Phase III Study Comparing Standard Radiotherapy With or Without Weekly Oxaliplatin in Treatment of Locoregionally Advanced Nasopharyngeal Ca
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《临床肿瘤学》
the Departments of Medical Oncology and Radiation Oncology, Cancer Center of Sun Yat-Sen University, Guangzhou, People's Republic of China
ABSTRACT
PURPOSE: A prospective, randomized, phase III study was performed to evaluate the feasibility and efficacy of concurrent weekly oxaliplatin with radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC).
PATIENTS AND METHODS: From January 2001 to January 2003, 115 patients with locoregionally advanced NPC were randomly assigned to either radiotherapy (RT) alone (56 patients) or concurrent chemoradiotherapy (CCRT; 59 patients). All patient characteristics were well balanced in both arms. CCRT with oxaliplatin 70 mg/m2 weekly was administered for six doses from the first day of RT.
RESULTS: All patients were eligible for toxicity and response analysis. Compliance with the protocol treatment was excellent, with 97% of patients completing all planned doses of oxaliplatin, and a lack of high-grade toxicity was observed. After a median follow-up time of 24 months, there was a significant difference in overall survival (OS), relapse-free survival (RFS), and metastasis-free survival (MFS) in favor of the CCRT arm. The 2-year OS rates were 100% for the CCRT arm and 77% for the RT arm (P = .01). The 2-year MFS rates were 92% for the CCRT arm and 80% for the RT arm (P = .02). The 2-year RFS rates were 96% for the CCRT arm and 83% for the RT arm (P = .02).
CONCLUSION: CCRT with weekly oxaliplatin is feasible and improves OS, MFS, and RFS rates in patients with locoregionally advanced NPC. Therefore, further randomized trials including oxaliplatin are warranted.
INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. Radiotherapy (RT) remains the standard treatment for NPC patients. Although a number of improvements have been achieved both in the technology and equipment of RT, the 5-year survival rate of NPC patient remains approximately 50%. Locoregionally advanced NPC patients have a poorer prognosis, with 5-year survival rates between 10% and 40%. The main cause of failure is locoregional relapse and distant metastasis.1-4
NPC is also a chemotherapy-sensitive disease, and concurrent chemoradiotherapy (CCRT) has been an important investigational subject for many years in the treatment of locoregional advanced NPC.5-13 Therefore, it is a major objective to seek the best combined modality of CCRT and explore new drugs and new regimens to improve outcome in this prevalent disease.
Oxaliplatin is a new analog of platinum that has no renal and fewer GI toxicities than cisplatin. The myelosuppression is also milder and easier to manage than the myelosuppression experienced with carboplatin. The main and dose-limiting toxicity of oxaliplatin is acute and cumulative short-term sensory peripheral neuropathy. Its mechanism of action is thought to be similar to that of cisplatin. Preclinical data have shown that oxaliplatin is active in a wide range of human and murine tumor cell lines. In clinical practice, oxaliplatin combined with fluorouracil/leucovorin has been approved as first-line treatment for advanced colorectal carcinoma14-23; the documented activity of oxaliplatin in head and neck cancer has also been reported in a phase II trial.24 In addition to the clinical synergy with fluorouracil and other cytotoxic agents, synergy with RT has been established both in vitro and in the clinic.25,26
Although CCRT has been considered standard practice in North America based on the results of the Intergroup 0099 trial, it is still unclear whether these results, which were derived from a heterogeneous histologic mix of patients, can be directly applied to WHO subtype III undifferentiated NPC patients. (In endemic areas such as southern China, the proportion of patients with WHO subtype III histology is greater than 90%). In addition, the results were unexpectedly inferior in the RT-alone arm.27 On the basis of these considerations, we initiated a prospective study to compare the objective response and safety profile of standard RT versus the same RT plus weekly oxaliplatin in patients with locoregionally advanced NPC.
PATIENTS AND METHODS
Eligibility Criteria
Patients were evaluated using the 1997 American Joint Committee on Cancer (AJCC)/International Union Against Cancer staging system.28 Patients were required to have had histologic proof of WHO subtype I, II, or III NPC. Disease stage had to be N2/N3 and any T or T3/T4 and any N without evidence of distant metastases (M0). Patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 2, and provided written informed consent. Adequate renal, hepatic, and bone marrow function (WBC count 4,000/μL and platelet count 100,000/μL) and normal ECG were also required. The study protocol was approved by the Research Ethics Committee of the Cancer Center of Sun Yat-Sen University.
Pretreatment Evaluation
The initial evaluation included medical history, physical examination, CBC with differentials, full biochemistry profile, ECG, and Epstein-Barr virus serology test. Tumor staging was determined on the basis of the patient's clinical examination, including nasopharyngoscopy, computed tomography (CT) or magnetic resonance imaging (MRI) scan of the head and neck, and chest x-ray. Hepatic ultrasonographies were performed as indicated. Radionuclide bone scan was performed in the patients with bone pain, elevated serum alkaline phosphatase, or N2 to N3 disease. All staging work-up should have been completed within 3 weeks before treatment.
RT
All patients were treated in an identical method by definitive-intent RT in both the RT and the CCRT arms. Details of our RT technique in Cancer Center of Sun Yat-Sen University have been reported previously.29,30 Irradiation fields were chosen according to the extension of the tumor. The target volume was delineated by CT scan or MRI and was the entire tumor with a 2-cm margin in all directions. Photons (6 MV) produced by linear accelerator (Varian, Palo Alto, CA) were used to treat the primary tumor and neck lymph nodes. Patients were treated by conventional fractionation (RT was administered five times a week at 2 Gy/d on Monday through Friday). The en bloc technique was used for the patients with upper cervical nodes, oropharyngeal involvement, or extensive parapharyngeal involvement. Forty grays were delivered with two lateral opposing facio-cervical portals to irradiate the nasopharynx and the upper neck. The lower neck was irradiated by a separate anterior 6-MV photon field to a similar dose as the primary tumor with midline structure shielded off. Thereafter, 30 to 34 Gy was delivered to the primary tumor by the shrinking-field technique (two lateral-opposed facial fields) to avoid excessive irradiation to the spinal cord. An anterior cervical field was used to treat the whole neck with a spinal cord block. The accumulated radiation doses to the primary tumor were 70 to 74 Gy. The accumulated doses were 60 to 64 Gy to the involved areas of the neck and 50 Gy to the uninvolved areas.
Boost doses of 10 Gy in 5 fractions were delivered to the skull base in the patients with involvement of skull bone and intracranial extension, and an anterior facial electron field was added in the case of nasal or ethmoidal involvement. For patients with a residual tumor in the primary site (especially in the parapharyngeal space) after a 70-Gy dose was delivered, the total dose could be boosted to 80 Gy with the cone-down technique. Any palpable residual nodes after external RT were boosted to 70 Gy at the 90% isodose level with an electron field (9 to 12 MeV).
When possible, salvage treatments were administered to patients after documented relapse or when disease was persistent. The salvage treatments included reirradiation, chemotherapy, and surgery.
Concurrent Chemotherapy
The concurrent chemotherapy regimen was oxaliplatin 70 mg/m2 by intravenous infusion over 2 hours weekly, repeated for six times. All patients received an antiemetic prophylaxis of 5-hydroxytryptamine-3 receptor antagonist. The dose of oxaliplatin was adjusted according to the neutrophil and platelet counts. If the neutrophil count was 1,500/μL and the platelet count was 100,000/μL, the patient was administered the full dose of oxaliplatin. If the neutrophil count was less than 1,500/μL and the platelet count was less than 100,000/μL, the patient's chemotherapy was postponed for 1 week. If the neutrophil count was still less than 1,500/μL on day 15, chemotherapy was discontinued. The dose of oxaliplatin was reduced by 25% in case of grade 3 peripheral neuropathy.
We chose this dose and schedule of oxaliplatin because of the following reasons. First, there were a lot of studies using a weekly oxaliplatin schedule in colorectal cancer, and the dose of oxaliplatin ranged from 50 to 65 mg/m2/wk. Given the favorable toxicity profile of the weekly oxaliplatin schedule in colorectal cancer, we chose a dose of 70 mg/m2/wk.23,31 Second, this study aimed to assess the efficacy and safety of oxaliplatin and RT; thus, we performed this trial in the following three steps. At the beginning, we enrolled 10 patients to check the tolerability of this dose and dose schedule combined with RT concurrently. When we found that it was feasible and tolerable, we enrolled more patients onto the study at this dose and schedule. After 39 patients were enrolled onto this study group, we reported preliminary results at the 39th Annual Meeting of the American Society of Clinical Oncology.32 Finally, we completed this study with 59 patients enrolled onto the CCRT arm.
Patient Assessment and Follow-Up
Three months after completion of treatment, tumor response was assessed by CT scan or MRI and clinically by flexible nasopharyngoscopy. All objective responses were evaluated 3 months after completion of treatment and reviewed by an external expert committee. Treatment response and systemic toxicities were evaluated according to the WHO criteria, except peripheral neurotoxicity.33 Radiation toxicities were graded according to the European Organisation for Research and Treatment of Cancer Radiation Therapy Oncology Group. Peripheral neurotoxicity was graded according to the following oxaliplatin-specific scale from Caussanel et al34: grade 1, paresthesias/hypoesthesias of short duration (less than 7 days); grade 2, paresthesias/hypoesthesias persisting for 8 to 14 days; grade 3, permanent paresthesia/dysesthesia without functional impairment; grade 4, paresthesia/dysesthesia resulting in functional impairment. Toxicity was assessed before every week in both treatment arms, and hematologic assessments were performed weekly. After completion of treatment, the patients were observed weekly until acute adverse effects resolved. Patients were then evaluated every 2 months during the first year, every 3 months during years 2 and 3, and every 6 months thereafter.
Follow-up duration was calculated from the day of random assignment to either the day of death or the day of the last examination. All local recurrences were diagnosed by flexible nasopharyngoscopy and biopsy and/or CT scan of the nasopharynx and the skull base showing progressive bone erosion and/or soft tissue swelling. Regional recurrences were diagnosed by clinical examination of the neck and, in doubtful cases, by fine-needle aspiration or CT scan of the neck. Distant metastases were diagnosed by clinical symptoms, physical examination, and imaging methods including chest x-ray, bone scan, CT scan, and abdominal sonography.
Statistical Analysis
The primary end point of the study was to compare the overall survival (OS) of locoregionally advanced NPC patients treated with standard RT versus the same RT regimen plus weekly oxaliplatin. The secondary end point was to evaluate and compare the objective response rate, the safety profile of the combination, and the relapse-free survival (RFS) and metastasis-free survival (MFS) rates in both arms. On the basis of our previous experience, a 3-year survival rate of 60% for RT alone in the NPC population, and the results of the Intergroup 0099 trial (the authors acquired a 30% additional improvement in 3-year survival rate from 46% to 76%),27 we hypothesized that our CCRT regimen would be of great interest if it resulted in a 85% 3-year survival rate in an NPC population. For a significance level of 0.05 with power equal to 80%, a minimum sample size of 94 patients was determined.
SPSS 10.0 statistical software was used (SPSS Inc, Chicago, IL). Time was measured from the date of random assignment until the time of first failure or the most recent follow-up. OS was defined as the time elapsed from the date of random assignment to the date of death. RFS was measured from the date of random assignment to the date of the first observation of progressive disease. MFS was measured from the date of random assignment to the date of the first observation of metastatic disease. Patients who died of any cause without locoregional recurrence or distant metastases were censored at the last follow-up in the case of RFS and MFS. The Kaplan-Meier product-limit method was used in the calculation of OS, RFS, and MFS rates.35 Toxicity and response rates were compared using the 2 test. Fisher's exact test method was used when a small sample size existed. The statistical significance of differences among survival curves was analyzed using the log-rank test or Breslow test36,37; P .05 was considered statistically significant. Statistical tests were based on the two-sided significance level.
RESULTS
January 2001 to January 2003, 115 patients were entered onto the study (56 patients in the RT arm and 59 patients in the CCRT arm), and all patients were eligible for toxicity, response, and survival analysis (Table 1). All patient characteristics were well balanced in both arms (P > .05). The median follow-up time for the whole study was 24 months (range, 13 to 35 months). Compliance with the protocol treatment was excellent, with 97% of patients completing all planned doses of oxaliplatin and RT. Fifty-five patients (93%) received all six doses of oxaliplatin, three patients (5%) received five doses, and one patient received seven doses. The mean dose-intensity of oxaliplatin received was 69.60 mg/m2/wk (range, 58.3 to 81.6 mg/m2/wk).
Treatment Response
Clinical responses of the primary tumor site and of metastatic neck adenopathy were coded separately (Tables 2 and 3). All patients were assessable for response at the primary site. The complete response rate reached 83% (95% CI, 74% to 92%) in CCRT arm compared with 66% (95% CI, 54% to 78%) in the RT-alone arm (P = .032). Ninety-one patients were assessable for neck response. Complete response rates were 88% (95% CI, 79% to 97%) in the CCRT arm and 95% (95% CI, 88% to 100%) in the RT-alone arm (P = .233) in cervical lymph nodes. In the RT arm, three patients with neck recurrence received neck dissection. Five patients with nasopharynx recurrence received reirradiation (one patient received CCRT with cisplatin, and three patients received intensity-modulated RT). In the CCRT arm, one patient with neck recurrence received neck dissection. Two patients with nasopharynx recurrence received reirradiation (one patient received intensity-modulated RT). No salvage surgery for primary recurrence was performed.
Survival
In this study, significantly improved OS, RFS, and MFS rates were obtained in the CCRT arm. The 2-year OS rate was 100% in the CCRT arm compared with 77% (95% CI, 66% to 88%) in the RT arm (P = .01, log-rank test; Fig 1). The 2-year MFS rates were 92% (95% CI, 85% to 99%) in the CCRT arm and 80% (95% CI, 69% to 90%) in the RT arm (P = .02, log-rank test; Fig 2). Because the data in Figure 3 suggested some departure from the proportional hazard assumption of the log-rank test in the case of RFS, the Breslow test was used in this condition in addition to the log-rank test. The 2-year RFS rates were 96% (95% CI, 91% to 100%) in the CCRT arm and 83% (95% CI, 73% to 93%) in the RT arm (P = .02, Breslow test; P = .09, log-rank test; Fig 3). The 2-year local control rates were 96% (95% CI, 91% to 100%) in the CCRT arm and 88% (95% CI, 80% to 97%) in the RT arm (P = .16, log-rank test). The 2-year regional control rates were 100% in the CCRT arm and 94% (95% CI, 88% to 100%) in the RT arm (P = .09, Breslow test; P = .39, log-rank test). It seemed that a better locoregional control came from the combination of local control and regional control. The survival benefits of CCRT seemed to be caused by both a better distant and locoregional control.
Toxicity
All patients were evaluated for safety. The type and degree of acute toxicities in both arms are listed in Table 4. Toxicity was compared by combining all of the grades (0 through 4) in both arms. No fatal toxicity related to planned treatment was observed in either arm. A higher incidence of grade 1 or 2 leukopenia and nausea and vomiting was observed in the patients in the CCRT treatment arm (P < .01). The peripheral neuropathy in patients in the CCRT arm was reversible, no oxaliplatin-specific orolaryngeal neurotoxicity occurred, and only 20% of patients (95% CI, 11% to 29%) experienced grade 1 or 2 toxicity, although there was a significant difference between the two arms (P = .0009). The rates of grades 2 and 3 mucositis were similar in the two arms. In the CCRT arm, six patients had grade 3 mucositis, there was no grade 4 mucositis toxicity, and no patients required admission for intravenous hydration. There was no renal toxicity in either arm. No difference in dry mouth, dysphagia, and skin reaction toxicity was seen between the two arms.
With limited follow-up, late toxicities, including xerostomia, skin reaction, mucositis, and dysphagia, were similar between the two arms. A trend in the rate of late complaints for patients treated with CCRT was not observed. No bone necrosis and neurotoxicity were observed in the two treatment arms. More information will be reported with a longer follow-up time.
DISCUSSION
Traditional fractionated RT alone has been the standard treatment for NPC, with 5-year survival rates from 10% to 55%. Although early-stage NPC is highly radiocurable, the cure rate with RT alone for locoregionally advanced NPC is low.1-4 Because NPC is a chemotherapy-sensitive tumor, chemotherapy added to RT in various manners (concomitant, neoadjuvant, and adjuvant) should be a method to improve survival rates.5-13,27-30,38-45
Neoadjuvant chemotherapy has some advantages, such as decreasing tumor burden and facilitating further RT, organ and function preservation, and eradication of distant micrometastases. The International Nasopharynx Cancer Study Group has reported the preliminary results of a randomized trial comparing three cycles of neoadjuvant chemotherapy using bleomycin, epirubicin, and cisplatin plus RT versus RT alone in AJCC stage IV ( N2, M0) undifferentiated NPC. With a median follow-up of 49 months, no survival benefit could be demonstrated with the addition of neoadjuvant chemotherapy.38 Another prospective randomized trial by Ma et al29 in our cancer center also reported no survival benefit and no effect in reducing distant metastasis from two or three cycles of neoadjuvant chemotherapy consisting of cisplatin, bleomycin, and fluorouracil, although a trend of improved RFS favoring the chemotherapy plus RT group was observed.
The use of adjuvant chemotherapy to treat patients with NPC has never been proven to be of benefit. The large randomized trial with 229 patients, who were treated in Institute Nazionale Tumori in Milan, failed to demonstrate any survival benefit for patients receiving 6 monthly cycles of vincristine, cyclophosphamide, and doxorubicin compared with patients receiving no adjuvant chemotherapy. The pattern of relapse at 4 years was similar in the two treatment arms. Distant metastases were the cause of treatment failure in approximately 50% of relapsing patients.39
A clinical benefit of CCRT for head and neck cancer has been demonstrated, with significantly better locoregional control and better survival in most trials.40,41 Also, the most promising role for chemotherapy is CCRT for patients with locoregionally advanced NPC. Intergroup 0099 was designed as a prospective and randomized phase III trial to test three cycles of concurrent cisplatin and conventional RT followed by three cycles of adjuvant cisplatin and fluorouracil compared with conventional RT alone for stage III or IV NPC patients without distant metastases (AJCC); the results showed a statistically significant improvement in 3-year survival (78% v 47%, respectively; P = .005) and progression-free survival (69% v 24%, respectively; P < .001).27 In endemic areas, a phase III study from Taiwan also showed a statistically significant improvement in 5-year OS rate in patients with locoregionally advanced NPC receiving two cycles of concurrent chemotherapy with cisplatin 20 mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour continuous infusion (72.3% for the CCRT arm and 54.2% for the RT-only arm, P = .0022). The 5-year progression-free survival rates were 71.6% for the CCRT group and 53.0% for the RT-only arm (P = .0012). The author thought that compliance with the combined treatment was good, although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis.42 Although a phase III randomized trial from Hong Kong reported no progression-free survival benefit of concurrent weekly cisplatin (40 mg/m2) chemotherapy compared with RT alone, there was significant benefit for the patients with advanced primary tumor and node stage, and the systemic and local toxicities were generally acceptable. The authors also suggest that concurrent cisplatin-RT should be offered as standard treatment to patients with advanced tumor and node stage NPC in endemic areas.43
Cisplatin-based chemotherapy has been demonstrated to have higher response rates in previously untreated, recurrent, or metastatic NPC patients than noncisplatin regimens.5-9,13 In our study, we chose oxaliplatin for three reasons. First, oxaliplatin is a new analog of platinum that has less renal and GI toxicity than cisplatin. Second, oxaliplatin is active in a wide range of cancers and has been found to be non–cross resistant with cisplatin in various cisplatin-resistant cell lines and tumors. Third, this chemotherapeutic agent has been shown to have radiosensitizing effects. Therefore, oxaliplatin may be an active and tolerable chemotherapeutic agent in the treatment of NPC.14-24
In our protocol, all patients had relatively good compliance, and most of the patients completed the treatment. Fifty-five patients in the CCRT arm completed the planned concurrent chemotherapy, and all patients were eligible for toxicity and response analysis. No fatal toxicity related to planned treatment was observed in either arm. The peripheral neurotoxicity was not common in the CCRT arm. Only 20% of patients experienced grade 1 or 2 acute toxicity (P = .0009), and at the end of treatment, there was complete regression of paresthesias. Compared with many other studies, our CCRT study had a low rate of neurotoxicity, and the maximum toxicity was grade 2. We think this difference is related to different schedules of oxaliplatin. In particular, the weekly administration of oxaliplatin was considered to be associated with considerably less neurotoxicity than other schedules.20-23,46 Although a higher incidence of grade 1 or 2 leukopenia and nausea and vomiting was observed in patients on the CCRT treatment arm (P < .01), our CCRT protocol was more tolerable, with less severe grade 3 to 4 leukopenia and emesis than many previous trials, as well as none of the renal toxicity and increased mucositis that limits compliance with cisplatin.27,42-45 No difference in dry mouth and mucositis toxicity was seen between the two arms. However, it should be noted that the P value of the skin reaction toxicity was marginal between the CCRT and RT arms (P = .062), there were more patients experiencing grade 3 incidence in the CCRT arm, and a difference was seen only if the grade 3 toxicity was observed between the two arms (P = .026). Skin reaction toxicity may be the dose-limiting toxicity, and it should be paid more attention to in further trials. Because there was no dose escalation and few patients had dose reductions, the optimal dose and the maximum-tolerated dose and associated dose-limiting toxicities were unclear. We think further evaluation of this combination to find the maximum-tolerated dose and dose-limiting toxicities may be helpful in acquiring more survival benefits.
Compared with the studies by Al-Sarraf et al27 and Lin et al,42 our study also showed significant survival benefits with respect to OS and MFS favoring the CCRT arm. A 2-year OS rate of 100% was observed in the CCRT arm compared with a rate of 77% in the RT arm (P = .01). The 2-year MFS rates were 92% and 80% in the CCRT and RT arms, respectively (P = .02). The 2-year RFS rates were 96% for the CCRT group and 83% for the RT-alone arm (P = .02). The survival benefits of concurrent chemotherapy seem to be a result of a better distant and locoregional control. Our CCRT protocol was effective not only in reducing distant metastasis but also in reducing locoregional relapse, and this advantage did translate into an improvement in OS.
In summary, the results of our study strongly support the superior efficacy of CCRT. CCRT with oxaliplatin weekly is feasible and improves the OS, RFS, and MFS rates in patients with locoregionally advanced NPC. Furthermore, our trial is the first to demonstrate an improved OS with concurrent chemotherapy with a single drug for locoregionally advanced NPC patients. We think it is warranted that some schedules that include oxaliplatin combined with other drugs, such as fluorouracil/leucovorin, be initiated during CCRT in an attempt to further reduce distant treatment failure rates and increase survival benefit. Further randomized phase III studies comparing these schedules with concurrent cisplatin-RT should be helpful.
Authors' Disclosures of Potential Conflicts of Interest
We thank Sanofi-Synthelabo Corporation for providing free samples (Eloxatin) for our study and Ying-Guo for her statistical consideration. We also thank all of the patients and their families for their willingness to take part in this study.
Acknowledgment
We thank Sanofi-Synthelabo Corporation for providing free samples (Eloxatin) for our study and Ying-Guo for her statistical consideration. We also thank all of the patients and their families for their willingness to take part in this study.
NOTES
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data—MACH-NC Collaborative Group: Meta-analysis of chemotherapy on head and neck cancer. Lancet 355:949-955, 2000
Lin J-C, Jan J-S, Hsu C-Y, et al: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: Positive effect on overall and progression-free survival. J Clin Oncol 21:631-637, 2003
Chan ATC, Teo PML, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20:2038-2044, 2002
Cooper JS: Concurrent chemotherapy and radiation therapy for advanced stage carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 48:1277-1279, 2000
Tan EH, Chua ET, Wee J, et al: Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: Toxicities and preliminary results. Int J Radiat Oncol Biol Phys 45:597-601, 1999
André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004(Li Zhang, Chong Zhao, Pei)
ABSTRACT
PURPOSE: A prospective, randomized, phase III study was performed to evaluate the feasibility and efficacy of concurrent weekly oxaliplatin with radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC).
PATIENTS AND METHODS: From January 2001 to January 2003, 115 patients with locoregionally advanced NPC were randomly assigned to either radiotherapy (RT) alone (56 patients) or concurrent chemoradiotherapy (CCRT; 59 patients). All patient characteristics were well balanced in both arms. CCRT with oxaliplatin 70 mg/m2 weekly was administered for six doses from the first day of RT.
RESULTS: All patients were eligible for toxicity and response analysis. Compliance with the protocol treatment was excellent, with 97% of patients completing all planned doses of oxaliplatin, and a lack of high-grade toxicity was observed. After a median follow-up time of 24 months, there was a significant difference in overall survival (OS), relapse-free survival (RFS), and metastasis-free survival (MFS) in favor of the CCRT arm. The 2-year OS rates were 100% for the CCRT arm and 77% for the RT arm (P = .01). The 2-year MFS rates were 92% for the CCRT arm and 80% for the RT arm (P = .02). The 2-year RFS rates were 96% for the CCRT arm and 83% for the RT arm (P = .02).
CONCLUSION: CCRT with weekly oxaliplatin is feasible and improves OS, MFS, and RFS rates in patients with locoregionally advanced NPC. Therefore, further randomized trials including oxaliplatin are warranted.
INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. Radiotherapy (RT) remains the standard treatment for NPC patients. Although a number of improvements have been achieved both in the technology and equipment of RT, the 5-year survival rate of NPC patient remains approximately 50%. Locoregionally advanced NPC patients have a poorer prognosis, with 5-year survival rates between 10% and 40%. The main cause of failure is locoregional relapse and distant metastasis.1-4
NPC is also a chemotherapy-sensitive disease, and concurrent chemoradiotherapy (CCRT) has been an important investigational subject for many years in the treatment of locoregional advanced NPC.5-13 Therefore, it is a major objective to seek the best combined modality of CCRT and explore new drugs and new regimens to improve outcome in this prevalent disease.
Oxaliplatin is a new analog of platinum that has no renal and fewer GI toxicities than cisplatin. The myelosuppression is also milder and easier to manage than the myelosuppression experienced with carboplatin. The main and dose-limiting toxicity of oxaliplatin is acute and cumulative short-term sensory peripheral neuropathy. Its mechanism of action is thought to be similar to that of cisplatin. Preclinical data have shown that oxaliplatin is active in a wide range of human and murine tumor cell lines. In clinical practice, oxaliplatin combined with fluorouracil/leucovorin has been approved as first-line treatment for advanced colorectal carcinoma14-23; the documented activity of oxaliplatin in head and neck cancer has also been reported in a phase II trial.24 In addition to the clinical synergy with fluorouracil and other cytotoxic agents, synergy with RT has been established both in vitro and in the clinic.25,26
Although CCRT has been considered standard practice in North America based on the results of the Intergroup 0099 trial, it is still unclear whether these results, which were derived from a heterogeneous histologic mix of patients, can be directly applied to WHO subtype III undifferentiated NPC patients. (In endemic areas such as southern China, the proportion of patients with WHO subtype III histology is greater than 90%). In addition, the results were unexpectedly inferior in the RT-alone arm.27 On the basis of these considerations, we initiated a prospective study to compare the objective response and safety profile of standard RT versus the same RT plus weekly oxaliplatin in patients with locoregionally advanced NPC.
PATIENTS AND METHODS
Eligibility Criteria
Patients were evaluated using the 1997 American Joint Committee on Cancer (AJCC)/International Union Against Cancer staging system.28 Patients were required to have had histologic proof of WHO subtype I, II, or III NPC. Disease stage had to be N2/N3 and any T or T3/T4 and any N without evidence of distant metastases (M0). Patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 2, and provided written informed consent. Adequate renal, hepatic, and bone marrow function (WBC count 4,000/μL and platelet count 100,000/μL) and normal ECG were also required. The study protocol was approved by the Research Ethics Committee of the Cancer Center of Sun Yat-Sen University.
Pretreatment Evaluation
The initial evaluation included medical history, physical examination, CBC with differentials, full biochemistry profile, ECG, and Epstein-Barr virus serology test. Tumor staging was determined on the basis of the patient's clinical examination, including nasopharyngoscopy, computed tomography (CT) or magnetic resonance imaging (MRI) scan of the head and neck, and chest x-ray. Hepatic ultrasonographies were performed as indicated. Radionuclide bone scan was performed in the patients with bone pain, elevated serum alkaline phosphatase, or N2 to N3 disease. All staging work-up should have been completed within 3 weeks before treatment.
RT
All patients were treated in an identical method by definitive-intent RT in both the RT and the CCRT arms. Details of our RT technique in Cancer Center of Sun Yat-Sen University have been reported previously.29,30 Irradiation fields were chosen according to the extension of the tumor. The target volume was delineated by CT scan or MRI and was the entire tumor with a 2-cm margin in all directions. Photons (6 MV) produced by linear accelerator (Varian, Palo Alto, CA) were used to treat the primary tumor and neck lymph nodes. Patients were treated by conventional fractionation (RT was administered five times a week at 2 Gy/d on Monday through Friday). The en bloc technique was used for the patients with upper cervical nodes, oropharyngeal involvement, or extensive parapharyngeal involvement. Forty grays were delivered with two lateral opposing facio-cervical portals to irradiate the nasopharynx and the upper neck. The lower neck was irradiated by a separate anterior 6-MV photon field to a similar dose as the primary tumor with midline structure shielded off. Thereafter, 30 to 34 Gy was delivered to the primary tumor by the shrinking-field technique (two lateral-opposed facial fields) to avoid excessive irradiation to the spinal cord. An anterior cervical field was used to treat the whole neck with a spinal cord block. The accumulated radiation doses to the primary tumor were 70 to 74 Gy. The accumulated doses were 60 to 64 Gy to the involved areas of the neck and 50 Gy to the uninvolved areas.
Boost doses of 10 Gy in 5 fractions were delivered to the skull base in the patients with involvement of skull bone and intracranial extension, and an anterior facial electron field was added in the case of nasal or ethmoidal involvement. For patients with a residual tumor in the primary site (especially in the parapharyngeal space) after a 70-Gy dose was delivered, the total dose could be boosted to 80 Gy with the cone-down technique. Any palpable residual nodes after external RT were boosted to 70 Gy at the 90% isodose level with an electron field (9 to 12 MeV).
When possible, salvage treatments were administered to patients after documented relapse or when disease was persistent. The salvage treatments included reirradiation, chemotherapy, and surgery.
Concurrent Chemotherapy
The concurrent chemotherapy regimen was oxaliplatin 70 mg/m2 by intravenous infusion over 2 hours weekly, repeated for six times. All patients received an antiemetic prophylaxis of 5-hydroxytryptamine-3 receptor antagonist. The dose of oxaliplatin was adjusted according to the neutrophil and platelet counts. If the neutrophil count was 1,500/μL and the platelet count was 100,000/μL, the patient was administered the full dose of oxaliplatin. If the neutrophil count was less than 1,500/μL and the platelet count was less than 100,000/μL, the patient's chemotherapy was postponed for 1 week. If the neutrophil count was still less than 1,500/μL on day 15, chemotherapy was discontinued. The dose of oxaliplatin was reduced by 25% in case of grade 3 peripheral neuropathy.
We chose this dose and schedule of oxaliplatin because of the following reasons. First, there were a lot of studies using a weekly oxaliplatin schedule in colorectal cancer, and the dose of oxaliplatin ranged from 50 to 65 mg/m2/wk. Given the favorable toxicity profile of the weekly oxaliplatin schedule in colorectal cancer, we chose a dose of 70 mg/m2/wk.23,31 Second, this study aimed to assess the efficacy and safety of oxaliplatin and RT; thus, we performed this trial in the following three steps. At the beginning, we enrolled 10 patients to check the tolerability of this dose and dose schedule combined with RT concurrently. When we found that it was feasible and tolerable, we enrolled more patients onto the study at this dose and schedule. After 39 patients were enrolled onto this study group, we reported preliminary results at the 39th Annual Meeting of the American Society of Clinical Oncology.32 Finally, we completed this study with 59 patients enrolled onto the CCRT arm.
Patient Assessment and Follow-Up
Three months after completion of treatment, tumor response was assessed by CT scan or MRI and clinically by flexible nasopharyngoscopy. All objective responses were evaluated 3 months after completion of treatment and reviewed by an external expert committee. Treatment response and systemic toxicities were evaluated according to the WHO criteria, except peripheral neurotoxicity.33 Radiation toxicities were graded according to the European Organisation for Research and Treatment of Cancer Radiation Therapy Oncology Group. Peripheral neurotoxicity was graded according to the following oxaliplatin-specific scale from Caussanel et al34: grade 1, paresthesias/hypoesthesias of short duration (less than 7 days); grade 2, paresthesias/hypoesthesias persisting for 8 to 14 days; grade 3, permanent paresthesia/dysesthesia without functional impairment; grade 4, paresthesia/dysesthesia resulting in functional impairment. Toxicity was assessed before every week in both treatment arms, and hematologic assessments were performed weekly. After completion of treatment, the patients were observed weekly until acute adverse effects resolved. Patients were then evaluated every 2 months during the first year, every 3 months during years 2 and 3, and every 6 months thereafter.
Follow-up duration was calculated from the day of random assignment to either the day of death or the day of the last examination. All local recurrences were diagnosed by flexible nasopharyngoscopy and biopsy and/or CT scan of the nasopharynx and the skull base showing progressive bone erosion and/or soft tissue swelling. Regional recurrences were diagnosed by clinical examination of the neck and, in doubtful cases, by fine-needle aspiration or CT scan of the neck. Distant metastases were diagnosed by clinical symptoms, physical examination, and imaging methods including chest x-ray, bone scan, CT scan, and abdominal sonography.
Statistical Analysis
The primary end point of the study was to compare the overall survival (OS) of locoregionally advanced NPC patients treated with standard RT versus the same RT regimen plus weekly oxaliplatin. The secondary end point was to evaluate and compare the objective response rate, the safety profile of the combination, and the relapse-free survival (RFS) and metastasis-free survival (MFS) rates in both arms. On the basis of our previous experience, a 3-year survival rate of 60% for RT alone in the NPC population, and the results of the Intergroup 0099 trial (the authors acquired a 30% additional improvement in 3-year survival rate from 46% to 76%),27 we hypothesized that our CCRT regimen would be of great interest if it resulted in a 85% 3-year survival rate in an NPC population. For a significance level of 0.05 with power equal to 80%, a minimum sample size of 94 patients was determined.
SPSS 10.0 statistical software was used (SPSS Inc, Chicago, IL). Time was measured from the date of random assignment until the time of first failure or the most recent follow-up. OS was defined as the time elapsed from the date of random assignment to the date of death. RFS was measured from the date of random assignment to the date of the first observation of progressive disease. MFS was measured from the date of random assignment to the date of the first observation of metastatic disease. Patients who died of any cause without locoregional recurrence or distant metastases were censored at the last follow-up in the case of RFS and MFS. The Kaplan-Meier product-limit method was used in the calculation of OS, RFS, and MFS rates.35 Toxicity and response rates were compared using the 2 test. Fisher's exact test method was used when a small sample size existed. The statistical significance of differences among survival curves was analyzed using the log-rank test or Breslow test36,37; P .05 was considered statistically significant. Statistical tests were based on the two-sided significance level.
RESULTS
January 2001 to January 2003, 115 patients were entered onto the study (56 patients in the RT arm and 59 patients in the CCRT arm), and all patients were eligible for toxicity, response, and survival analysis (Table 1). All patient characteristics were well balanced in both arms (P > .05). The median follow-up time for the whole study was 24 months (range, 13 to 35 months). Compliance with the protocol treatment was excellent, with 97% of patients completing all planned doses of oxaliplatin and RT. Fifty-five patients (93%) received all six doses of oxaliplatin, three patients (5%) received five doses, and one patient received seven doses. The mean dose-intensity of oxaliplatin received was 69.60 mg/m2/wk (range, 58.3 to 81.6 mg/m2/wk).
Treatment Response
Clinical responses of the primary tumor site and of metastatic neck adenopathy were coded separately (Tables 2 and 3). All patients were assessable for response at the primary site. The complete response rate reached 83% (95% CI, 74% to 92%) in CCRT arm compared with 66% (95% CI, 54% to 78%) in the RT-alone arm (P = .032). Ninety-one patients were assessable for neck response. Complete response rates were 88% (95% CI, 79% to 97%) in the CCRT arm and 95% (95% CI, 88% to 100%) in the RT-alone arm (P = .233) in cervical lymph nodes. In the RT arm, three patients with neck recurrence received neck dissection. Five patients with nasopharynx recurrence received reirradiation (one patient received CCRT with cisplatin, and three patients received intensity-modulated RT). In the CCRT arm, one patient with neck recurrence received neck dissection. Two patients with nasopharynx recurrence received reirradiation (one patient received intensity-modulated RT). No salvage surgery for primary recurrence was performed.
Survival
In this study, significantly improved OS, RFS, and MFS rates were obtained in the CCRT arm. The 2-year OS rate was 100% in the CCRT arm compared with 77% (95% CI, 66% to 88%) in the RT arm (P = .01, log-rank test; Fig 1). The 2-year MFS rates were 92% (95% CI, 85% to 99%) in the CCRT arm and 80% (95% CI, 69% to 90%) in the RT arm (P = .02, log-rank test; Fig 2). Because the data in Figure 3 suggested some departure from the proportional hazard assumption of the log-rank test in the case of RFS, the Breslow test was used in this condition in addition to the log-rank test. The 2-year RFS rates were 96% (95% CI, 91% to 100%) in the CCRT arm and 83% (95% CI, 73% to 93%) in the RT arm (P = .02, Breslow test; P = .09, log-rank test; Fig 3). The 2-year local control rates were 96% (95% CI, 91% to 100%) in the CCRT arm and 88% (95% CI, 80% to 97%) in the RT arm (P = .16, log-rank test). The 2-year regional control rates were 100% in the CCRT arm and 94% (95% CI, 88% to 100%) in the RT arm (P = .09, Breslow test; P = .39, log-rank test). It seemed that a better locoregional control came from the combination of local control and regional control. The survival benefits of CCRT seemed to be caused by both a better distant and locoregional control.
Toxicity
All patients were evaluated for safety. The type and degree of acute toxicities in both arms are listed in Table 4. Toxicity was compared by combining all of the grades (0 through 4) in both arms. No fatal toxicity related to planned treatment was observed in either arm. A higher incidence of grade 1 or 2 leukopenia and nausea and vomiting was observed in the patients in the CCRT treatment arm (P < .01). The peripheral neuropathy in patients in the CCRT arm was reversible, no oxaliplatin-specific orolaryngeal neurotoxicity occurred, and only 20% of patients (95% CI, 11% to 29%) experienced grade 1 or 2 toxicity, although there was a significant difference between the two arms (P = .0009). The rates of grades 2 and 3 mucositis were similar in the two arms. In the CCRT arm, six patients had grade 3 mucositis, there was no grade 4 mucositis toxicity, and no patients required admission for intravenous hydration. There was no renal toxicity in either arm. No difference in dry mouth, dysphagia, and skin reaction toxicity was seen between the two arms.
With limited follow-up, late toxicities, including xerostomia, skin reaction, mucositis, and dysphagia, were similar between the two arms. A trend in the rate of late complaints for patients treated with CCRT was not observed. No bone necrosis and neurotoxicity were observed in the two treatment arms. More information will be reported with a longer follow-up time.
DISCUSSION
Traditional fractionated RT alone has been the standard treatment for NPC, with 5-year survival rates from 10% to 55%. Although early-stage NPC is highly radiocurable, the cure rate with RT alone for locoregionally advanced NPC is low.1-4 Because NPC is a chemotherapy-sensitive tumor, chemotherapy added to RT in various manners (concomitant, neoadjuvant, and adjuvant) should be a method to improve survival rates.5-13,27-30,38-45
Neoadjuvant chemotherapy has some advantages, such as decreasing tumor burden and facilitating further RT, organ and function preservation, and eradication of distant micrometastases. The International Nasopharynx Cancer Study Group has reported the preliminary results of a randomized trial comparing three cycles of neoadjuvant chemotherapy using bleomycin, epirubicin, and cisplatin plus RT versus RT alone in AJCC stage IV ( N2, M0) undifferentiated NPC. With a median follow-up of 49 months, no survival benefit could be demonstrated with the addition of neoadjuvant chemotherapy.38 Another prospective randomized trial by Ma et al29 in our cancer center also reported no survival benefit and no effect in reducing distant metastasis from two or three cycles of neoadjuvant chemotherapy consisting of cisplatin, bleomycin, and fluorouracil, although a trend of improved RFS favoring the chemotherapy plus RT group was observed.
The use of adjuvant chemotherapy to treat patients with NPC has never been proven to be of benefit. The large randomized trial with 229 patients, who were treated in Institute Nazionale Tumori in Milan, failed to demonstrate any survival benefit for patients receiving 6 monthly cycles of vincristine, cyclophosphamide, and doxorubicin compared with patients receiving no adjuvant chemotherapy. The pattern of relapse at 4 years was similar in the two treatment arms. Distant metastases were the cause of treatment failure in approximately 50% of relapsing patients.39
A clinical benefit of CCRT for head and neck cancer has been demonstrated, with significantly better locoregional control and better survival in most trials.40,41 Also, the most promising role for chemotherapy is CCRT for patients with locoregionally advanced NPC. Intergroup 0099 was designed as a prospective and randomized phase III trial to test three cycles of concurrent cisplatin and conventional RT followed by three cycles of adjuvant cisplatin and fluorouracil compared with conventional RT alone for stage III or IV NPC patients without distant metastases (AJCC); the results showed a statistically significant improvement in 3-year survival (78% v 47%, respectively; P = .005) and progression-free survival (69% v 24%, respectively; P < .001).27 In endemic areas, a phase III study from Taiwan also showed a statistically significant improvement in 5-year OS rate in patients with locoregionally advanced NPC receiving two cycles of concurrent chemotherapy with cisplatin 20 mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour continuous infusion (72.3% for the CCRT arm and 54.2% for the RT-only arm, P = .0022). The 5-year progression-free survival rates were 71.6% for the CCRT group and 53.0% for the RT-only arm (P = .0012). The author thought that compliance with the combined treatment was good, although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis.42 Although a phase III randomized trial from Hong Kong reported no progression-free survival benefit of concurrent weekly cisplatin (40 mg/m2) chemotherapy compared with RT alone, there was significant benefit for the patients with advanced primary tumor and node stage, and the systemic and local toxicities were generally acceptable. The authors also suggest that concurrent cisplatin-RT should be offered as standard treatment to patients with advanced tumor and node stage NPC in endemic areas.43
Cisplatin-based chemotherapy has been demonstrated to have higher response rates in previously untreated, recurrent, or metastatic NPC patients than noncisplatin regimens.5-9,13 In our study, we chose oxaliplatin for three reasons. First, oxaliplatin is a new analog of platinum that has less renal and GI toxicity than cisplatin. Second, oxaliplatin is active in a wide range of cancers and has been found to be non–cross resistant with cisplatin in various cisplatin-resistant cell lines and tumors. Third, this chemotherapeutic agent has been shown to have radiosensitizing effects. Therefore, oxaliplatin may be an active and tolerable chemotherapeutic agent in the treatment of NPC.14-24
In our protocol, all patients had relatively good compliance, and most of the patients completed the treatment. Fifty-five patients in the CCRT arm completed the planned concurrent chemotherapy, and all patients were eligible for toxicity and response analysis. No fatal toxicity related to planned treatment was observed in either arm. The peripheral neurotoxicity was not common in the CCRT arm. Only 20% of patients experienced grade 1 or 2 acute toxicity (P = .0009), and at the end of treatment, there was complete regression of paresthesias. Compared with many other studies, our CCRT study had a low rate of neurotoxicity, and the maximum toxicity was grade 2. We think this difference is related to different schedules of oxaliplatin. In particular, the weekly administration of oxaliplatin was considered to be associated with considerably less neurotoxicity than other schedules.20-23,46 Although a higher incidence of grade 1 or 2 leukopenia and nausea and vomiting was observed in patients on the CCRT treatment arm (P < .01), our CCRT protocol was more tolerable, with less severe grade 3 to 4 leukopenia and emesis than many previous trials, as well as none of the renal toxicity and increased mucositis that limits compliance with cisplatin.27,42-45 No difference in dry mouth and mucositis toxicity was seen between the two arms. However, it should be noted that the P value of the skin reaction toxicity was marginal between the CCRT and RT arms (P = .062), there were more patients experiencing grade 3 incidence in the CCRT arm, and a difference was seen only if the grade 3 toxicity was observed between the two arms (P = .026). Skin reaction toxicity may be the dose-limiting toxicity, and it should be paid more attention to in further trials. Because there was no dose escalation and few patients had dose reductions, the optimal dose and the maximum-tolerated dose and associated dose-limiting toxicities were unclear. We think further evaluation of this combination to find the maximum-tolerated dose and dose-limiting toxicities may be helpful in acquiring more survival benefits.
Compared with the studies by Al-Sarraf et al27 and Lin et al,42 our study also showed significant survival benefits with respect to OS and MFS favoring the CCRT arm. A 2-year OS rate of 100% was observed in the CCRT arm compared with a rate of 77% in the RT arm (P = .01). The 2-year MFS rates were 92% and 80% in the CCRT and RT arms, respectively (P = .02). The 2-year RFS rates were 96% for the CCRT group and 83% for the RT-alone arm (P = .02). The survival benefits of concurrent chemotherapy seem to be a result of a better distant and locoregional control. Our CCRT protocol was effective not only in reducing distant metastasis but also in reducing locoregional relapse, and this advantage did translate into an improvement in OS.
In summary, the results of our study strongly support the superior efficacy of CCRT. CCRT with oxaliplatin weekly is feasible and improves the OS, RFS, and MFS rates in patients with locoregionally advanced NPC. Furthermore, our trial is the first to demonstrate an improved OS with concurrent chemotherapy with a single drug for locoregionally advanced NPC patients. We think it is warranted that some schedules that include oxaliplatin combined with other drugs, such as fluorouracil/leucovorin, be initiated during CCRT in an attempt to further reduce distant treatment failure rates and increase survival benefit. Further randomized phase III studies comparing these schedules with concurrent cisplatin-RT should be helpful.
Authors' Disclosures of Potential Conflicts of Interest
We thank Sanofi-Synthelabo Corporation for providing free samples (Eloxatin) for our study and Ying-Guo for her statistical consideration. We also thank all of the patients and their families for their willingness to take part in this study.
Acknowledgment
We thank Sanofi-Synthelabo Corporation for providing free samples (Eloxatin) for our study and Ying-Guo for her statistical consideration. We also thank all of the patients and their families for their willingness to take part in this study.
NOTES
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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