Excel l ent Di sease Cont rol and Survi val i n Pat i ent s Wi t h
Advanced Nasopharyngeal Cancer Treat ed Wi t h
Chemoradi at i on By Danny Rischin, June Corry, Jennifer Smith, Josephine Stewart, Peter Hughes, and Lester Peters Purpose: To determine the efcacy and safety of epirubicin, cisplatin, and infusional uorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally ad- vanced nasopharyngeal cancer. Patients and Methods: Thirty-ve patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m 2 and cisplatin 75 mg/m 2 combined with continuous-infusion 5-FU 200 mg/m 2 daily for 9 weeks, followed by concurrent chemoradia- tion of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m 2 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 re- lapse 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 mucosi- tis, 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. J Clin Oncol 20:1845-1852. 2002 by American Society of Clinical Oncology. N ASOPHARYNGEAL 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 nasopha- ryngeal 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 benet of adding chemotherapy to the primary treatment of nasopharyngeal cancer. Nasopharyngeal cancer is a rela- tively 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 uorouracil (5-FU). 8 Although the results of this trial altered practice in many centers, other investigators have expressed concern that the high propor- tion 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 chemo- radiation 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 induc- tion phase of the treatment program, as this regimen has demonstrated impressive activity in a number of malignan- cies, 10,11 good tolerability, and includes three drugs with proven activity in nasopharyngeal cancer. PATIENTS AND METHODS Eligibility Patients were required to have histologically proven carcinoma of the nasopharynx (any WHO type), International Union Against Cancer, From the Division of Hematology and Medical Oncology, Division of Radiation Oncology, and Statistical Center, Peter MacCallum Cancer Institute, Melbourne, Australia. Submitted September 5, 2001; accepted January 2, 2002. Address reprint requests to Danny Rischin, MD, Division of Hema- tology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag No 1, ABeckett St, Melbourne 8006, Australia; email: drischin@petermac.unimelb.edu.au. 2002 by American Society of Clinical Oncology. 0732-183X/02/2007-1845/$20.00 1845 Journal of Clinical Oncology, Vol 20, No 7 (April 1), 2002: pp 1845-1852 10.1200/JCO.2002.07.011 Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. 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 10 9 /L, platelet count 100 10 9 /L, creatinine clearance or glomerular ltration 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 nonmela- noma skin cancer or carcinoma-in-situ of the cervix, signicant hearing impairment unless attributable to nasopharyngeal cancer, pre-existing motor or sensory neurotoxicity WHO grade 2, active uncontrolled infection, unstable cardiac disease requiring treatment, contraindication to insertion of a suitable indwelling venous cathe- ter, and pregnancy or lactation. Pretreatment and Follow-Up Evaluations Before enrollment, all patients underwent a full history, physical examination, complete blood count (CBC) with differential, electro- lytes, liver function tests, 24-hour urinary creatinine clearance, mag- netic resonance imaging (MRI) and/or computed tomography (CT) scans of the head and neck, chest x-ray, liver imaging, and bone scan. 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 chemo- therapy. 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. Antitu- mor 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 signicant. Similarly, nonpalpable, nonnecrotic nodes less than 1 cm seen on follow-up scans were not deemed to be signicant. Treatment Plan Three cycles of epirubicin and cisplatin were administered at 3-week intervals. Infusional 5-FU was commenced on day 1 and was continued for 9 weeks, stopping 24 hours before the commencement of radiation (Fig 1). Epirubicin was given 5 to 30 minutes before cisplatin on day 1 of each cycle. Hydration with cisplatin was according to our standard protocol with 1 L of normal saline and 400 mL of 10% mannitol before cisplatin, and 2 L of normal saline after cisplatin. All patients had an indwelling central venous catheter device, and the 5-FU was delivered via an ambulatory infusion pump. The doses were epirubicin 50 mg/m 2 , cisplatin 75 mg/m 2 , and 5-FU 200 mg/m 2 /d. During radiation, cisplatin was administered daily at a dose of 20 mg/m 2 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 recombi- nant granulocyte colony-stimulating factor support was not permitted. Radiation Therapy Planned radiation therapy consisted of 60 Gy in 30 fractions over 6 weeks to all known sites of disease and 50 Gy to sites of potential spread including the uninvolved neck. The treatment volume was determined on the basis of the extent of disease at presentation and was not inuenced by the response to chemotherapy. The maximum spinal cord dose was 45 Gy; the maximum brainstem dose was 54 Gy. In seven patients, the upper level of the eld was reduced in the last week of treatment so as to limit the optic chiasm dose to 54 Gy as permitted in the protocol, and one other patient with very extensive intracranial disease received 54 Gy to the whole volume. Seventeen patients were treated by parallel opposed photon elds junctioned at the level of the thyroid notch to an anterior neck eld with 20-mm spinal cord shielding to a dose of 40 Gy. Thereafter, the lateral elds were reduced off cord and inferiorly to the level of the mandible and junctioned to anteroinferior neck elds for the last 10 Gy (uninvolved neck) or 20 Gy (involved neck). Eighteen patients were treated with parallel opposed photon elds to 36 Gy in 18 fractions; then, the nal 24 Gy was given via two asymmetric arc elds. These elds were junctioned with a 50-Gy (uninvolved neck) or 60-Gy (involved neck) bilateral anterior photon eld, with spinal cord shielding. The total dose of 60 Gy was chosen on the basis of previous experience in our own institution using concurrent cisplatin and radiotherapy and the difculty, if not impos- sibility, of achieving a minimum tumor dose of 70 Gy to the full planning target volume (PTV) in many cases of advanced nasopharyn- geal cancer using then-available technology. Dose Modication for Toxicity During induction chemotherapy, grade 4 neutropenia lasting 7 days, febrile neutropenia, or grade 3 or 4 thrombocytopenia required a 25% dose reduction of all drugs. Grade 3 or 4 mucositis or diarrhea required discontinuation of 5-FU for at least 1 week, and then it could be restarted with a 25% dose reduction of 5-FU and epirubicin. Other grade 3 or 4 nonhematologic toxicity required a 25% dose reduction of all drugs. If the glomerular ltration rate (GFR) decreased to less than 0.9 mL/sec, carboplatin targeting an area under the curve of 5 (Calvert formula) was to be substituted for cisplatin. Grade 2 peripheral neuropathy also required changing to carboplatin, whereas grade 3 or 4 neuropathy required cessation of chemotherapy. Before giving cisplatin and epirubicin on day 1 of each cycle, the neutrophil count had to be 1.5 10 9 /L and the platelet count had to be 100 10 9 /L. Between cycles, 5-FU was to be discontinued for 1 week if grade 4 neutropenia or grade 3 or 4 thrombocytopenia developed. 5-FU could be recommenced if the neutrophil count was 1.0 10 9 /L and the Fig 1. Treatment schedule. E, epirubicin 50 mg/m 2 ; C, cisplatin 75 mg/m 2 when administered with epirubicin and 20 mg/m 2 /d when given during RT. 1846 RISCHIN ET AL Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. platelet count was 75 10 9 /L. During radiation, if carboplatin needed to be substituted for cisplatin, the dose was to target an area under the curve of 4 according to the Calvert formula, divided into ve equal doses. Statistical Methods Overall survival, progression-free survival, and time to develop grade 3 or 4 late effects from commencement of induction chemother- apy were estimated using the Kaplan-Meier (product-limit) method, with condence intervals calculated using the logit transformation. The potential follow-up time for each patient was the time from treatment start to the close-out date for all analyses (February 5, 2001, or the date of last contact for two patients lost to follow-up). For overall survival, all deaths were counted regardless of cause, and survival times for living patients were censored at the close-out date. For progression-free survival, the rst progression at any site or death without progression was counted as an event, and times were censored at the close-out date for patients who were alive at that date without progression. 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 rst 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. RESULTS Patient Characteristics From September 1995 to February 1999, 35 patients were enrolled onto this study. Patients had predominantly undif- ferentiated 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 classied as T3 rather than T4. Also, only N3 nodal disease (not N2) counts as stage IV under the new system. These changes in classication 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. Efcacy After completion of induction chemotherapy, 30 (86%) of 35 patients (95% condence 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 assess- able patients were in complete response, on the basis of clinical examination alone, but eight had a residual abnor- mality on imaging and hence were deemed to be in partial response. The median potential follow-up time from com- mencing 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 remis- sion, 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 com- mencing treatment. This was one of the patients who had the Table 1. Patient Characteristics Characteristic No. of Patients (N 35) Age, years Median 43 Range 17-63 WHO performance status 0 27 1 7 2 1 WHO histology 1 5 2 4 3 26 Ethnicity White 6 Chinese/Southeast Asian 23 Mediterranean 6 Table 2. Tumor Stage Versus Node Stage (UICC, ed 4, 1992) Stage T1 T2 T3 T4 Total N1 0 1 2 0 3 N2 6 8 3 11 28 N3 2 0 1 1 4 Total 8 9 6 12 35 Table 3. Tumor Stage Versus Node Stage (UICC, ed 5, 1997) Stage T1 T2 T3 T4 Total N1 5 4 1 0 10 N2 6 2 3 6 17 N3 3 3 2 0 8 Total 14 9 6 6 35 1847 CHEMORADIATION FOR NASOPHARYNGEAL CANCER Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. upper level of their treatment eld 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 compli- cated by febrile neutropenia. Seven patients had central venous catheterrelated 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, exclud- ing 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 reduc- tion 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 cere- bral 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-FUrelated cardiac arrhythmia. Her 5-FU was ceased and she proceeded with chemoradia- tion, 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 Fig 2. Progression-free survival (censored times are indicated as tick marks on the curves). Fig 3. Overall survival (censored times are indicated as tick marks on the curves). Table 4. Toxicity During Induction Chemotherapy WHO Grade (% of 35 patients) 0 1 2 3 4 Hemoglobin 74 26 0 0 0 Neutrophils 3 26 40 17 14 Platelets 97 3 0 0 0 Oral 34 23 31 9 3 Nausea and vomiting 3 23 49 26 0 Diarrhea 66 20 11 3 0 Cutaneous 86 11 3 0 0 Alopecia 9 6 54 31 1848 RISCHIN ET AL Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. 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 chemo- therapy 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 commenc- ing chemoradiation as a percentage of weight on commenc- ing 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-specied 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-specied, 42 days). The 34 patients who com- pleted treatment all received two cycles of chemotherapy during radiation. One patient received carboplatin in the rst 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%) experi- enced ear or hearing difculties 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 impair- ment 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 pe- ripheral 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. DISCUSSION 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 con- current 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 supe- riority 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 Table 5. Acute Toxicity Caused by Chemoradiation WHO Grade (% of 35 patients) 0 1 2 3 4 Hemoglobin 37 54 6 3 0 Neutrophils 49 23 11 14 3 Platelets 86 6 9 0 0 Nausea and vomiting 11 29 37 20 3 Infection 69 20 3 6 3 Alopecia 3 6 31 60 Skin (in the radiation eld) 3 29 46 23 0 Mucosa* 0 6 63 31 0 *Mucositis graded according to RTOG acute toxicity criteria. Table 6. Late Toxicity RTOG/NCI-CTC Grade (% of 34 patients) 0 1 2 3 4 Skin 38 53 9 0 0 Subcutaneous tissue 32 59 3 6 0 Mucous membrane 9 47 41 3 0 Salivary glands 0 0 76 24 0 Ear/hearing* 50 9 32 9 0 Peripheral neuropathy* 76 21 3 0 0 Abbreviation: NCI-CTC, National Cancer Institute common toxicity criteria. *Graded according to NCI-CTC acute toxicity criteria. 1849 CHEMORADIATION FOR NASOPHARYNGEAL CANCER Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. 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 signicant differences in patient populations and treatment regimens in the two trials. Al- though 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 chemo- therapy after radiation for head and neck cancer has proven difcult 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 adminis- tered 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/m 2 in weeks 1, 4, and 7 of radiation, whereas in our regimen there were two planned cycles of 20 mg/m 2 /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. Impor- tantly, in our trial the prior administration of induction chemotherapy did not compromise the delivery of chemo- radiation. 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 ve 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 induc- tion 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% com- plete 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 ndings, 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 signicance, 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 chemo- therapy 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 Can- cer 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 undifferen- tiated carcinomas and used an induction regimen of three cycles of bleomycin, epirubicin, and cisplatin, signicant toxicity and 8% treatment-related mortality was reported. In the Asian-Oceanian Clinical Oncology Association Trial, which was restricted to patients with Hos 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/m 2 ) and cisplatin (60 mg/m 2 ). In a recently reported trial performed in Guangzhou, China, no difference in overall survival was seen, although there was a signicant difference in relapse- free survival. 14 In this trial, the chemotherapy regimen consisted of two to three cycles of cisplatin (100 mg/m 2 ), bleomycin (10 mg/m 2 on days 1 and 5), and 5-FU (800 mg/m 2 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 difculty in administering the protocol-specied chemo- therapy in the Guangzhou trial. The combination of cispla- tin and 5-FU is the standard regimen for patients with metastatic nasopharyngeal carcinoma and the one adminis- tered in the Intergroup trial. We chose to base our regimen around this combination, but altered the 5-FU schedule to 1850 RISCHIN ET AL Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. continuous infusion and added epirubicin. The ECF regi- men has impressive activity, is well tolerated in other malignancies, 10,11 and contains three drugs active in naso- pharyngeal cancer. However, we used a higher dose of cisplatin than in the standard ECF regimen. As already discussed, one advantage of induction com- pared with adjuvant chemotherapy is the greater ability to administer full-dose chemotherapy as planned. Another potential advantage of induction over adjuvant chemother- apy 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 random- ized trials of induction chemotherapy without concurrent chemotherapy have not demonstrated any signicant differ- ences in overall survival, these trials do suggest that induction chemotherapy may improve locoregional con- trol. 9,12,14 In the International Cancer Study Group trial, the improved disease-free survival was attributable to a de- crease in both locoregional relapses and distant metastases as sites of rst failure. 12 In the Asian-Oceanian Clinical Oncology Association Trial, the subgroup analysis in pa- tients with bulky neck nodes showed a signicant 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 rst failure. 9 Similarly, in the Guangzhou trial there was a signicant 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 re- ceived two cycles of induction chemotherapy compared with patients treated with radiation alone for locally ad- vanced node-positive nasopharyngeal carcinoma. 15 Multi- variate analysis identied administration of chemotherapy as being of independent signicance 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 signicant 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 induc- tion or adjuvant chemotherapy and concurrent chemother- apy are required to achieve a signicant improvement in overall survival in patients with locally advanced nasopha- ryngeal 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 chemother- apy may also contribute to locoregional control in these patients, as well as being potentially benecial 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 child- hood 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 nom- inal dose administered to patients with advanced nasopha- ryngeal 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 specied 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 eld 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 elds. With the advent of intensity-modu- lated 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 conrming 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 1851 CHEMORADIATION FOR NASOPHARYNGEAL CANCER Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved. 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 signicant ben- et. 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 locore- gional 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 strate- gies would seem indicated. ACKNOWLEDGMENT 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. REFERENCES 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 2. Qin D, Hu Y, Yan J, et al: Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer 61:1117-1124, 1988 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 4. Boussen H, Cvitkovic E, Wendling JL, et al: Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and uorouracil. J Clin Oncol 9:1675-1681, 1991 5. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally ad- vanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 6. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999 7. Schaake-Koning C, Van Den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326:524-530, 1992 8. 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 com- paring cisplatin and epirubicin followed by radiotherapy versus radio- therapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83:2270-2283, 1998 10. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin and uorouracil versus uorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997 11. Jones AL, Smith IE, OBrien MER, et al: Phase II study of continuous infusion uorouracil with epirubicin and cisplatin in pa- tients with metastatic and locally advanced breast cancer: An active new regimen. J Clin Oncol 12:1259-1265, 1994 12. International Nasopharynx Cancer Study Group: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV ( N2, M0) undifferentiated nasopharyngeal carci- noma: A positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 35:463-469, 1996 13. Chan ATC, Teo PML, Leung TWT, et al: A prospective randomized study of chemotherapy adjunctive to denitive radiother- apy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569-577, 1995 14. Ma J, Mai H-Q, Hong M-H, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiother- apy 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 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 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 1852 RISCHIN ET AL Downloaded from jco.ascopubs.org on June 8, 2014. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved.
Prophylactic Cranial Irradiation Improved The Overall Survival of Patients With Surgically Resected Small Cell Lung Cancer, But Not For Stage I Disease
A Complete Pathological Response to Neoadjuvant Chemoradiotherapy in A Young Female with Local-Progressed Low Rectal Cancer Following ‘Wait-And-Watch’ Surveillance: A Case Report