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Induction Chemotherapy With Mitomycin, Epirubicin, Cisplatin, Fluorouracil, and Leucovorin Followed by Radiotherapy in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma

From the Departments of Oncology, Otolaryngology, and Radiation Therapy, National Taiwan University Hospital, National Taiwan University; and National Taiwan University Hospital Cooperative Ward, Division of Cancer Research, National Health Research Institute, Taipei, Taiwan.

Address reprint requests to Ruey-Long Hong, MD, PhD, Department of Oncology, National Taiwan University Hospital, National Taiwan University, No 7, Chung-Shan South Rd, Taipei 10016, Taiwan; email: rlhong{at}ha.mc.ntu.edu.tw

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy.

PATIENTS AND METHODS: Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL).

RESULTS: From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis–free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis–free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival.

CONCLUSION: The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

	INTRODUCTION

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EVEN THOUGH nasopharyngeal carcinoma (NPC) is a radiosensitive tumor, long-term survival for patients with advanced disease remains poor.^1-3 According to a recent report from Singapore,⁴ with radiotherapy alone, the 5-year survival rate of stage IVA and IVB (according to the American Joint Committee on Cancer [AJCC] classification, 1997)⁵ is 35% and 28%, respectively. The major challenges in the treatment of advanced NPC are how to improve locoregional control and prevent distant metastasis.^2,6,7

NPC is also a highly chemosensitive tumor. Even in its metastatic state, a small number of patients are still cured with conventional chemotherapy.⁸ However, randomized clinical trials using induction or adjuvant chemotherapy have not shown a survival benefit when compared with radiotherapy alone.^9-13 The Intergroup Study of North America clearly demonstrated the advantage of concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy over radiotherapy alone, but this approach is still flawed by a high rate of late systemic recurrence.¹⁴ A retrospective CCRT plus adjuvant chemotherapy study from an endemic area demonstrated excellent locoregional control, but the distant metastasis rate of stage IV disease is up to 39%.¹⁵ Further investigation to reduce distant metastasis is urgently needed, especially for stage IV disease.¹⁶

A combination of mitomycin, doxorubicin, and cisplatin has a high response rate in metastatic NPC, and some patients experience long-term remission of metastatic lesions.¹⁷ Other investigators using a similar approach have made similar observations.^8,18 Mitomycin is active in hypoxic conditions¹⁹ and works against G0 cells.²⁰ We reasoned that inclusion of mitomycin in cisplatin-based chemotherapy might help to overcome resistance conferred by hypoxia and eradicate tumor cells, even those not in the cell cycle. In this study, we explored the effect of a combination of mitomycin, epirubicin, and cisplatin plus fluorouracil and leucovorin (MEPFL) on the outcome of locoregionally advanced NPC. Stage IV patients (AJCC 1992) with unfavorable prognostic features were treated with three courses of MEPFL followed by conventional radiotherapy.

	PATIENTS AND METHODS

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Patients with histologically proven stage IV (AJCC 1992) NPC and unfavorable prognostic features were recruited for this study.^21-24 Eligibility criteria for entry onto the study included AJCC 1992 stage IV disease with at least one of the following poor prognostic features: obvious intracranial invasion,²⁵ supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level (> 460 U/L)^22,23 but without evidence of distant metastasis. Patients should not have had previous treatment for their diseases and were required to have a pretreatment Eastern Cooperative Oncology Group performance status of 2. Adequate bone marrow reserves were required, with a leukocyte count of at least 4,000/µL and a platelet count of at least 100,000/µL. A serum bilirubin level of less than 1.5 mg/dL and a serum creatinine level of less than 1.5 mg/dL were also required. Patients were treated with induction chemotherapy followed by definitive radiotherapy at the National Taiwan University Hospital, Taipei, Taiwan. Treatment options (radiotherapy alone or induction chemotherapy then radiotherapy) were explained and verbal consent was obtained from each patient. After the publication of the revised AJCC staging system in 1997,⁵ data of all patients were reviewed and their staging reclassified according to the new criteria.

Pretreatment evaluation included a complete physical examination, complete blood cell count, and biochemical profile. All patients had fiberoptic endoscopy and biopsy of the nasopharynx and computed tomography of the nasopharynx and neck for staging of the primary disease. Magnetic resonance imaging was not routinely performed. Metastatic work-up included chest radiograph, ultrasound imaging of the liver, and bone scan.

Neoadjuvant Chemotherapy
The MEPFL chemotherapy consisted of intravenous (IV) administration of mitomycin 8 mg/m², epirubicin 60 mg/m², and cisplatin 60 mg/m² on day 1 with hydration and diuresis. Serotonin antagonist and corticosteroids were routinely given for prophylaxis of nausea and vomiting. Fluorouracil 450 mg/m² and leucovorin 30 mg/m² were given on day 8. This cycle was repeated every 3 weeks if hemogram measurements were adequate (leukocyte count 3,500/µL and platelet count 100,000). If the leukocyte count was between 3,000 and 3,500/µL or the platelet count was between 75,000 and 100,000/µL on day 28, the subsequent cycle was modified by a 20% reduction in the dosage of mitomycin and epirubicin. Three cycles were planned unless severe side effects occurred.

Radiotherapy
Curative radiotherapy began within 3 weeks after completion of the last cycle of chemotherapy.²⁶ Megavoltage photons (6 MV) were used and the irradiation fields were designed according to the extension of the tumor. The initial treated target volume was the gross target volume with a 2-cm margin in all directions and shrinkage to avoid excessive irradiation to the pons and spinal cord after 46 Gy.

All patients, except those with stage N3b disease, were treated with bilateral opposing portals to cover the primary tumor and neck; the fraction size was 2 Gy. After 36 Gy, the primary and neck were treated by the split-field technique. The primary was irradiated with shrinkage bilateral opposing fields, using 2.5 Gy as the fraction size, and an additional 10 Gy was given. The intracranial lesion was excluded from the treatment portal after 46 Gy. An additional 24 Gy in 10 fractions to the nasopharynx was delivered via bilateral anterior oblique infra-orbital portals. The accumulated radiation dose to nasopharynx was 70 Gy in 32 fractions, whereas the accumulated dose to intracranial lesion was 46 Gy in 22 fractions. For patients with nasal or ethmoid involvement, the three-field technique (anterior field and bilateral opposing fields) was used instead of infra-orbital portals, with 24 Gy in 12 fractions.

The neck was treated using anterior-posterior opposing portals after 36 Gy in 18 fractions for patients with N0 to N3a disease, with the spinal cord shielded. For N3b cases, the neck was treated using anterior-posterior opposing portals initially and blocked spinal cord after 40 Gy in 20 fractions. The accumulated dose was 50 Gy in 25 fractions to uninvolved neck and 60 Gy in 30 fractions to involved regions. An additional 5 Gy in two fractions was given to residual neck masses after 60 Gy.

Assessment and Follow-Up
Criteria for response were as follows: a complete response was defined as complete regression of all evidence of disease; a partial response required a 50% decrease of the summed products of the two largest perpendicular diameters of all measurable lesions, without an increase in size of more than 25% in any lesion or the appearance of new lesions; stable disease was defined as no significant change or any change in tumor size that was less than a partial response but not large enough to be considered progressive disease; and progressive disease was defined as an increase of at least 25% in the size of measurable lesions or the appearance of any new lesion. A computed tomography scan was performed for the assessment of the chemotherapy response after the completion of induction chemotherapy. In patients with assessable disease in both the primary site and cervical lymph nodes, the worst response was recorded as the overall response to chemotherapy. Response after radiotherapy was assessed 3 months after completion of the treatment. This required an endoscopy and a computed tomography scan, as well as a biopsy of the nasopharynx if it was indicated. Patients with a complete response to treatment were followed-up at least every 3 months. Follow-up clinical examinations included a mirror examination of the nasopharynx. Chest radiographs were taken every 6 months, whereas computed tomography and other investigations, such as bone scan, were only performed when clinically indicated.

Data Analysis and Statistics
The major end points used for assessment in the current analysis were relapse-free survival (RFS) and overall survival (OS). RFS was defined as the time from the start of chemotherapy to the date of first observation of disease. Because of the common presence of locally advanced disease, computed tomography scan might detect residual changes 3 months after radiotherapy, even though both fiberoptic endoscopy and biopsy could not detect any evidence of disease. These cases were assumed to have disease under control and were followed-up closely. OS was defined as the date from the start of chemotherapy to death. All patients entered onto the study were included in the survival analysis (intent-to-treat analysis). The survival curves were estimated by the Kaplan-Meier product-limit method. The difference between survival curves was tested using the Mantel-Cox log-rank test. The relationship between disease progression or survival and the potential explanatory factors was determined using the Cox proportional hazards technique. The stepwise inclusion procedure was used to determine statistically significant prognostic factors, including sex, age, histologic type, T stage, N stage, largest lymph node diameter, laterality of lymph node involvement, serum LDH level, the interval between diagnosis and treatment, cycle number of the chemotherapy, the interval between radiotherapy and chemotherapy, neck node enlargement before radiotherapy (NEBRT; > 25% lymph node enlargement compared with the best response during the period between chemotherapy and radiotherapy), interruption during radiotherapy, and tumor response after radiotherapy.

	RESULTS

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Patient Characteristics
Between January 1994 and December 1997, we had 657 newly diagnosed patients with NPC, of which 111 patients were recruited for this study. Table 1 lists their characteristics. According to AJCC 1997, 47% had T4 disease, 24% had N3a disease, and 36% had N3b disease. Ninety-three patients (83%) were stage IV and thirty-one patients (28%) had elevated serum LDH levels.

Toxicity
All patients were evaluated for chemotherapy toxicity, which is summarized in Table 2. The main nonhematologic toxicities were nausea, vomiting, and alopecia, with 13% experiencing grade 3 nausea, 5% experiencing grade 3 or 4 vomiting, and 78% of patients experiencing grade 2 hair loss. Hematologic toxicity was moderate; 55% of the patients developed grade 3 leukopenia and 4% developed grade 4 leukopenia. Febrile neutropenia occurred in 1% of the patients. One percent of patients experienced grade 2 nephrotoxicity; no grade 3 nephrotoxicity was observed. Three patients with chronic hepatitis B viral infection had grade 3 hepatitis delaying their radiotherapy for weeks.

Mean body weight was 64.9 ± 11.6 kg (mean ± SD) before chemotherapy, 63.7 ± 12.7 kg before radiation, and 58.2 ± 10.1 kg after radiation.

Response
Patients having received two or more courses of chemotherapy were evaluated for responses. Neck lymph node disease had a higher response rate to chemotherapy (94.5%) compared with primary tumors (72.5%). The complete response rate of the primary tumor and neck node was 6.4% and 45.4%, respectively. No patients experienced disease progression during chemotherapy, but 15 patients, after remission postchemotherapy, had neck lymph node enlargement during the rest period before radiotherapy (NEBRT).

After irradiation, 67 patients achieved complete remission, 32 achieved partial remission, and one achieved clinically stable disease. Two patients still had palpable neck nodes 3 months after treatment. They were classified as having partial remission, although no viable tumor cells were identified after neck dissection. For the other 30 cases, minimal changes could be detected at the primary site from image studies, but fiberoptic examinations were negative. They were closely followed up and biopsied if there was any evidence of disease activity.

RFS and Failure Pattern
The median follow-up period was 43 months (34 to 80 months, for the survivors). Most of the recurrence, either loco-regional or distant metastasis, occurred within 3 years (Fig 1). Twenty-four patients failed locoregionally (Table 3). Eighteen failed at the nasopharynx and nine at the neck. The 5-year locoregional control rate was 70% (95% confidence interval [CI], 55% to 84%; Fig 1). T4 tended to have early nasopharynx progression, but there was no difference in the locoregional RFS between T stages (Fig 2; P = .18). The higher early nasopharyngeal failure of T4 reflects the commonly presented extensive intracranial invasion in this series, but it plateaued after 2 years, with a 5-year locoregional control rate of 67% (95% CI, 53% to 81%).

View larger version (16K): [in this window] [in a new window]   Fig 1. RFS: local, distant and overall RFS of 100 patients who completed induction chemotherapy with MEPFL and radiotherapy. Overall RFS of all 111 patients was also shown based on intent-to treat analysis. DM, distant metastasis.

View larger version (12K): [in this window] [in a new window]   Fig 2. Locoregional RFS of 100 patients who completed induction MEPFL chemotherapy and radiotherapy grouped by T stage (P = .15; Mantel-Cox test).

View larger version (13K): [in this window] [in a new window]   Fig 3. Distant metastasis–free survival of 100 patients who completed induction MEPFL chemotherapy and radiotherapy grouped by N stage (P = .18; Mantel-Cox test).

Survival
The 5-year actuarial survival rate of the entered 111 patients was 70% (95% CI, 60% to 80%; Fig 4). Among the patients who had completed chemotherapy and radiotherapy, 18 died of the disease and three died of unrelated diseases: hepatitis, pneumonia, or other malignancy. The 5-year actuarial survival rate of this group was 75% (n = 100; 95% CI, 64% to 85%; Fig 4). The 5-year disease-specific survival rate of patients who completed the protocol treatment was 78% (n = 100; 95% CI, 68% to 89%).

View larger version (13K): [in this window] [in a new window]   Fig 4. OS of all 111 patients entered (100 patients completing treatment and 11 violating protocol).

View larger version (13K): [in this window] [in a new window]   Fig 5. OS of 111 patients entered onto the study as grouped by stage (P = .42; Mantel-Cox test).

	DISCUSSION

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The prognostic factors for survival in this series were pretreatment serum LDH level and NEBRT. Serum LDH level reflects the tumor mass, and high value might represent large tumor load and a higher probability of developing clones resistant to treatment. A CCRT plus adjuvant chemotherapy study also found that infiltration of the clivus by the tumor and LDH greater than 410 U/L are the two independent prognostic factors. NEBRT reflects the growth rate of tumors. Patients with rapid tumor growth might have short survival. Conventional prognostic factors such as T and N stages were not of prognostic value in this study. An effective treatment might alter the prognostic factor of a specific type of cancer.

CCRT improves locoregional control and survival of head and neck cancer by radiosensitization effect of chemotherapeutic drugs.²⁹ The Intergroup Study first demonstrated that CCRT can improve the survival of NPC.¹⁴ In endemic areas, a phase III study from Hong Kong showed improved 2-year progression free survival with concurrent weekly cisplatin.³⁰ Whether there is advantage in survival remains to be validated after longer follow-up. Although the role of CCRT in NPC in endemic areas will be answered by the ongoing phase III study, we speculate that distant metastasis will remain a major problem in advanced diseases. A phase II study of Singapore adopts an approach similar to that of the Intergroup Study and demonstrates the feasibility of CCRT.³¹ However, they note that the median survival of patients with stage IVB disease is 21 months. A retrospective study of CCRT plus adjuvant chemotherapy, reported by Cheng et al from Taiwan³² and showing an excellent local control rate and good long-term survival in patients with stage III and IV disease, supports the effectiveness of CCRT in an endemic area (Table 5).³³ However, 35% of all patients with stage IV disease without distant metastases at presentation manifested distant disease subsequently. Among patients with stage IVB disease (ie, having N3 disease), the rate increases to 39%. Obviously, patients with stage IV disease need more effective systemic therapy.³³

These results are somewhat disappointing and unexpected, as cisplatin-based chemotherapy has been reported to achieve long-term remission or cure in a portion of patients with metastatic NPC.⁸ If macroscopic metastasis could be cured, why can’t chemotherapy eradicate microscopic subclinical metastasis? Possible explanations include high treatment-related mortality,¹¹ reduced survival among patients with prior exposure to chemotherapy,¹¹ suboptimal intensity of treatment, or that the regimens used are simply unable to eradicate the micrometastasis.

From the point of view of cell kinetics, induction or adjuvant chemotherapy may not be very helpful in locoregional control,^38,39 but it may be able to reduce distant metastasis.⁴⁰ In contrast, CCRT improves locoregional control through radiosensitization effect of chemotherapy, but because of limitation by enhanced radiation toxicity, the dosage used cannot decrease distant metastasis. For radiation oncologists who are not so familiar with NPC, CCRT plus adjuvant chemotherapy reduces locoregional recurrence and distant metastasis and increases survival significantly. In endemic area, radiotherapy alone achieves relatively good local control (Table 6); therefore, chemotherapy must drastically reduce distant metastasis to have survival impact. From this point of view, patient selection is also critical. There is a marked difference in stage distribution among the published phase III studies (Table 6). Although these studies vary in staging systems, the majority of cases entered onto three induction studies do not have the highest risk of distant failure. This may nullify the power of the study to detect the effect of chemotherapy. In contrast, the Intergroup Study 0099 recruits cases with the highest risk in the majority of patients.

Our study, with the largest number of patients with AJCC 1997 stage IV disease among the reported phase II or III studies and an adequate follow-up period, demonstrated that induction with MEPFL followed by radiotherapy has a low distant metastasis rate, even in N3a and N3b diseases. However, the locoregional control was less satisfactory for T4. This might be due to the advanced local diseases and the use of computed tomography scan rather than magnetic resonance imaging for tumor mapping. Furthermore, as remaining locoregional disease predicted distant metastasis and several patients with local progression had distant failure after a time lag, improved local control might also help in further reducing the distant metastatic rate. We are studying the incorporation of MEPFL induction with CCRT to enhance local control and to reduce distant metastasis. A further phase III study to confirm the benefits of this approach is warranted.

	ACKNOWLEDGMENTS

 
We thank Dr Chee-Jen Chang, Department of Clinical Medicine, National Taiwan University Hospital, for his help in statistical analysis, and Shiang-Yih Ho for assistance in patient follow-up.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 29, 2000; accepted July 26, 2001.

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