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© 2002 American Society for Clinical Oncology Excellent Disease Control and Survival in Patients With Advanced Nasopharyngeal Cancer Treated With ChemoradiationByFrom the Division of Hematology and Medical Oncology, Division of Radiation Oncology, and Statistical Center, Peter MacCallum Cancer Institute, Melbourne, Australia. Address reprint requests to Danny Rischin, MD, Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag No 1, A’Beckett St, Melbourne 8006, Australia; email: drischin{at}petermac.unimelb.edu.au
PURPOSE: To determine the efficacy and safety of epirubicin, cisplatin, and infusional fluorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally advanced nasopharyngeal cancer. PATIENTS AND METHODS: Thirty-five patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m2 and cisplatin 75 mg/m2 combined with continuous-infusion 5-FU 200 mg/m2 daily for 9 weeks, followed by concurrent chemoradiation of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m2 daily for 5 days in weeks 1 and 6. RESULTS: Median age was 43 years, 74% had World Health Organization type III histology, and 91% had stage IV disease (International Union Against Cancer, ed 4). All patients received three cycles of induction chemotherapy, and 97% completed chemoradiation. The estimated 4-year progression-free survival rate was 81% (95% CI, 59% to 93%), and the estimated 4-year overall survival rate was 90% (95% CI, 74% to 97%). Only two patients have had a locoregional relapse by the close-out date despite the use of only 60 Gy. Induction chemotherapy was well tolerated, with 11% grade 3 or 4 stomatitis, 26% grade 3 vomiting, and no episodes of febrile neutropenia. Acute toxicities of chemoradiation were as follows: 23% grade 3 or 4 vomiting, 6% febrile neutropenia, 31% grade 3 mucositis, and 23% grade 3 skin toxicity. The most prevalent grade 3 late effects were xerostomia and hearing loss. CONCLUSION: This regimen was well tolerated, can be delivered as planned, and has resulted in excellent locoregional disease control and survival in patients with locally advanced nasopharyngeal cancer.
NASOPHARYNGEAL CANCER has traditionally been treated with radiation alone. However, high rates of both locoregional recurrence and distant metastases have been reported in patients with locally advanced nasopharyngeal cancer treated with radiation alone.1-3 The poor results in patients with locally advanced disease, with 5-year survival of 15% to 50%, has led to the investigation of the benefit of adding chemotherapy to the primary treatment of nasopharyngeal cancer. Nasopharyngeal cancer is a relatively chemosensitive disease,4 hence the rationale for using induction or adjuvant chemotherapy to decrease distant metastases. Furthermore, there is increasing evidence that concurrent chemoradiation in a variety of malignancies may improve locoregional control and overall survival.5-7 The Intergroup trial demonstrated a marked improvement in progression-free and overall survival from the addition of concurrent cisplatin during radiation followed by three cycles of cisplatin and fluorouracil (5-FU).8 Although the results of this trial altered practice in many centers, other investigators have expressed concern that the high proportion of patients with World Health Organization (WHO) stages I and II histology casts doubt on the relevance of the results to populations with predominantly undifferentiated nasopharyngeal carcinomas.9 Moreover, the practicality of the Intergroup regimen has been questioned: on the chemoradiation arm, only 73% patients completed treatment as planned, with 63% receiving all three cycles of concurrent chemotherapy and 55% receiving the three planned cycles of adjuvant chemotherapy. In this trial, we set out to investigate an induction and concurrent chemoradiation regimen with the radiation dose limited to 60 Gy, that we postulated may be feasible to deliver in a high proportion of patients with acceptable toxicity. We chose to study the epirubicin/cisplatin/5-FU (ECF) regimen, with a higher cisplatin dose, in the induction phase of the treatment program, as this regimen has demonstrated impressive activity in a number of malignancies,10,11 good tolerability, and includes three drugs with proven activity in nasopharyngeal cancer.
Eligibility Patients were required to have histologically proven carcinoma of the nasopharynx (any WHO type), International Union Against Cancer, ed 4 (UICC, ed 4), stage III or IV disease, and no systemic metastatic disease (M0) on staging. Other eligibility criteria were age  16 years, WHO performance status 0 to 2, absolute neutrophil count 2.0 x 109/L, platelet count 100 x 109/L, creatinine clearance or glomerular filtration rate 1.0 mL/sec, serum bilirubin  1.5 times upper limit of normal, and left ventricular ejection fraction measured by gated cardiac scan within the normal range. Written informed consent was obtained from all patients, and the Institutional Ethics Committee approved the protocol.
Patients were excluded from the trial for any of the following: prior chemotherapy or radiotherapy, prior malignancy apart from nonmelanoma skin cancer or carcinoma-in-situ of the cervix, significant hearing impairment unless attributable to nasopharyngeal cancer, pre-existing motor or sensory neurotoxicity
Pretreatment and Follow-Up Evaluations While on induction chemotherapy, patients were clinically assessed weekly for toxicity and CBC including differential. Electrolytes, serum creatinine, and liver function tests were performed every 3 weeks. During radiotherapy, patients were clinically assessed weekly for toxicity, and CBC including differential, electrolytes, serum creatinine, and liver function tests were performed before each cycle of chemotherapy. Assessment of tumor response by clinical examination was performed after every cycle during induction chemotherapy, and every 2 months after completion of treatment. MRI or CT scanning took place after completion of induction chemotherapy and 2 months after completion of radiotherapy. Thereafter, imaging was based on clinical indications only. Systemic toxicity from treatment was graded according to WHO criteria. Mucous membrane radiation toxicity was graded according to the European Organization for Research and Treatment of Cancer–Radiation Therapy Oncology Group (RTOG) toxicity criteria. Antitumor activity was assessed according to the WHO response criteria. Nonpalpable, nonnecrotic lymph nodes less than 1 cm seen on pretreatment MRI or CT scans were not considered to be significant. Similarly, nonpalpable, nonnecrotic nodes less than 1 cm seen on follow-up scans were not deemed to be significant.
Treatment Plan
During radiation, cisplatin was administered daily at a dose of 20 mg/m2 for 5 days in weeks 1 and 6, and given approximately 15 to 45 minutes before radiation on those days. Antiemetics, including a 5-hydroxytryptamine antagonist and 8 mg of dexamethasone, were given daily on days cisplatin was administered. Prophylactic recombinant granulocyte colony-stimulating factor support was not permitted.
Radiation Therapy
Dose Modification for Toxicity
Statistical Methods Late effects were recorded if they occurred or persisted for more than 6 months after completing chemoradiation and were graded using the RTOG criteria, except for peripheral neuropathy and ototoxicity, which were graded by National Cancer Institute common toxicity criteria. For estimating time to develop grade 3 or 4 late effects, the first grade 3 or 4 late effect was counted as an event and times were censored for patients who did not develop any grade 3 or 4 late effect before the close-out date. The date of censoring was the date of death for one patient who died before completing chemoradiation, the date of last assessment for patients who progressed or died more than 6 months after chemoradiation, and the close-out date for the remaining patients.
Patient Characteristics From September 1995 to February 1999, 35 patients were enrolled onto this study. Patients had predominantly undifferentiated carcinomas (WHO type 3), with the details of patient characteristics listed in Table 1. According to the original staging criteria stipulated in the protocol (UICC, ed 4, 1992) three patients (9%) had stage III disease, and 32 (91%) had stage IV disease (Table 2). During the conduct of the trial, new staging criteria (UICC criteria, ed 5, 1997) became available (Table 3). Under the new staging system, skull base or clivus invasion is classified as T3 rather than T4. Also, only N3 nodal disease (not N2) counts as stage IV under the new system. These changes in classification reduced the number of patients in stage IV to 40%. However, it is noteworthy that of these, six had documented intracranial extension and eight had large-volume and/or supraclavicular lymphadenopathy. Thirty-two patients (91%) had a baseline MRI scan of head and neck, with the remaining 9% having a CT scan only. All patients had a baseline chest x-ray and bone scan, and 34 (97%) had a liver CT scan or ultrasound.
Efficacy After completion of induction chemotherapy, 30 (86%) of 35 patients (95% confidence interval [CI], 70% to 95%) achieved a response on clinical and MRI/CT examination, with two achieving a complete response and 28 a partial response. After completion of chemoradiation, all 34 assessable patients were in complete response, on the basis of clinical examination alone, but eight had a residual abnormality on imaging and hence were deemed to be in partial response. The median potential follow-up time from commencing treatment to the close-out date was 43 months (range, 23 to 65 months). Thirty patients remained alive and in remission at the close-out date. One patient died of unrelated causes (scleroderma) while in complete remission, and one patient died after a sagittal sinus thrombosis while on treatment. One patient died after developing local recurrence and distant metastases 21.2 months after commencing treatment. This was one of the patients who had the upper level of their treatment field reduced to limit the dose to the optic chiasm to 54 Gy. Another two patients relapsed but remained alive at the close-out date; one developed distant metastases 3.3 months after commencing treatment, and another had a regional nodal recurrence 47.9 months after commencing treatment. The regional nodal recurrence occurred at a site that had previously received 50 Gy, as it was below the level of his known nodal disease at initial diagnosis. Progression-free and overall survival curves are shown in Figs 2 and 3. The 4-year progression-free survival rate was estimated to be 81% (95% CI, 59% to 93%), and the 4-year overall survival rate was estimated to be 90% (95% CI, 74% to 97%).
Toxicity Induction chemotherapy was generally well tolerated (Table 4). Grade 3 or 4 neutropenia occurred in 11 patients (31%) during induction chemotherapy but was not complicated by febrile neutropenia. Seven patients had central venous catheter–related infections. Grade 3 or 4 5-FU–related stomatitis occurred in four patients (11%), and nine patients (26%) experienced grade 3 vomiting after receiving cisplatin and epirubicin. During induction chemotherapy, all patients developed grade 2 or worse toxicity and 21 patients (60%) developed at least one grade 3 or 4 toxicity, excluding alopecia. All patients received three cycles of induction chemotherapy. Five patients (14%) had a dose reduction of cisplatin and/or epirubicin. Sixteen patients (46%) had a dose delay of 5 days, most commonly because of delayed neutrophil recovery. Nine patients (26%) had a dose reduction of 5-FU, most commonly because of stomatitis. Five days after the third cycle of induction chemotherapy while still on 5-FU, a 50-year-old woman had a syncopal episode with a subsequent seizure and evidence of watershed cerebral infarcts on MRI. She made a complete recovery over a period of several days. She was presumed to have been hypotensive during the syncopal episode, to account for the watershed cerebral infarcts. The cause of the syncopal episode and possible associated hypotension is not known, but one possibility was a 5-FU–related cardiac arrhythmia. Her 5-FU was ceased and she proceeded with chemoradiation, and completed treatment successfully.
Toxicities during and after chemoradiation are listed in Table 5. All patients developed grade 2 or worse toxicity and 28 (80%) developed at least one grade 3 or 4 toxicity, excluding alopecia. Grade 3 or 4 neutropenia occurred in six (17%) patients and was complicated by febrile neutropenia in two patients. Another two patients had chest infections not associated with neutropenia. Grade 3 or 4 nausea and vomiting caused by the cisplatin occurred in eight (23%). There was one death while on treatment. A 46-year-old man developed a sagittal sinus thrombosis at the end of the second week of radiotherapy, which was subsequently complicated by a massive cerebral hemorrhagic infarct. His condition continued to deteriorate and he died 2 weeks later. It was thought that he may have had a septic thrombosis, but all cultures were negative. He was not neutropenic, and his peripherally inserted central venous catheter remained in the correct position and there was no clinical evidence of infection. He had no past history of thrombosis. He had achieved an excellent partial response to induction chemotherapy and was very well until his acute presentation with the sagittal sinus thrombosis.
Acute radiation toxicity was as expected, with 31% and 23% patients experiencing grade 3 mucositis and skin toxicity, respectively (Table 5). The median duration of acute mucositis RTOG grade 2 was 9 weeks (range, 0 to 30 weeks). Thirteen patients (37%) required enteral feeding via a percutaneous endoscopic gastrostomy or nasogastric tube. The median weight loss within 90 days of commencing chemoradiation as a percentage of weight on commencing radiotherapy was 11% (range, 2% to 22%). The median duration of WHO grade 2 skin reaction was 4 weeks (range, 0 to 19 weeks). Thirty-three patients (94%) received the protocol-specified radiation dose of 60 Gy to the primary tumor and involved neck. One patient received a planned dose of 54 Gy in 30 fractions, as permitted in the protocol, owing to the intracranial extent of his disease, which precluded administration of a higher dose. The patient who died during treatment received 20 Gy before cessation of treatment. In the 34 patients who completed radiation, the duration of radiotherapy was 39 to 44 days (protocol-specified, 42 days). The 34 patients who completed treatment all received two cycles of chemotherapy during radiation. One patient received carboplatin in the first week because of a decrease in his GFR to 0.8 mL/min. An additional three patients received carboplatin in week 6 because of a reduction in GFR in two cases and severe emesis with prior cisplatin in the other patient. One patient had a dose reduction of cisplatin in week 6 because of febrile neutropenia after the previous cycle. The patient who had received carboplatin in week 1 only received 2 days of carboplatin in week 6, as he developed grade 3 neutropenia on the second day. The late toxicities of combined treatment are listed in Table 6. Apart from hearing loss and peripheral neuropathy, these were similar to those reported with radiation alone for nasopharyngeal cancer. Seventeen patients (50%) experienced ear or hearing difficulties beyond 6 months after radiotherapy. Five patients had mild or moderate otitis externa; 12 patients had middle ear effusions or infections that resulted in some hearing impairment, with one being graded as severe; and seven patients had hearing impairment resulting from inner ear problems, with two being graded as severe. These patients had no clinically apparent hearing impairment before treatment, although baseline audiometry was not performed on this trial. During and after treatment, 16 patients (46%) developed symptoms of peripheral neuropathy, which persisted beyond 6 months after treatment in eight patients, grade 2 in one instance but grade 1 in the others. All 34 patients who survived at least 6 months after completing radiotherapy developed grade 2 or worse late effects. The estimated actuarial risk of grade 3 late effects at 4 years was 35% (95% CI, 20% to 53%), and no grade 4 late toxicity was observed.
In this phase II trial, we have demonstrated that a regimen of induction chemotherapy with epirubicin, cisplatin, and continuous-infusion 5-FU, followed by radiation with concurrent cisplatin in weeks 1 and 6 in patients with locally advanced nasopharyngeal cancer, is well tolerated and results in excellent 4-year progression-free and overall survival rates. The U.S. Intergroup trial, which demonstrated the superiority of chemoradiation followed by three cycles of cisplatin and 5-FU chemotherapy compared with radiation alone, reported 3-year progression-free and overall survival rates of 69% and 78%, respectively, in the chemoradiation arm, with a median follow-up of 32 months.8 Our 4-year results of 81% and 90% with a median follow-up of 43 months compare favorably, but such comparisons between trials need to be interpreted with caution. The results for both trials are derived from relatively short follow-up for nasopharyngeal cancer, and further relapses are inevitable with time. There were significant differences in patient populations and treatment regimens in the two trials. Although the stage distribution was similar, there was a higher proportion of patients with undifferentiated carcinomas (WHO type 3) in our trial. We administered induction rather than adjuvant chemotherapy, as administration of chemotherapy after radiation for head and neck cancer has proven difficult to deliver in previous trials. This is borne out by the Intergroup trial, in which only 55% of patients received all three planned cycles of adjuvant chemotherapy and 33% did not receive any adjuvant chemotherapy.8 In contrast, 100% of patients on our trial received all three cycles of induction chemotherapy. The chemotherapy regimens differed, with our regimen containing epirubicin, and the 5-FU was administered as a continuous infusion over 9 weeks rather than as three cycles of infusional 5-FU for 96 hours every 4 weeks. The cisplatin doses were similar, but were administered every 3 weeks in our trial and every 4 weeks in the Intergroup trial. The radiation dose in the Intergroup trial was 70 Gy, whereas we administered 60 Gy. Both trials gave concurrent cisplatin during radiation. In the Intergroup trial, there were three planned cycles of 100 mg/m2 in weeks 1, 4, and 7 of radiation, whereas in our regimen there were two planned cycles of 20 mg/m2/d for 5 days in weeks 1 and 6. All our patients completed chemoradiation (apart from the patient who died during treatment), but in the Intergroup trial 27% patients did not complete chemoradiation. Importantly, in our trial the prior administration of induction chemotherapy did not compromise the delivery of chemoradiation. The design of the Intergroup trial does not permit one to determine the relative contributions of concurrent versus adjuvant chemotherapy to the improved outcome compared with radiation alone. Similarly, with the excellent results achieved in our phase II trial, it is not possible to determine the relative contributions of the induction in addition to the concurrent chemotherapy, the administration of each concurrent cisplatin cycle in five divided doses rather than as a single dose, or the use of sophisticated radiation treatment planning techniques. Reported response rates to induction chemotherapy and to chemoradiation are quite variable. Most reports of induction chemotherapy in nasopharyngeal cancer have reported clinical assessment of response rates without any imaging assessments. In such trials, response rates of 65% to 91% have been reported, with complete response rates of 5% to 47%.9,12,13 In our trial, the equivalent clinical response rate after induction chemotherapy was 89%, with a 40% complete response (CR) rate. With the incorporation of imaging, predominantly MRI, into the assessment of response, the response rate in our trial remains high at 86%, but the CR rate drops to 6%. Assessment of response after radiation/chemoradiation has more often incorporated CT findings, with CR rates of 49% to 55% reported.8,12 In our trial, the response rate after chemoradiation was 97%, with a 74% CR rate. Twenty-three percent had a residual abnormality on MRI of uncertain significance, with no patient having any evidence of residual disease on clinical assessment. The relevance of residual abnormalities on MRI is uncertain, as only two patients had experienced a locoregional relapse by the close-out date. The primary rationale for induction or adjuvant chemotherapy in nasopharyngeal cancer has been to decrease the risk of developing distant metastases. The three large trials of induction without concurrent chemotherapy have not demonstrated improved overall survival compared with radiation alone.9,12,14 The International Nasopharynx Cancer Study Group trial demonstrated improved disease-free survival, but not improved overall survival.12 In that trial, which was restricted to patients with N2 or N3 undifferentiated carcinomas and used an induction regimen of three cycles of bleomycin, epirubicin, and cisplatin, significant toxicity and 8% treatment-related mortality was reported. In the Asian-Oceanian Clinical Oncology Association Trial, which was restricted to patients with Ho’s T3 or N2 or N3 or any stage with node size greater than 3 cm and poorly or undifferentiated carcinomas, no difference in relapse-free or overall survival was reported.9 Subset analyses in assessable patients and in patients with nodes greater than 6 cm favored the chemotherapy arm. The chemotherapy regimen was two to three cycles of epirubicin (110 mg/m2) and cisplatin (60 mg/m2). In a recently reported trial performed in Guangzhou, China, no difference in overall survival was seen, although there was a significant difference in relapse-free survival.14 In this trial, the chemotherapy regimen consisted of two to three cycles of cisplatin (100 mg/m2), bleomycin (10 mg/m2 on days 1 and 5), and 5-FU (800 mg/m2 continuous infusion on days 1 to 5), with only 32% receiving three cycles and 68% receiving two cycles. The chemotherapy regimens used in these three trials may not have been optimal, with the bleomycin, epirubicin, and cisplatin regimen having unacceptable toxicity, a relatively low dose of cisplatin in the Asian-Oceanian trial, and difficulty in administering the protocol-specified chemotherapy in the Guangzhou trial. The combination of cisplatin and 5-FU is the standard regimen for patients with metastatic nasopharyngeal carcinoma and the one administered in the Intergroup trial. We chose to base our regimen around this combination, but altered the 5-FU schedule to continuous infusion and added epirubicin. The ECF regimen has impressive activity, is well tolerated in other malignancies,10,11 and contains three drugs active in nasopharyngeal cancer. However, we used a higher dose of cisplatin than in the standard ECF regimen. As already discussed, one advantage of induction compared with adjuvant chemotherapy is the greater ability to administer full-dose chemotherapy as planned. Another potential advantage of induction over adjuvant chemotherapy is the reduction in tumor bulk juxtaposed to vital dose-limiting structures before radiation. In our trial, PTVs were not reduced on the basis of chemotherapy-induced response; however, the tumor bulk reduction after induction chemotherapy increased the probability that gross residual disease received the full radiation dose. Although randomized trials of induction chemotherapy without concurrent chemotherapy have not demonstrated any significant differences in overall survival, these trials do suggest that induction chemotherapy may improve locoregional control.9,12,14 In the International Cancer Study Group trial, the improved disease-free survival was attributable to a decrease in both locoregional relapses and distant metastases as sites of first failure.12 In the Asian-Oceanian Clinical Oncology Association Trial, the subgroup analysis in patients with bulky neck nodes showed a significant difference in relapse-free survival that was attributable to improved local control in the induction chemotherapy arm, without any difference in incidence of distant metastases as the site of first failure.9 Similarly, in the Guangzhou trial there was a significant difference in relapse-free survival that was attributable to improved local control.14 Recently, a large retrospective series from Hong Kong has been reported demonstrating improved local control in patients who received two cycles of induction chemotherapy compared with patients treated with radiation alone for locally advanced node-positive nasopharyngeal carcinoma.15 Multivariate analysis identified administration of chemotherapy as being of independent significance in determining the local failure rate. The role of concurrent chemotherapy alone (without induction or adjuvant chemotherapy) has not been studied in depth for nasopharyngeal cancer. In a preliminary report of a randomized trial of concurrent cisplatin conducted in Hong Kong, there was a borderline significant improvement in progression-free survival compared with radiation alone.16 It seems likely, on the basis of the available randomized trial data and our own results, that both induction or adjuvant chemotherapy and concurrent chemotherapy are required to achieve a significant improvement in overall survival in patients with locally advanced nasopharyngeal cancer. Although it is anticipated that concurrent chemotherapy will improve locoregional control, and hence its major impact would be in patients with advanced T-stage disease,17 it is possible that induction chemotherapy may also contribute to locoregional control in these patients, as well as being potentially beneficial in patients with advanced N-stage or low-neck disease, the group most at risk for distant metastases.18 The excellent locoregional control achieved in our trial with the moderate radiation dose of 60 Gy is noteworthy, especially because most recent trials have used higher doses of around 70 Gy.8,9,12,14,16 Two factors warrant discussion in this regard. First, a positive contribution of chemotherapy to locoregional control of nasopharyngeal cancer is much more convincing than for other head and neck cancers. Nasopharyngeal cancer is a chemosensitive tumor, and by analogy with tumors such as lymphomas and certain childhood cancers, it is not unreasonable to expect that high rates of locoregional control can be achieved with combined-modality treatment, using lower radiation doses than would be required with radiotherapy alone. Second, using standard radiotherapy techniques, the nominal dose administered to patients with advanced nasopharyngeal cancer is often greater than the actual dose to parts of the PTV, because of technical limitations to radiation dose delivery. In this trial, we used sophisticated treatment planning and delivery techniques to ensure that the specified tumor dose of 60 Gy was in fact received by a PTV encompassing all gross disease, unless the PTV included the optic chiasm (when a superior field reduction was made at 54 Gy). In cases where the disease had bilateral high posterolateral parapharyngeal extension and/or bilateral high posterior lymphadenopathy, this involved the use of asymmetric arc fields. With the advent of intensity-modulated radiation therapy, the technical constraints on dose delivery are reduced and it would now be possible to undertake dose escalation if necessary. On the other hand, if the results we have reported are maintained with longer follow-up, there may be no need to use a higher radiation dose for WHO type 3 disease when treated with induction and concurrent chemotherapy. However, a randomized trial confirming at least equivalent locoregional control would be required before it could be recommended that a radiation dose of 60 Gy rather than 70 Gy be widely adopted. The corollary of using a lower radiation dose is that the probability of late radiation toxicity should be less than with regimens using a tumor dose of 70 Gy. Our data would appear to bear out this prediction in that there have been to date no grade 4 late toxicities observed and no CNS toxicities of any grade. Nonetheless, late toxicity is still of some concern. In addition to xerostomia, which occurred to a moderate to severe degree in nearly all patients, we did encounter troublesome ototoxicity affecting the external, middle, and inner ear. The relative contribution of radiation and cisplatin to the incidence of sensorineural hearing loss is unclear. Ototoxicity is poorly documented in most reports on nasopharyngeal cancer treated by radiotherapy alone, probably because it is not included in the RTOG late toxicity criteria, but it is likely more common than generally believed. As discussed in regard to tumor dose escalation, new technologies such as intensity-modulated radiation therapy allow much more elegant dose distributions to be obtained than has hitherto been possible. In the context of treatment-related morbidity, reduced doses to the salivary glands and auditory apparatus would have significant benefit. Ototoxicity could also be reduced by development of less cisplatin-intensive chemotherapy regimens. Both these approaches are now under investigation. In summary, we have achieved excellent rates of locoregional control and survival in a series of patients with disease at least as advanced anatomically as those in the Intergroup trial. A phase III trial comparing the two strategies would seem indicated.
We thank Alan McKenzie for reviewing the MRI and CT scans of all patients treated on this trial and Paul Harari for critically reviewing the manuscript.
1. Petrovich Z, Cox JD, Middleton R, et al: Advanced carcinoma of the nasopharynx: 2. Pattern of failure in 256 patients. Radiother Oncol 4: 15-20, 1985[Medline] 2. Qin D, Hu Y, Yan J, et al: Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer 61: 1117-1124, 1988[CrossRef][Medline] 3. Lee AWM, Poon YF, Foo W, et al: Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: Overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 23: 261-270, 1992[Medline] 4. Boussen H, Cvitkovic E, Wendling JL, et al: Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol 9: 1675-1681, 1991[Abstract]
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Al-Sarraf M, LeBlanc M, Giri PGS, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16: 1310-1317, 1998 9. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83: 2270-2283, 1998[CrossRef][Medline]
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Ma J, Mai H-Q, Hong M-H, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19: 1350-1357, 2001 15. Teo PML, Chan ATC, Lee WY, et al: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43: 261-271, 1999[CrossRef][Medline] 16. Chan AT, Teo PM, Ngan RK, et al: A phase III randomized trial comparing concurrent chemotherapy-radiotherapy with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. Proc Am Soc Clin Oncol 19: 415a, 2000 (abstr 1637) 17. Sanguineti G, Geara FB, Garden AS, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of local and regional control. Int J Radiat Oncol Biol Phys 37: 985-996, 1997[CrossRef][Medline] 18. Geara FB, Sanguineti G, Tucker SL, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of distant metastasis and survival. Radiother Oncol 43: 53-61, 1997[CrossRef][Medline] Submitted September 5, 2001; accepted January 2, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
