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Japanese Journal of Clinical Oncology Advance Access originally published online on August 12, 2006
Japanese Journal of Clinical Oncology 2006 36(10):620-625; doi:10.1093/jjco/hyl083
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© 2006 Foundation for Promotion of Cancer Research

Efficacy and Feasibility of Cisplatin-Based Concurrent Chemoradiotherapy for Nasopharyngeal Carcinoma*

Yusuke Demizu1, Ryohei Sasaki1, Toshinori Soejima1,3, Tsutomu Maruta1,4, Yoshiaki Okamoto1, Kazunari Yamada1,5, Eisaku Yoden1,3, Yasuo Ejima1, Yosuke Ota1, Haruhiko Ishida2, Kenichi Nibu2 and Kazuro Sugimura1

Divisions of 1 Radiology and of 2 Otorhinolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, 3 Department of Radiation Oncology, Hyogo Medical Center for Adults, Akashi, Hyogo, 4 Department of Radiology, National Hospital Organization Himeji Medical Center, Himeji, Hyogo and 5 Department of Radiation Oncology, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan

For reprints and all correspondence: Ryohei Sasaki, Division of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan. E-mail: rsasaki{at}med.kobe-u.ac.jp

Received January 4, 2006; accepted June 26, 2006


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Objective: To investigate the efficacy and feasibility of a cisplatin-based concurrent chemoradiotherapy (CRT) protocol based on Intergroup Study 0099 for nasopharyngeal carcinoma (NPC).

Methods: Sixteen patients with stage II–IVB NPC were treated with a protocol of cisplatin-based concurrent CRT and adjuvant chemotherapy from 1998 to 2002. Three courses of cisplatin (80 mg/m2) were scheduled during 70 Gy of radiotherapy (RT), and two agents of adjuvant chemotherapy (FP regimen: cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day by 4-day continuous infusion) were challenged. Overall survival (OS) and relapse-free survival (RFS) rates were calculated by the Kaplan–Meier method.

Results: Median follow-up duration was 45 months. Both 3-year OS and RFS rates were 81%. Proportions of patients who tolerated each scheduled treatment were 94% for RT, 63% for concurrent chemotherapy and 38% for adjuvant chemotherapy.

Conclusions: Our protocol of the cisplatin-based concurrent CRT followed by adjuvant chemotherapy consisting of FP regimen was effective for Japanese patients with NPC. However, the doses and numbers of cycle of chemotherapy need to be modified because of the low compliance rate. Larger numbers of data accumulation and/or multi-institutional trials may be warranted to confirm the efficacy of this protocol.

Key Words: nasopharyngeal carcinoma • radiotherapy • concurrent chemoradiotherapy • cisplatin • Intergroup Study 0099


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Nasopharyngeal carcinoma (NPC) is a relatively rare disease in Japan as well as in North America and Europe, compared with East Asian countries (1). NPC has been primarily treated with radiotherapy (RT) rather than surgery (2–4). In an analysis of ~1400 patients treated with RT alone in China, the 5-year survival for patients with stage I was 86%, while those for stage II, III and IV were 60, 46 and 29%, respectively (2). Combination therapy of RT and cisplatin-based chemotherapy has been applied to patients with stage III-IVB NPC patients and favorable results have been reported (5,6). A phase III randomized Intergroup Study (IGS) 0099, coordinated by the South West Oncology Group (SWOG), showed that the protocol consisting of concurrent chemoradiotherapy (CRT, cisplatin 100 mg/m2) followed by adjuvant chemotherapy [cisplatin 80 mg/m2 and 5-fluorouracil (5-FU) 1000 mg/m2/day] was significantly superior to RT alone in patients with stage III-IVB NPC (7). Several groups followed the protocol and tested the efficacy and feasibility of IGS 0099 (8–13). As a result, reports from non-Japanese countries demonstrated that their results were favorable and toxicities seemed to be acceptable. On the other hand, a report from single Japanese institution demonstrated that severe skin and mucosal complications led to discontinuation of the planned therapy, suggesting that the protocol may not be feasible for Japanese patients with NPC (11). As far as we investigated, there have been only few papers showing feasibility of the protocol against Japanese patients. Recently, a result of relatively large-scale multi-institutional survey for NPC in Japan has been reported (14). However, efficacy and feasibility of cisplatin-based concurrent CRT followed by adjuvant chemotherapy for Japanese patients with NPC are still unclear and thus need to be clarified.

At our institution, a protocol of sequential CRT consisting of cisplatin and 5-FU (FP regimen) followed by 70 Gy of RT had been applied to patients with stage II-IVB NPC since 1989 to early 1998. However, local control and overall survival (OS) seemed to be unsatisfactory. Therefore, another protocol consisting of the cisplatin-based concurrent CRT followed by adjuvant chemotherapy, modified from IGS 0099, has been tried since 1998. The purpose of the present study was to determine whether the concurrent CRT followed by adjuvant chemotherapy is effective and feasible for Japanese patients.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 References
 
PATIENTS
From 1998 to 2002, 18 patients with stage II-IVB NPC were treated at our institution. Two patients were treated with palliative intent due to poor general condition. Thus, 16 patients who satisfied the following criteria were treated by a cisplatin-based concurrent CRT protocol followed by adjuvant chemotherapy. (1) Biopsy-proven stage II-IVB NPC (UICC-TNM 1997), (2) no history of previous RT to the head and neck regions nor chemotherapy, (3) an age of 75 or younger, (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, (5) written informed consent, (6) the following laboratory data: WBC count >4000/µl, platelet count >100 000/µl, hemoglobin >9.0 g/dl, total bilirubin <1.5 mg/dl, AST <100 IU/l, ALT <100 IU/l, creatinine concentration <1.6 mg/dl, and/or creatinine clearance > 60 ml/min. Table 1 shows patient characteristics.


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  		Table 1. Patient characteristics

 
The feasibility of RT, concurrent chemotherapy and adjuvant chemotherapy was independently evaluated. Acute and late toxicities were assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) Late Morbidity Scoring Scheme, respectively.

CHEMOTHERAPY
In the concurrent CRT, three courses of chemotherapy were planned, consisting of a single agent of cisplatin 80 mg/m2 on days 1, 22 and 43. In the following adjuvant chemotherapy, three courses were planned, consisting of two agents of cisplatin 80 mg/m2 on days 71, 99 and 127 and 5-FU 800 mg/m2/day by 4-day continuous infusion on days 71–74, 99–102 and 127–130. As prophylactic hydration, more than 500, 3000, 1500 and 1000 ml intravenous infusions were performed on day 0, 1, 2 and 3–5, respectively, for each course of chemotherapy.

Chemotherapy was not performed until WBC count was >4000/µl and platelet count was >100 000/µl. If the creatinine concentration was >2 mg/dl and creatinine clearance <60 ml/min, carboplatin was administered instead of cisplatin under the time–concentration curve (AUC) of 4 mg min/ml.

RADIOTHERAPY
Patients were initially treated with 4 MV X-ray by parallel opposed lateral fields to primary tumor and upper neck (wedges were used occasionally) and a single anterior field to the lower neck. At 40 Gy of RT, spinal cord was shielded and posterior neck fields were treated by 9 MeV electron. After 50 Gy, a boost field for the primary tumor and positive nodes (>1 cm) via opposed reduced portals was used. The total planned dose was 70 Gy by 35 fractions in 7 weeks to the primary tumor and positive nodes and 50 Gy by 25 fractions in 5 weeks to the prophylactic area. Two patients received a little higher dose (74 and 72 Gy) in the early period, while one patient was irradiated 72.4 Gy because the treatment was started at another hospital and he moved to our hospital later on.

STATISTICS
Survival time was calculated from the initial date of the treatment to the first occurrence of the considered events. OS was defined as the time between the initial date of the treatment and death from any cause. Relapse-free survival (RFS) was defined as the time between the initial date of the treatment and first recurrence of the disease (locoregional or distant recurrence) or death from any cause. The data were analyzed using StatView version 5.0 statistical software (SAS Institute Inc., Cary, NC, USA). The survival and local control rates were calculated by the Kaplan–Meier method (15).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 References
 
SURVIVAL RATES, CAUSES OF DEATH AND TUMOR CONTROL
The median follow-up duration was 45 (range: 11–81) months. Both 3-year OS and RFS rates were 81% (Fig. 1). Three of 16 (19%) patients' deaths were identified. Two (13%) patients died of the disease and the other died of an intercurrent disease. Only one (6%) patient experienced a locoregional recurrence (5-year local control rate was 93%).


Figure 1
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  		Figure 1. Overall survival (a) and relapse-free survival (b) curves of all 16 patients with stage II–IVB nasopharyngeal carcinoma.

 
ACUTE AND LATE TOXICITIES
Incidence of acute and late toxicities is summarized in Table 2. No treatment-related death was observed. The most significant acute toxicity was leukopenia (≥grade 2, 15 patients: 94%). Among them, 3 (19%) patients who showed grade 2 or 3 leukopenia could not receive their scheduled adjuvant chemotherapy because of the poor bone marrow recovery. Other hematological toxicities did not affect the treatment schedule. The major non-hematological toxicities were mucositis (≥grade 2, 14 patients: 88%), dysphagia (≥grade 2, 14 patients: 88%) and nausea/vomiting (≥grade 2, 10 patients: 63%). Relatively common late toxicities were subcutaneous tissue toxicity (neck stiffness, 6 patients: 38%) and salivary gland toxicity (xerostomia, 4 patients: 25%) but not serious (≤grade 2). The severest one was bone grade 4 toxicity (mandibular bone necrosis, 1 patient). Other late toxicities were not clinically significant.


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  		Table 2. Incidence of acute and late toxicities

 
FEASIBILITY OF RADIOTHERAPY AND CHEMOTHERAPY
Details of the treatments, toxicities causing discontinuity of the protocol and durations to recurrence are summarized in Table 3.


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  		Table 3. Details of the treatments, toxicities causing discontinuity of the protocol and durations to recurrence

 
One (6%) patient refused to continue his RT at 58 Gy due to grade 3 mucositis, dysphagia, and dermatitis, while other 15 (94%) patients completed their scheduled doses. Therefore, 70 Gy of RT seemed to be feasible even if the previously described dose of cisplatin was administered concurrently.

Overall, 11 (69%) patients could not complete the scheduled chemotherapy. Proportions of patients who received 3, 2 and 1 course(s) of the concurrent chemotherapy were 63% (10 patients), 25% (4 patients) and 13% (2 patients), respectively. Carboplatin was used instead of cisplatin in three patients for one or two courses. In concurrent regimen, two and two patients could not continue their chemotherapy schedules because of slow bone marrow recovery and severe (grade 3) nausea/vomiting, respectively. The patient who refused RT at 58 Gy also refused chemotherapy after the second course of concurrent chemotherapy. Another patient experienced grade 3 renal toxicity (high creatinine concentration) and electrolyte abnormality after the first course of concurrent chemotherapy and discontinued the planned schedule. Proportions of patients who received 3, 2 and 1 course(s) of the adjuvant chemotherapy were 38% (6 patients), 19% (3 patients) and 13% (2 patients), respectively. Carboplatin was used instead of cisplatin in six patients for 1–3 courses. The reasons of discontinuing the adjuvant chemotherapy were various, such as slow bone marrow recovery, renal toxicity (low creatinine clearance), laryngeal edema and persistent otitis media. Both the patients who experienced recurrences received insufficient chemotherapy.


   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
References
 
The protocol consisting of concurrent CRT (cisplatin 80 mg/m2) followed by adjuvant chemotherapy (cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day) modified from IGS 0099 (7) has been challenged since 1998 at our institution. We adopted the reduced doses of cisplatin and 5-FU compared with IGS 0099 (cisplatin 100 mg/m2 for concurrent regimen; cisplatin 80 mg/m2 and 5-FU 1000 mg/m2/day for adjuvant regimen) because the doses of IGS 0099 seemed too toxic for Japanese patients and we needed a protocol that could be safely performed at our institution and affiliate hospitals. Moreover, to make the protocol more tolerable, we used carboplatin instead of cisplatin if renal toxicities were observed, because several studies had shown the tolerability and possible efficacy of carboplatin as an alternative for cisplatin in NPC treatment (16–19). Table 4 summarizes recent studies of concurrent CRT for NPC based on IGS 0099. All reports other than those by Tan et al. (8) and Wee et al. (12) (these two reports were from the same group) adopted the same CRT protocol as IGS 0099. In the studies of Tan et al. and Wee et al., cisplatin was administered at 25 mg/m2 for 4 days in concurrent regimen and at 20 mg/m2 for 4 days in adjuvant regimen, that is, the total dose of cisplatin was the same as IGS 0099.


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  		Table 4. Comparison of chemoradiotherapy studies for nasopharyngeal carcinoma based on Intergroup Study 0099

 
Our results showed favorable 3-year OS (81%) and RFS (81%) compared with other studies listed in Table 4, though our analysis included stage IIB patients (3 of 16 patients: 19%). Hematological acute toxicities in our protocol were severer than those in IGS 0099 (7) (e.g. grade 3 leukopenia: 50% versus 29%) even though the doses of chemotherapeutic agents were reduced. Non-hematological acute toxicities in our protocol generally seemed milder than those in IGS 0099 (e.g. ≥grade 3 mucositis: 19% versus 37%). Isobe et al. (11) attempted to adopt the same combined modality treatment as IGS 0099 for three Japanese patients with locoregionally advanced NPC; however, they observed severe (grade 3 and/or 4) non-hematological acute toxicities in all of them, which led to the discontinuation of the planned chemotherapy. Moreover, two of them experienced recurrences in early periods and died of NPC. Most reports on IGS 0099-based CRT have focused on acute toxicities, whereas only one report mentioned late toxicities (13). This report showed that ~20% of the patients experienced grade 3 or greater late toxicities and ear toxicities (otitis/hearing loss) were observed most frequently. Compared with this, our patients' late toxicities were much milder (≥grade 3, 1 of 16 patients: 6%) and most of them seemed to be acceptable.

Feasibility of the protocol should also be discussed because incomplete treatment may result in recurrence of the disease. The compliance of RT was satisfactory (93–99%) in all studies listed in Table 4, but that of chemotherapy was generally unsatisfactory (52–75% in concurrent regimen and 38–76% in adjuvant regimen), even in IGS 0099. Our study showed average compliance in concurrent regimen and the poorest compliance in adjuvant regimen; however, OS and RFS were favorable. We could not find any correlation between treatment outcome and feasibility.

Although several groups have widely followed IGS 0099 protocol outside Japan, few Japanese groups have. Mizowaki et al. (20) recommended that full-dose CRT should be applied, based on their unsatisfactory results of a low-dose cisplatin regimen. Recently, a survey of 17 Japanese institutions reported by Kawashima et al. (14) revealed that only 123 of 333 patients (37%) have received platinum-based concurrent CRT. At our institution from 1998 to 2002, 16 of 18 patients (89%) had been treated on the policy of cisplatin-based concurrent CRT with satisfying results as noted above. And from 2002 to present, 12 patients have been successfully treated by a similar but less intensive protocol consisting of cisplatin-based concurrent CRT (cisplatin 80mg/m2 x 2 cycles) and outpatient-based adjuvant chemotherapy [carboplatin (AUC 2 mg min/ml) and TS-1 (80–120 mg/body), data not shown]. As a whole, from our experience, 28 of 30 patients (93%), who are all Japanese patients, have been safely treated with cisplatin-based concurrent CRT protocols. However, the doses and numbers of cycle of chemotherapy should be carefully adjusted, since its compliance was poor. Although accumulation of more data and/or multi-institutional trials would be warranted, we believe that our results provide important and useful information for the future strategy.

Recently, lots of efforts have been made for the treatment of NPC, both in order to increase radiation dose for tumors and to reduce it for critical organs, by using new techniques such as intensity modulated radiotherapy (IMRT) and 3-dimensional conformal radiotherapy (3D-CRT) (21,22). Although acute and late toxicities may have been decreased, it is still unclear whether radiation dose escalation will improve the outcome itself. On the other hand, for staging and management of NPC, (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) may have a potential to become a more valuable tool than magnetic resonance imaging (23,24). As it is reported that FDG-PET has a potential to predict outcomes in non-small cell lung cancer (25), we are planning to employ FDG-PET examinations in the staging and the response evaluation of NPC. The recent therapeutic (IMRT, 3D-CRT) and diagnostic (FDG-PET) progress is likely to improve outcomes of NPC in the next era.

In conclusion, our protocol of the cisplatin-based concurrent CRT followed by adjuvant chemotherapy consisting of FP regimen was effective for Japanese patients with NPC. However, the doses and numbers of cycle of chemotherapy need to be modified because of the low compliance rate. Larger number of data accumulation and/or multi-institutional trials may be warranted to confirm the efficacy of this protocol.


   Acknowledgments
 
A part of costs for this publication was supported by Grants-in-Aid for Scientific Research, 17790859, from the Ministry of Education, Science, Sports and Culture of Japan.


   Notes
 
* Presented at the 62nd Annual Meeting of Japan Radiological Society, 11–13 April 2003, Yokohama, Japan. Back


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
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