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© 2000 American Society for Clinical Oncology Long-Term Disease-Free Survivors in Metastatic Undifferentiated Carcinoma of Nasopharyngeal TypeFrom the Institut Gustave Roussy "La Grange," Savigny le Temple; Department of Radiotherapy, Institut Gustave Roussy, Cvitkovic and Associates, Consultants, and Hôpital Paul Brousse, Villejuif, France; Oncology Service, Rabat, Morocco; and Department of Oncology, Institut Sallah Azaiz, Tunis, Tunisia. Address reprint requests to E. Cvitkovic, MD, Fédération des Services des Maladies Sanguines Immunitaires et Tumorales, Paul Brousse Hospital, 12-14 Avenue Paul-Vaillant Couturier, 94804 Villejuif Cedex, France; email e.cvitkovic{at}cvitkovic-ac.fr
PURPOSE: To review incidence and analyze profile of long-term complete responders among patients with undifferentiated carcinoma of nasopharyngeal type (UCNT) treated at a single institution. PATIENTS AND METHODS: We present a cohort of 20 long-term unmaintained complete responders to chemotherapy for metastatic UCNT treated at the Institut Gustave Roussy between April 1978 and November 1996. A patient was considered a long-term survivor if he or she was disease-free for more than 36 months without treatment after obtaining a complete response by chemotherapy. Patient characteristics were as follows: sex, 17 men and three women; median age, 28 years (range, 9 to 62 years); median World Health Organization performance status, 1; and initial tumor-node-metastasis stage (International Union Against Cancer–American Joint Committee on Cancer, 1987) of T3 to T4, 60%, and of N2b to N3, 75%. Epstein-Barr virus serology was characteristic in 19 patients. Of 16 pretreated patients, 11 were pretreated by radiotherapy alone and five by chemotherapy and radiotherapy. Thirteen patients had metastatic relapses of locally controlled UCNT. Tumor sites were bone in 15 patients, lung in four, and liver (biopsy-proven) in two. Chemotherapy included the following: cisplatin, bleomycin, and fluorouracil in five patients; bleomycin, epirubicin, and cisplatin in seven patients; fluorouracil, mitomycin, epirubicin, and cisplatin in four patients; and fluorouracil, bleomycin, epirubicin, and cisplatin in one patient. Three patients were treated with platinum-based regimens before 1985. Patients received a median of six cycles (range, three to 13). Thirteen patients with bone metastases received consolidating radiotherapy. RESULTS: As of June 1999, 14 of 20 patients were still alive with no evidence of disease after treatment (disease-free survival time, 82+ to 190+ months), three patients died of other causes while in complete response at 61, 109, and 208 months after treatment, and three patients died of disease at 42, 89, and 115 months after treatment. Long-term complete responses were obtained in both bone and visceral disease. CONCLUSION: Our data support a curative role for chemotherapy in metastatic UCNT and are a major incentive to continue research for better combinations to increase the percentage of patients with metastatic UCNT who attain complete responses and long-term survival.
UNDIFFERENTIATED carcinoma of nasopharyngeal type (UCNT) is an endemic Epstein-Barr virus (EBV)–related neoplasm that occurs commonly in Southeast Asia and the Mediterranean basin and, more rarely, in Japan, Europe, and North America.1,2 Most patients at presentation have disease that is localized to the primary site and regional neck nodes. Of all the epidermoid head and neck cancers, this indication is the most prone to metastasis, with the incidence of metastatic disease being linked to initial stage, especially nodal volume.3-5 It is a highly radiosensitive malignancy, and local control rates greater than 80% are obtained when doses of more than 60 Gy over 6 weeks are given, even in patients with high tumoral volumes. Improvements in irradiation techniques and modern imaging have increased local control, but distant failures remain the primary problem for patients with locoregional bulky disease.6-9 The chemosensitivity of UCNT is well known,10-13 and the benefits of chemotherapy in the management of bulky locoregional disease have been demonstrated recently in randomized trials.14,15 The general consensus that chemotherapy is of limited benefit in recurrent or metastatic head and neck cancer may not be applicable to nasopharyngeal carcinoma. High objective response rates and a substantial proportion of durable complete responses have been attained in metastatic/recurrent disease.16 Our experience in this context has been rewarding. We present the data concerning 20 long-term, unmaintained complete responders to chemotherapy for metastatic UCNT who were treated at the Institut Gustave Roussy between April 1978 and November 1996.
Between 1978 and 1985, 877 patients with UCNT were treated at Institut Gustave Roussy. We estimated that approximately 40% of the patients who were seen had metastatic disease. Less than 100 of these patients received chemotherapy, which was prescribed sporadically, with an estimated 25% of these being treated with empirically determined cisplatin-based combinations. We reviewed the clinical records of these patients to identify long-term survivors (LTSs) in the population who had been treated with cisplatin-based combinations. We also reviewed the clinical records of 230 patients who were treated consecutively at Institut Gustave Roussy for metastatic UCNT between October 1985 and November 1996. These patients, all of whom had histologically or cytologically confirmed metastases of UCNT origin, underwent the following evaluations: clinical history, physical examination, head and neck examination and endoscopy, chest radiography, head and neck computed tomography scan, bone scintigraphy, bone marrow biopsy and aspiration, abdominal echography and other radiologic examinations, biochemical profile, complete blood cell count, serum electrolyte analysis, creatinine clearance, erythrocyte sedimentation rate, and lactate dehydrogenase and EBV serology (immunoglobulins G and A anti–viral capsid antigen and early antigen). Patients who were to receive bleomycin-based chemotherapy underwent functional respiratory tests at baseline, after the second cycle of chemotherapy, and when the total bleomycin dose given exceeded 300 mg/m2. Work-up was repeated after two chemotherapy cycles and every 6 months or yearly thereafter. Antitumoral response (according to World Health Organization criteria)17 was assessed by reviewing the results of serial physical examinations, biochemical tests, and radiologic investigations. A complete response was defined as the complete disappearance of all evidence of disease and normalization of all biochemical abnormalities. Recalcification of bone lesions had to be maintained on two consecutive evaluations that were more than 3 months apart. For bone metastasis evaluation, we used the criteria of the National Prostatic Cancer Project.18 Radiation therapy to bone sites was performed before or after chemotherapy with the use of palliative radiotherapy schedules (2 x 8.5 Gy or 30 Gy over 10 sessions). In all cases, to qualify as an LTS, a patient had to have a disease-free period longer than 36 months without treatment after attaining a complete response by chemotherapy.
Twenty patients with metastatic UCNT satisfied the criteria for being disease-free LTSs. Three of these patients were selected from among those treated for UCNT with cisplatin-based chemotherapy at Institut Gustave Roussy between 1978 and 1985, whereas the other 17 came from our prospective medical oncology program for this disease. The demographic characteristics and sites of disease at the start of chemotherapy treatment are presented in Table 1. There were 17 men and three women, nine from North Africa and 11 from the European Mediterranean basin, with a median age of 28 years. Epstein-Barr virus serology was characteristic of the UCNT in 19 of the patients (the status was unknown for the other one). Seven patients had metastatic disease at presentation, whereas 13 of 20 patients had had metastatic relapses of locally controlled UCNT. Metastatic disease sites included bone (15 of 20 patients), lung (four of 20 patients), and liver confirmed by biopsy (two of 20 patients). The number of bone metastases was less than or equal to three in 13 of the 15 patients with bone involvement. Sixteen patients had been pretreated for their locoregional disease, 11 with radiotherapy alone and five with radiotherapy combined with chemotherapy.
Of the patients treated with cisplatin-containing regimens before 1985, three LTS patients were identified. Each of these three patients had received a different chemotherapy regimen (cisplatin + vindesine + cyclophosphamide, cisplatin + doxorubicin, and cisplatin + vincristine + doxorubicin + bleomycin + cyclophosphamide). One is alive at the time of writing without evidence of disease and with a disease-free survival of 190+ months after treatment. The two others died of unrelated causes while still in complete remission at 109+ months (pulmonary fibrosis) and 208+ months (victim of a crime) after treatment. From 1985 to 1996, four consecutive combination chemotherapy protocols were evaluated in phase II studies.10,13,19,20 The regimens are described in Table 2, and the results in metastatic patients are listed in Table 3. The last follow-up was performed in June 1999. In the cisplatin + bleomycin + fluorouracil study,10 five of 49 patients were LTSs, three of whom are alive at the time of writing, without disease, and with disease-free survival periods of 151+, 152+, and 155+ months after treatment. One patient had a fatal hemorrhagic episode (postradiation necrosis) while still in complete remission (at 61 months after treatment), and one patient died of disease after a disease-free period of 115 months after treatment. Seven of 44 patients from the bleomycin + epirubicin + cisplatin series are LTSs at the time of this writing,13 five of whom are alive without disease, with disease-free survival periods of 94+, 110+, 116+, 117+, and 128+ months after treatment. Two patients died of disease after disease-free periods of 42 and 89 months after treatment, respectively. The third study, fluorouracil + mitomycin + epirubicin + cisplatin,19 had four LTS patients. They are still alive at the time of writing without disease with disease-free survival periods of 93+, 96+, 100+, and 115+ months after treatment. Two of them had biopsy-proven liver metastases. The last generation protocol, fluorouracil + bleomycin + epirubicin + cisplatin,20 had one LTS patient. She is still alive at the time of writing without disease and with a disease-free period of 82+ months after treatment.
Despite the known chemosensitivity of UCNT, before the late 1980s there were only sporadic reports concerning the treatment of patients with metastatic disease. In an extensive literature review, we were able to identify 31 isolated reports of LTSs. Many of these patients were reported as being free of disease for less than the 36-month standard established for the present report but, nevertheless, were included in our analysis. The literature reports regarding long-term remission in metastatic UCNT patients, along with available disease and treatment characteristics, are summarized in Table 4. Choo and Tannock11 reported two LTS patients in a retrospective series of 70 patients who were treated for recurrent or metastatic carcinoma of the nasopharynx. Forty patients received nonaggressive chemotherapy (single-agent or noncisplatin-containing regimen), and no LTS was observed in this group. Among the 30 patients who received aggressive chemotherapy (lymphoma-type protocols or cisplatin-based chemotherapy), two patients were still alive without evidence of disease after 3 and 12 years of follow-up.
Su et al,21 in Taiwan, treated 25 patients with cisplatin, infusional fluorouracil, and bleomycin. The response rate in this retrospective analysis was 40%, with one complete response. One patient with local recurrence and two bone metastases was alive without evidence of disease at 28 months after treatment. As in our series, this patient received consolidating radiotherapy to bone metastases. In a small series of 12 metastatic patients who were treated with cisplatin-based chemotherapy, Al-Kourainy et al22 reported one LTS who was alive without evidence of disease at 84+ months after treatment. Two other reports on children with nasopharyngeal cancer mention one LTS each, with disease-free survival periods of 16 years and 74 months after treatment, respectively.23,24 Both patients had bone metastases and received consolidating radiotherapy. In the pediatric report of Ghim et al,25 in which 12 UCNT patients were treated with fluorouracil, vincristine, cyclophosphamide, and doxorubicin plus radiotherapy, only one patient had metastatic disease and was alive without evidence of disease 24 months after the completion of treatment. Another patient who developed bone metastases after completion of radiotherapy was treated with VP-16 and ifosfamide and remained disease-free for 11 years after treatment. In the report of Jenkin et al,26 which concerned a pediatric population of 119 patients at Princess Margaret Hospital, two patients with bone metastases were alive without disease at 73+ and 55+ months after treatment. Siu et al,27 from the same institution, reported four LTS patients out of a total of 51 metastatic UCNT patients who were alive without evidence of disease at more than 5 years after treatment. Kwan et al,28 from Hong Kong, treated one patient with metastases to mediastinal and lymph nodes by chemotherapy and consolidation radiotherapy. The patient was alive without evidence of disease 66+ months after treatment completion. In a second report from Hong Kong, Teo et al29 described four disease-free LTSs (64+ to 117+ months after treatment) out of 289 metastatic UCNT patients who were treated with aggressive multimodal treatments (chemotherapy plus radiotherapy [three patients] and chemotherapy plus surgery [one patient]). The same team reported one disease-free LTS at 52 months after treatment.30 Hsu and Tu31 reported five LTSs (three with lung metastases and two with skin metastases) who survived more than 5 years after retreatment. Castro Vita et al,32 Leung et al,33 and Galligioni et al34 each reported one metastatic LTS at 70+, 32+ (fluorouracil + cisplatin combination), and 18+ months (doxorubicin + bleomycin + vinblastine + dacarbazine regimen) after treatment, respectively. Recently, Hong et al,35 in Taiwan, reported three LTSs out of 32 metastatic UCNT patients who were treated with mitomycin, doxorubicin, and cisplatin who were still in remission 13, 14, and 21 months after treatment, respectively. In the present study, we analyzed a substantial number of LTS patients from a single institution and confirmed the potential curative role of chemotherapy in metastatic UCNT. In our successive, progressively incremental chemotherapy programs, complete responses were observed in bone and soft tissue, as well as in bone marrow and liver metastases. Of note, approximately 10% of all metastatic patients who were seen and treated by our team since 1985 have been LTSs, despite the progressively higher tumor burden and worse pretreatment characteristics of patients treated under our four successive protocols (Table 2). These four consecutive studies show an incremental trend in dose-intensity and number of drugs administered, and we believe that the dose-response effect of the aggressive cisplatin-based combinations has played a major role in obtaining long-term complete responses. Other chemosensitive malignancies, such as lymphoma, leukemia, and testicular cancer, have had their prognoses transformed as a result of optimized chemotherapy regimens. It is of note that UCNT, like these other chemocurable neoplasias, has a monoclonal origin.36 Several reports underline the fact that p53 gene mutations occur infrequently in UCNT. The preserved functionality of p53 may lead to a more efficient apoptotic process subsequent to DNA damage that is induced by radiation or a chemotherapeutic agent.37-39 We have described the differentiated iconographic characteristics of radiologic contrast-enhanced tumoral vascularization in UCNT-involved lymph nodes, which is uniform and functional when compared with that seen in lymph nodes involved with head and neck squamous cell cancer.40 This results in both a better oxygenation of the tumor, which may be partially responsible for its increased radiosensitivity, and in a better, more uniform systemic distribution of chemotherapeutic agents. The normal p53 functionality, the monoclonal nature of the tumoral proliferation,36,41 and the preserved functional angiogenesis characteristics of UCNT40 all may be contributing factors to the acknowledged chemosensitivity and radiosensitivity of this disease. Further exploration with alternative regimens or a maximalist approach that uses either recombinant or cellular hematopoietic support is needed to determine whether these cases constitute the limit for currently available therapeutic possibilities (such as in small-cell lung cancer) and whether the frequency of such clinical and therapeutic results can be increased and thus improve on the results of currently available regimens (as in germ-cell tumors and lymphomas). Although the issue has not been analyzed or reported, it is important to emphasize that, when left untreated or when unresponsive to chemotherapy, metastatic UCNT remains a lethal disease that progresses rapidly. We have not found any instances of smoldering, untreated metastatic UCNT that results in prolonged patient survival (ie, beyond 1 year), nor are we aware of any spontaneous remissions in patients with either locally advanced or metastatic UCNT. The positive results in locoregionally advanced disease and the high chemosensitivity of metastatic disease constitute major clinical arguments for the multimodality of combination treatment of locally advanced disease with high risk of metastatic spread. The search for better combinations to increase the percentage of complete responders and LTSs among metastatic UCNT patients is also a clinical research priority. Recent reports on the activity of taxane-containing regimens42,43 should encourage the evaluation of new active agents with the aim of optimizing the treatment of this disease.
We are grateful to Lydia Devesa-Perez and Marie-Jo Ferreira for typing assistance and to Michelle Hughes for reviewing the English version of the article.
Presented at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
