Japanese Journal of Clinical Oncology 33:331-335 (2003)
© 2003 Foundation for Promotion of Cancer Research
High-dose Chemotherapy and Hematopoietic Stem Cell Transplantation for Patients with Nasopharyngeal Cancer: a Feasibility Study
1 Division of Hematology and Oncology, Department of Internal Medicine and 2 Department of Radiotherapy, National Cheng Kung University Hospital, Tainan, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Nasopharyngeal cancer (NPC) is a highly chemosensitive malignancy. The purpose of this study was to evaluate the clinical efficacy of high-dose chemotherapy (HDCT) in combination with hematopoietic stem cell transplantation in patients with locally advanced or metastatic NPC.
Methods: Nine patients with locally advanced or metastatic NPC were recruited after three to four courses of cisplatin-based chemotherapy followed by a single course of cyclophosphamide 1600 mg/m2 day 1–4, carboplatin 400 mg/m2 day 1–3, and thiotepa 120 mg/m2 day 1–4 or melphalan 120 mg/m2 day 5. Chemoirradiation was administered after HDCT only if the patient had never received radiotherapy or had residual cervical nodes.
Results: A median of 8.32 x 106 CD34+ cells/kg was collected. Two patients were rendered disease-free before HDCT, one by massectomy and one by cisplatin-based chemotherapy. All patients recovered rapidly after peripheral blood stem cell transplantation (PBSCT). Among seven assessable patients, response to HDCT was observed in four patients. Only one patient achieved complete response after HDCT. The median time to failure and median survival after HDCT was eight and 18 months, respectively. One patient died of pulmonary hemorrhage two months after transplantation. No long-term disease-free survival was noted.
Conclusion: HDCT with autologous PBSCT is feasible with an acceptable toxicity, and can convert partial remission into complete remission. While no long-term disease-free survival was observed in this study, further investigations are needed to establish the role of HDCT in the treatment of NPC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Nasopharyngeal cancer (NPC) is an endemic Epstein-Barr virus (EBV)-related neoplasm that occurs commonly in Southern China, Southeast Asia, North Africa and the Middle East (1,2). In most patients, tumors are localized to the primary site and the regional neck nodes. Of all the epidermoid head and neck cancers, NPC is the most prone to metastasis, with the incidence of metastasis linked to the initial stage, especially the nodal volume (3–5). It is also a highly radiosensitive tumor and thus, radical external radiotherapy is the mainstay for its treatment. Despite the high cure rate for patients with stage I and II NPC, the prognosis for patients with stage III and IV is still disappointing with the 5-year survival rate ranging from 10–45% and 0–30% for stages III and IV, respectively (6,7). Improvements in irradiation and modern imaging techniques have improved local control, but distant failures remain the primary problem for patients with locoregional bulky disease (8–11).
Nasopharyngeal cancers are sensitive to systemic chemotherapy (12–15). Patients with recurrent or metastatic cancer who achieved a complete response to chemotherapy showed prolonged survival and were possibly cured (12,13,15). Long-term disease-free survivors of metastatic NPC have been reported by several groups (13,16,17). Fandi et al. (17) reported that 10% of the metastatic patients treated at their center were long-term survivors (>36 months by their definition). Long-term complete remission was observed in patients with bone, lung, and even liver metastases. The researchers believe that the dose–response effect of their aggressive cisplatin-based combination played a major role in achieving long-term complete responses. On the other hand, because of the success of high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT) in the treatment of hematologic malignancies, these methods are being used more frequently to treat patients with solid tumors where a dose–response relationship is thought to exist (18–23). However, reports in literatures on the use of autologous PBSCT in NPC are scarce. Whether HDCT improves the outcome of patients with NPC has also not been established. This paper reports the results of a retrospective study of HDCT, followed by PBSCT, in patients with recurrent or metastatic NPC in partial remission (PR) or complete remission (CR) after conventional therapy.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Selection
Between February 1995 and June 1999, nine patients with locally advanced and/or metastatic NPC received HDCT treatment supported by PBSCT at our medical center. All had measurable disease and biopsy-proven NPC confirmed by the Department of Pathology. They were all under 56 years of age (range, 26–45 years; median, 41 years) and their performance status was not over 2. The characteristics of these patients are listed in Table 1. Four of these patients were recurrent from previous radiotherapy, two were refractory to chemoirradiation, four had metastatic diseases, and one had locally advanced disease with intracranial invasion. The sites of recurrence and the number of metastatic sites per patient are listed in Table 1. Three patients received more than one regimen of chemotherapy. All had normal cardiac, pulmonary, and hepatic functions as determined by routine clinical and laboratory examinations. Bilateral bone marrow biopsy samples were examined by hematoxylin and eosin staining. Written informed consent was obtained from all patients.
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A complete response was defined as the disappearance of all detectable malignant disease. A partial response was defined as a >50% decrease in tumor volume. Patients with bone metastases were said to have a partial response if all the measurable disease showed a 50% decrease in volume, and persistent or improved bone abnormalities were present on radiographs. The response duration was measured from the initiation of the protocol therapy until progressive disease. Toxic reactions were evaluated according to the Eastern Cooperative Oncology Group criteria.
Conventional Dose Induction Chemotherapy and Mobilization of PBSCs
All nine patients were treated with three to four courses of cisplatin-based induction regimens. When multicycle therapy was administered, harvesting was usually performed in the last course of chemotherapy. But two patients received high-dose cyclophosphamide and two other patients received granulocyte-colony stimulating factor (G-CSF) only for mobilization. All the patients received 300 µg of G-CSF subcutaneously from the day after chemotherapy until the end of the harvest.
High Dose Chemotherapy and PBSCT Support
The treatment schedule for patients 1 to 5 was as follows: thiotepa 120 mg/m2 once daily intravenously for four consecutive days, day –7 to –4; cyclophosphamide 1600 mg/m2 for four consecutive days, day –7 to –4; carboplatin 400 mg/m2 once daily, intravenously for three consecutive days, day –7 to –5. For patients 6 to 9, instead of thiotepa, melphalan 120 mg/m2 was administered on day –3. All patients received antiemetic therapy with granisetron and dexamethasone. PBSCT was performed on day 0. From day 1, rhG-CSF (Neupogen®, Kirin-Amgen K. K., Tokyo, Japan) 300 µg, daily, administered subcutaneously, (regardless of body weight), was added to the medication until the absolute neutrophil count (ANC) exceeded 1 x 109/l. Patients also received oral prophylaxis with ciprofloxacin (500 mg, twice daily) and fluconazole (400 mg, once daily) prior to HDCT until their body temperature exceeded 38.5°C. Empiric antibiotic treatment with ceftazidime and vancomycin was continued until the ANC returned to 1 x 109/l and fever remitted. Irradiated platelet transfusions were administered if platelet counts decreased to <20 x 109/l. A hemoglobin level >8 g/dl was maintained by irradiated packed red blood cells transfusion. Total parenteral nutrition was administered when necessary. Post-HDCT chemoirradiation was performed if patients had any residual loco-regional tumor or had never received any radiotherapy before.
Autologous Stem Cell Harvest and Cryopreservation
Patients received PBSCs collected after four days of rhG-CSF or cisplatin-based chemotherapy followed by rhG-CSF. Leukocyte apheresis was started when the white blood cell count exceeded 1 x 109/l. The harvesting procedure was carried out using a CS-3000 continuous flow device. Dimethyl sulfoxide (DMSO, 5% final concentration) was added to fractions containing mononuclear cells. The samples were frozen using a controlled rate freezer and stored in liquid nitrogen until further use. The number of CD34+ cells in the mononuclear cells (MNCs) obtained were evaluated by flow cytometry. A graft size of 2.0 x 106 CD34+ cells/kg body weight was considered sufficient for sustained bone marrow recovery.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PBSC Mobilization and Engraftment
Patients received chemotherapy followed by rhG-CSF, or rhG-CSF alone for PBSC mobilization, and a median of 8.32 x 106 CD34+ cells/kg (range, 0.40 to 20.10 x 106) was collected with a median of 2 (range, 1–4) aphereses. All patients were assessable for engraftment. All patients received PBSCs and achieved 0.5 x 109/l granulocytes and platelet transfusion independence (>20 x 109/l) at a median of 10 (range, 8 to 11) and 13 days (range, 5 to 24) after stem cell infusion, respectively.
Toxicity
Toxicities are listed in Table 2. One patient with E. coli sepsis, bilateral pneumonia, and acute renal failure required intubation, but recovered after the treatment; another had candidiasis, which was controlled by amphotericin B. Serum creatinine and blood urea nitrogen levels were elevated in one patient but returned to normal after completion of the treatment. There was one sudden death due to pulmonary hemorrhage on day 64 (patient 5) after discharge from the hospital. The patient achieved neutophil and platelet engraftment on day 9 and 16. This was attributed to regimen-related toxicities (diffuse alveolar hemorrhage in stem cell transplantation recipients).
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Response to HDCT
Treatment results are summarized in Table 1. Two patients achieved CR before HDCT, one because of massectomy (patient 7) and one just after induction chemotherapy (patient 8), so only seven patients could be assessed for responses after HDCT. Four patients responded to the treatment (one CR and three PR), two were in stable disease, while the disease progressed in only one patient. The median time to failure after HDCT was 8 months. Sites of relapse for complete responders were predominantly loco-regional and original metastatic sites. After HDCT, patients 1 and 4 received chemoirradiation for residual cervical nodes and patients 8 and 9 for consolidation. All four patients tolerated the procedure well.
Survival after HDCT
The median survival time after HDCT was 18 months. Most of the patients died after relapse or because their disease was refractory to treatment, however, three patients survived after relapse for even longer than their response periods. The latter survived for over 36 months after HDCT, although one still has lung metastasis (patient 1), one has bone metastasis (patient 9) (Table 1), and one is in the second CR after resection of recurrent tumor followed by concomitant chemoirradiation 15 months after HDCT.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It is now well acknowledged that HDCT achieves higher response rates (including higher CR rates) than conventional dose therapy for a variety of hematologic and epithelial malignancies. This feasibility study proves that HDCT with hematopoietic cell support is safe for heavily pretreated NPC patients. Only one patient died of lung hemorrhage after engraftment. Adequate mobilization was noted even in patients receiving multiple cycles of radiotherapy and chemotherapy. Four patients received concurrent chemoirradiation after HDCT, and the toxicities in these cases were low. Loco-regional radiotherapy after HDCT appears to be feasible. There were three long-term survivors, although two lived with the disease. HDCT might have delayed distant metastasis in these three patients.
The results are, however, somewhat disappointing and unexpected, as cisplatin-based chemotherapy has been reported to achieve long-term remission or cure in a substantial portion of patients with metastatic NPC (17). We attribute this to the fact that most of the patients had bulky tumor and had been heavily pretreated by either chemotherapy or radiotherapy or both. The treatment failure was due to both local and distant failures. High rates of relapse in sites of prior tumor involvement may be explained by factors such as greater tumor burden, possible presence of drug-resistant clones, poorer drug delivery, or intratumoral resistance factors such as hypoxia, or in the case of autograft contamination, by the possibility of homing and microenvironmental support for the tumor in loco-regional sites. Tumor contamination of stem cells may be a source of relapse, particularly since stem cells must be protected from HDCT. It should be pointed out that bone marrow is one of the most common metastatic sites in NPC. As demonstrated by gene-marking studies, residual tumor cells contribute to relapse in certain hematologic malignancies and neuroblastoma (24–26). However, it is not clear whether these cells are the sole cause for relapse or whether their presence indicates that the patient has an increased systemic chemotherapy-resistant tumor burden.
There are several ways in which these results can be improved. Firstly, the chemotherapeutic combination may not have been optimal. A high-dose regimen of cyclophosphamide, carboplatin, and thiotepa is widely used in the treatment of breast cancer. Cyclophosphamide and carboplatin are both active drugs in the treatment of NPC, but we do not know whether thiotepa or melphalan can be used for the same. Thus, the result could be improved by using more sensitive drug combinations. Secondly, the timing of HDCT administration could be changed. Early treatment in an adjuvant setting may yield better results. HDCT should be tried in patients with a high risk of recurrence just after concurrent chemoirradiation, or should be incorporated into the whole treatment plan for patients with advanced NPC or a high-risk of recurrence, either before concurrent chemoirradiation or just after. Bulky tumors seemed to have a poor response to HDCT in NPC. Thirdly, patients could be provided with a more intensive induction regimen. Induction therapy reduces the tumor burden and allows the selection of patients with chemosensitive tumors for subsequent dose intensification. Moreover, reduction of micrometastases in the marrow and/or circulating buffy coat should be achieved. In the present study, only conventional cisplatin-based regimens were used for induction, but some of the new active chemotherapeutic agents, taxane for example, might improve the outcome.
Airoldi et al. (27) have reported six cases of recurrent undifferentiated NPC, receiving HDCT followed by autologous PBSCT, in Italy. The conditioning regimen included ifosfamide, carboplatin, and etoposide. After HDCT, they had three more cases of CR, one more case of PR and two long-term disease-free survivors. However, NPC in Caucasians is histologically and biologically different from that in Asians (EBV infection is absent in the former, while it is invariable in the latter). Therefore, these results may not be directly relevant to the Asian population.
Because NPC is highly radio- and chemo-sensitive, CR after HDCT could result in more long-term survivors than CR after conventional chemotherapy. Although the results were not completely satisfying in the present series, some benefits (one CR and three PR in seven assessable patients) were observed. Further studies with more careful patient selection or more active regimens may improve outcomes.
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FOOTNOTES |
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+ For reprints and all correspondence: Tsai-Yun Chen, Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan. E-mail: teresa{at}mail.ncku.edu.tw
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Received April 5, 2003; accepted June 11, 2003
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