Japanese Journal of Clinical Oncology 33:391-395 (2003)
© 2003 Foundation for Promotion of Cancer Research
The Limited Efficacy of Methotrexate, Actinomycin D and Cisplatin (MAP) for Patients with Advanced Testicular Cancer
Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Combination chemotherapy of methotrexate, actinomycin D and cisplatin (MAP) is reported to be effective against gestational choriocarcinoma.
Methods: Eight patients with metastatic testicular cancer who had elevated ß-hCG were treated with MAP. They included three refractory cases and two relapsed cases. An additional three patients received MAP as part of the induction therapy. The MAP therapy consisted of methotrexate (10 mg/m2) on days 1–5, actinomycin D (0.01 mg/kg) on days 1–5 and cisplatin (70 mg/m2) on day 1.
Results: In all three refractory patients, MAP failed to achieve tumor marker normalization. However, the elevated tumor markers normalized after MAP in the two cases of relapse. Of these two, one patient relapsed again 7 months after MAP and was subsequently salvaged with high-dose chemotherapy. The other patient relapsed and died of the disease 30 months after receiving MAP. Of the three patients who received MAP as part of the induction chemotherapy, one with pure choriocarcinoma achieved tumor marker normalization after MAP and is still alive without disease progression. In the other two patients, MAP failed to achieve marker normalization and the patients received high-dose chemotherapy. The toxicities were mainly bone marrow suppression and mucositis, which were almost acceptable.
Conclusions: The results demonstrated the limited efficacy of MAP as salvage therapy. In addition, the efficacy of MAP as part of induction chemotherapy was negligible. However, there might be some role for MAP as a salvage therapy for patients with pure choriocarcinoma.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Disseminated testicular cancers have been successfully treated with combination chemotherapy consisting of cisplatin, bleomycin and etoposide (1). Nevertheless, there are still patients who either fail to achieve complete remission (CR) or who relapse after an initial CR. The standard dose salvage chemotherapy currently available with cisplatin, ifosfamide and either etoposide or vinblastine (VIP or VeIP) can achieve complete responses in ~50% of patients. However, since the remissions are short in duration, the long-term disease-free survival rate is only 10–25% (2,3).
One possible approach to overcome this limitation is to include new active drugs in the chemotherapy regimen. Methotrexate (MTX) and actinomycin D, although less often applied in testicular cancer, have been widely used for gestational choriocarcinoma (4,5). With the use of MTX, actinomycin D and cyclophosphamide (MAC) chemotherapy in the treatment of high-risk metastatic gestational choriocarcinoma patients, reported cure rates range from 63 to 80% (4).
In addition, several investigators have reported some activity of combination chemotherapy containing MTX for testicular cancer (6,7). Since both MTX and actinomycin D are key drugs for choriocarcinoma, a regimen containing the two drugs is considered more suitable for patients with active choriocarcinoma elements. Based on these backgrounds, we conducted the present study to test the efficacy of MTX, actinomycin D and cisplatin (MAP) for testicular cancer with abnormally elevated serum ß-human chronic gonadotoropin (ß-hCG) levels.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Between 1992 and 1999, eight patients with metastatic testicular cancer were treated with MAP at Tsukuba University Hospital. The median age at treatment was 30 years (range 19–61 years). All patients had histologically confirmed testicular cancer and assessable disease. The serum ß-hCG was measured with a Solid phase-ELSA system (CIS Bio International). The assay kit detects the ß subunit of the free ß-hCG but not the intact hCG. We also measured the serum level of intact hCG using a Delfia hCG kit (Pharmacia Upjohn, Tokyo, Japan) to evaluate prognosis of advanced cases. The ß-hCG was abnormally elevated in all patients at the initiation of MAP. In contrast, the serum AFP levels were within normal limits. Pretreatment evaluation included a history and physical examination, chest X-ray and routine blood chemistry. Depending on the sites of metastatic disease, all patients underwent a computed tomography (CT) scan of the chest and abdomen and/or pelvis.
Treatment Program
All patients received chemotherapy with methotrexate (10 mg/m2) on days 1–5 by intravenous infusion, actinomycin D (0.01 mg/kg) on days 1–5 by intravenous infusion and cisplatin (70 mg/m2) by intravenous infusion on day 1. Folinic acid (40 mg/day) was administered by oral inoculation or folinic acid (24 mg/day) was administered parenterally.
Patients received granulocyte colony-stimulating factor (G-CSF) at 5 µg/kg daily by subcutaneous injection if necessary. If the white blood cell count exceeded 10 000/µl, G-CSF therapy was discontinued. Courses were planned to be repeated every 21 days. All patients provided written informed consent to be treated with MAP.
Evaluation of Response and Toxicities
The clinical response was evaluated according to the criteria in the General Rules for Clinical and Pathological Studies on Testicular Tumors (8). Complete remission (CR) was defined as complete disappearance of known sites of disease including normalization of tumor markers for at least 4 weeks. Partial remission (PR) was defined as >50% reduction of the sum of products of the largest diameter for all measurable lesions. The survival time was measured from the first day of MAP to the last follow-up appointment or until death. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (second version, 1999) (9).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Six patients had non-seminoma and two patients had seminoma histologies at the primary site. The characteristics of refractory or relapsed patients at the initiation of MAP are described in Table 1. There was evidence of disease progression during or within 4 weeks of the last cisplatin-based chemotherapy in three refractory patients. Two relapsed patients suffered from disease progression 7 and 2 months after the last chemotherapy. All patients were treated with more than six cycles of cisplatin-based chemotherapy or high-dose chemotherapy (HDCT) prior to MAP.
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Table 2 summarizes the characteristics of patients who received MAP as part of their induction chemotherapy. Two patients (cases 6 and 8) were defined as poor and intermediate prognosis by the pretreatment intact hCG levels according to the IGCCC (International Germ Cell Consensus Classification) (10). In addition, pretreatment radiological examination revealed multiple liver metastases in case 6.
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The remaining one patient was enrolled in the study because the first-line chemotherapy failed to achieve serum ß-hCG normalization.
Treatment and Toxicities
The toxicity of MAP was considered tolerable, except in one patient (case 6). Since that patient developed severe pharyngeal mucositis during the first course of MAP, further treatment was discontinued. Myelosuppression was the major toxicity, as shown in Table 3. Almost all patients developed grade 3 or 4 leukocytopenia. Red blood cell transfusions were needed for three of the eight patients. Platelet transfusions were needed for five of the eight patients. Two patients developed neutropenic fever, but were successfully treated with empirical broad-spectrum antibiotics. All patients developed more than grade 2 pharyngeal mucositis and nausea. Grade 3 mucositis and grade 3 nausea were observed in three and two patients, respectively.
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Response and Survival
The response to MAP is summarized in Tables 1 and 2. MAP did not show an objective response and also failed to achieve ß-hCG normalization in all three refractory cases. Subsequently, those three patients were treated with radiotherapy and other chemotherapy regimens, including HDCT. One patient (case 5) developed multiple brain metastases during MAP; the patient was successfully salvaged with gamma–knife radiosurgery followed by paclitaxel-containing chemotherapy. The remaining two patients died of disease progression.
In contrast, two relapsed patients responded to MAP and achieved ß-hCG normalization. However, they relapsed again 7 and 1 month after MAP therapy, respectively. Of these two patients, one (case 2) was subsequently salvaged with HDCT.
All of the three patients who received MAP as part of induction chemotherapy had an elevated ß-hCG at the initiation of MAP. The tumor markers decreased to a normal level after MAP in two patients. One patient (case 6) with multiple liver metastases has been free from disease progression for 10 years. The patient received only one course of MAP therapy and refused further therapy because of mucositis. Since the patient received seven courses of BEP and VIP prior to MAP therapy, it is difficult to conclude what the exact role of MAP therapy was in this case. However, one course of MAP therapy successfully normalized the ß-hCG level, which had been in plateau slope during the prior VIP therapy. Hence MAP therapy might have played some role in the favorable outcome in this case.
The second patient (case 8) received additional treatment with HDCT and surgery and was rendered free of disease. Because the tumor marker did not return to a normal level after PVB in one seminoma patient (case 7), this patient received MAP, but failed to achieve ß-hCG normalization. The patient received HDCT, but failed to be salvaged.
In summary, MAP showed objective responses and ß-hCG normalization in four of eight patients. However, three patients suffered from disease progression within relatively short intervals. Only one patient achieved long-term remission after MAP.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MTX is an active drug in the first-line treatment of gestational choriocarcinoma. Multidrug combination chemotherapy such as MTX, actinomycin D and cyclophosphamide (MAC) or etoposide, MTX, actinomycin D, cyclophosphamide and oncovin (ECMO-CO) have been shown to induce remission in about 70% of gestational choriocarcinoma patients (11). The activities of combination chemotherapy containing MTX for testicular cancer have also been investigated. Newlands et al. reported that multidrug chemotherapy consisting of cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide was an effective first-line treatment against testicular cancer (12). Several investigators studied the activity of MTX for treatment of relapsed and refractory testicular cancer (6,7,13). Based on the results of these studies, we tested MAP as a salvage treatment for patients with unfavorable prognostic features and also as part of induction chemotherapy for advanced patients. In this series, all patients showed an elevation of ß-hCG at the start of MAP therapy. Since free ß-hCG is known to increase in testicular cancer with histologies of non-choriocarcinoma including pure seminoma, the elevation of free ß-hCG does not necessarily indicate the presence of elements of choriocarcinoma (14,15). However, six of eight patients in the present study had choriocarcinoma elements at the primary site.
MAP as a salvage chemotherapy showed an objective response with ß-hCG normalization in two of five patients. However, those two patients relapsed again after a relatively short remission period. In contrast, MAP as part of induction chemotherapy achieved ß-hCG normalization in two of three patients. Of them, one was rendered continuously disease free after MAP.
In this study, all of the relapsed and refractory cases had been treated with two or more different chemotherapy protocols before MAP. Of these, two patients had already been treated with HDCT. Taking into consideration their heavy pretreatment history, MAP was relatively well tolerated.
Table 4 summarizes the results of previously reported studies of chemotherapy containing MTX, including the present one. Atkinson et al. (13) concluded that high-dose MTX as a single agent did not have a useful role in the salvage therapy of testicular cancer. In contrast, when MTX was used with other active drugs, the objective response rates were as high as 50–60%. However, the long-term disease-free survival rates were only in the range 10–30%. Hence salvage therapy which contains MTX, including the MAP presented here, does not appear to be a more effective treatment than the conventional VeIP or VIP therapy.
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It is hoped that a future investigation combining new active drugs such as paclitaxel, gemcitabine (16) and irinotecan (17) may lead to the development of a more effective salvage chemotherapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Jun Miyazaki, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1–1–1 Tennodai, Tsukuba-City, Ibaraki 305-8575, Japan. E-mail: kontama{at}v004.vaio.ne.jp
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Received April 17, 2003; accepted July 11, 2003
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