 toxicity was observed in fewer than 5% of patients overall, and no patient deaths occurred that were related to chemotherapy toxicity.

View larger version (12K): [in this window] [in a new window]   Fig 2. Time to any treatment failure (P > .05; corrected for group sequential design). RT, radiation therapy; CDDP, cisplatin.

Local and Regional Tumor Control
Patients in the combined-treatment arm demonstrated a significantly higher rate of local tumor control at 2.5 and 5 years (respectively, 69% and 64% v 45% and 36% for radiotherapy alone). Locoregional control rates at 2.5 and 5 years were also improved for combined treatment (respectively, 55% and 51% v 42% and 33% for radiotherapy alone; Fig 3). The difference in terms of nodal (regional) failure was not statistically significant. Salvage surgery at the primary site was performed in one patient (radiotherapy arm); neck dissection for persistent or recurrent lymph nodes was necessary for five patients receiving combined treatment and seven patients receiving radiotherapy only.

View larger version (12K): [in this window] [in a new window]   Fig 3. Time to locoregional failure (P = .039). RT, radiation therapy; CDDP, cisplatin.

Overall Survival
As shown in Figure 4, overall survival at 2.5 and 5 years was 59% and 46% in the combined-treatment arm, compared with 49% and 32% in the radiotherapy arm (log-rank test, P = .15), respectively. For the failure-free survival curves (Figs 2 and 3), a plateau appears beyond 5 years, indicating that a proportion of patients were cured.

View larger version (12K): [in this window] [in a new window]   Fig 4. Overall survival (P = .147). RT, radiation therapy; CDDP, cisplatin.

Late Toxicity
Maximal late toxicities of grades 3 and 4 are listed in Table 6. Late toxicity data were unavailable because of death in seven and five patients, and partial noncompliance in seven patients and one patient in the experimental and standard arms of the trial, respectively. Late toxicity was comparable in both arms (not significant), with the highest incidence observed for permanent xerostomia and dysphagia (> 20% in both arms). No lethal complications occurred among patients in either group.

	DISCUSSION

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Note that our trial was powered to detect a 15% difference in time to treatment failure, which was not observed. However, we have demonstrated that cisplatin chemotherapy enhances the therapeutic ratio when combined with hyperfractionated radiotherapy, as confirmed by the significant improvement noted in locoregional control and the absence of increased complications among patients in the combined-treatment arm. Among previously reported trials comparing concomitant chemoradiotherapy and radiotherapy, two studies are similar to ours, and used a continuous course of hyperfractionated radiotherapy with cisplatin alone²² or cisplatin and fluorouracil.²³ Both studies completed accrual when our trial started, with 120 and 122 patients, respectively, and were performed primarily at single institutions.^22,23 As was also noted in our results, locoregional tumor control rates were comparable in the control arms and significantly improved by chemotherapy.^22,23 Only one trial, however, demonstrated improved patient survival.²¹ In our trial, the higher number of nontumor-related deaths in the combined arm may have obscured the survival advantage.

Swallowing was temporarily or permanently impaired in more than 20% of our patients, whereas in the above-cited publications, this type of late toxicity was not mentioned. We did not observe evidence of increased late toxicity after combined treatment in our trial.

Salvage surgery for persistent or recurrent primary disease was performed in one patient only, although 65% of primary tumors were initially considered resectable. This may be due to patient refusal, extent of tumor at the time of local treatment failure, or the poor prognosis radioresistant tumors usually bear; however, a detailed report on treatment decisions was not requested in our study.

The ideal combination of chemotherapy and radiotherapy is still a matter of debate, especially regarding single-agent chemotherapy versus multidrug regimens and fractionation of radiotherapy in combination with chemotherapy. Higher doses of obviously more toxic multidrug regimens given as induction treatment and in combination with hyperfractionated and accelerated radiotherapy have been reported to induce 3-year progression-free survival of 80%, whereas distant metastases were equally frequent as locoregional failures.²⁴ We conclude that most currently used chemoradiotherapy regimens are not sufficient to eradicate micrometastases. In our trial, distant metastasis was a relatively rare event among patients with favorable locoregional tumor control, and distant metastasis–free survival was significantly superior among those receiving combined treatment. Furthermore, intensified chemoradiotherapy schedules reach the tolerance levels of these often comorbid patients, and may therefore induce more adverse effects. Data illustrating late toxicity after chemoradiotherapy and alternate fractionation schedules are scarce,²⁵ and long-term data are needed.

We have shown that the addition of two cycles of cisplatin monotherapy significantly prolongs time to local failure, time to locoregional failure, and time to distant metastatic relapse, with a tendency toward improved overall survival. The beneficial effects of cisplatin on time to any treatment failure and time to locoregional failure seem to be intensified in patients with stage N3 disease. Future clinical trials should combine chemoradiotherapy with alternating schedules of radiotherapy, and compare the addition of (poly-)chemotherapy versus a response-modifying agent such as an epidermal growth factor inhibitor, modulators of angiogenesis, or hypoxic cell sensitizers.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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13. Huguenin P, Glanzmann C, Taussky D, et al: Hyperfractionated radiotherapy and simultaneous cisplatin for stage-III and -IV carcinomas of the head and neck. Strahlenther Onkol 174:397-402, 1998[Medline]

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16. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication 48. Geneva, Switzerland, WHO, 1979, 1985

17. Lan KKG, DeMets DL: Discrete sequential boundaries for clinical trials. Biometrika 70:659-663, 1983[Abstract/Free Full Text]

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24. Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320-326, 2003[Abstract/Free Full Text]

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Submitted December 30, 2003; accepted July 21, 2004.

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