Japanese Journal of Clinical Oncology Advance Access originally published online on June 20, 2006
Japanese Journal of Clinical Oncology 2006 36(7):425-431; doi:10.1093/jjco/hyl053
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© 2006 Foundation for Promotion of Cancer Research
Completion and Toxicity of Induction Chemotherapy for Metastatic Testicular Cancer: An Updated Evaluation of Japanese Patients
University of Tsukuba, Graduate School of Comprehensive Human Sciences, Institute of Clinical Medicine, Department of Urology, Tsukuba, Ibaraki, Japan
For reprints and all correspondence: Koji Kawai, MD, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305, Japan. E-mail address: rkawa{at}md.tsukuba.ac.jp
Received December 25, 2005; accepted April 3, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Combination of bleomycin, etoposide and cisplatin (BEP) remains the standard chemotherapy for testicular cancer. Since the development of BEP in the 1980s, there has been a considerable advance in supportive therapies, such as granulocyte colony-stimulating-factor and 5-HT3 antagonists. Therefore, we re-evaluated the completion and toxicity of BEP combined with modern supportive care.
Methods: The medical records of all 42 testicular cancer patients who received induction chemotherapy at Tsukuba University Hospital were reviewed. Toxicities during the induction chemotherapy were graded according to the Japanese CTCAE v3.0.
Results: Dose reduction was needed in only three patients. The subsequent chemotherapy was started at the planned 3 week interval or within 3 days of postponement in 89% of the treatment cycles. The average relative dose intensity (RDI) of bleomycin was 0.95, while that for etoposide and cisplatin was 0.97. There was no death due to toxicity. The most frequent toxicity was leukopenia (grade 3 in 44% and grade 4 in 55%). Post-chemotherapy diffusion capacity was significantly decreased in 30% of patients. Two patients developed bleomycin-induced pneumonitis, but recovered successfully. Sixteen patients received second line or salvage chemotherapy after BEP, subsequently. The overall 5 year cause-specific survival rate was 85%.
Conclusion: BEP with high RDIs is acceptable if combined with modern supportive care, with acceptable toxicity profile in most patients.
Key Words: testicular cancer • BEP • toxicity • IGCCCG classification
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The treatment outcome of metastatic testicular cancer has improved substantially since the introduction of cisplatin, vinblastine and bleomycin (PVB) in the late 1970s (1). Subsequently, randomized clinical trials comparing bleomycin, etoposide and cisplatin (BEP) with PVB demonstrated that the BEP regimen had lower toxicity and a higher cure rate (2). Therefore, BEP has become the standard chemotherapy since the mid-1980s. Because most attempts to use higher dose chemotherapy or alternative regimens have not proved superior to BEP (3,4), the original BEP regimen remains the standard treatment for testicular cancer.
To achieve optimal outcome, however, BEP should be given without any dose reduction at 3 week intervals to the extent possible. Several investigators demonstrated that maintaining the relative dose intensity (RDI) of induction chemotherapy is an important principle for optimal response (5,6). From this point of view, the European Germ Cell Cancer Consensus Group recommended that postponing treatment, at a maximum of 3 days for each decision, should only be considered in cases of existing fever, neutrophil counts <500/mm3 or platelet counts <100 000/mm3 on day 1 of the subsequent cycle (7).
Several investigations reported improvement of outcome for patients treated in the past decade (8–10). Multiple factors, including wide use of BEP, the introduction of intensified salvage chemotherapy and surgery, may be responsible for this progress. Along with these new therapeutic modalities, there has been a remarkable progress in supportive care, such as administration of granulocyte colony-stimulating-factor (G-CSF) and 5-HT3 antagonists, in the same period. It is likely that the progress in supportive care has contributed to the improvement of the efficacy of BEP treatment. However, there is limited data concerning the toxicity profile and completion of BEP treatment with the use of modern supportive care, especially in Japanese testicular cancer patients.
The objective of the present study was to analyze the detailed toxicity profile and completion of BEP in induction chemotherapy for the patients treated at Tsukuba University Hospital (TUH) between 1991 and 2005. Toxicities were graded according to the Japanese Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE, v3.0). To our knowledge, this investigation is one of the largest series of toxicity assessments in Japanese patients treated with BEP using modern supportive care.
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PATIENTS AND METHODS |
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PATIENTS
A total of 42 advanced germ cell tumor patients were given induction chemotherapy at TUH between March 1991 and January 2005. Of them, 40 patients had metastatic testicular tumor, and the remaining 2 patients were diagnosed with extragonadal germ cell tumor originating from the retroperitoneum. They included 29 patients with non-seminomatous germ cell tumor (NSGCT) and 13 patients with seminoma. The median age at diagnosis was 31 years (range, 17–66 years). Pretreatment staging consisted of physical examination, determination of serum tumor marker levels and radiological examination. Patients were classified into the relevant prognostic category according to the classification defined by the International Germ Cell Cancer Collaborative Group (IGCCCG) (11). The characteristics of the 42 patients are summarized in Table 1.
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TREATMENT
All patients except one received a BEP protocol consisting of bleomycin, etoposide and cisplatin as the induction chemotherapy (2). The remaining patient, whose disease was complicated by active asthma, received four courses of etoposide and cisplatin (EP) (12). The schedule of BEP at TUH is 100 mg/m2 of cisplatin on day 1, 100 mg/m2 of etoposide on days 1–5, and 30 mg/body of bleomycin on days 1, 8 and 15 with recycling on day 22. Therefore, the planned drug intensities were 33.3 mg/m2/week for cisplatin, 166.7 mg/m2/week for etoposide and 30 mg/body/week for bleomycin. Recombinant human G-CSF was administered by subcutaneous injection when the leukocyte count was below 2000/mm3. To ameliorate chemotherapy-related nausea, 5-HT3 antagonists were used in combination with methylprednisolone and metoclopramide.
Our program for induction chemotherapy was as follows: three courses of BEP for low-risk patients, three or four courses of BEP for intermediate-risk patients and four courses of BEP for high-risk patients. In patients with intermediate- or high-risk, when response after the third course of BEP was inadequate, a second-line chemotherapy was started with the subsequent treatment cycle. The second-line chemotherapy most frequently used was paclitaxel, ifosfamide and cisplatin (TIP) (13,14). Because paclitaxel, the key drug of this regimen, has not been approved by the Japanese government for treatment of testicular cancer, the University Hospital Investigative Fund was used for the purchase of paclitaxel.
The other second-line or salvage chemotherapy used was high-dose chemotherapy (HDCT) (15,16) or ifosfamide-containing standard dose chemotherapy (Table 1) (17). In principle, patients underwent surgical resection of residual operable masses when all tumor makers were normalized by chemotherapy, but surgery was not performed for patients with adequately responding retroperitoneal lymph node (RPLN) mass (less than 3 cm in diameter in seminoma patients, and less than 1 cm in diameter in NSGCT patients without a teratomatous element). In these cases, most patients received one additional course of EP as consolidation chemotherapy.
EVALUATION OF TOXICITIES
The medical records of the patients were reviewed with special attention to symptoms, physical examinations and routine blood determinations. Routine blood examinations including blood cell counts and blood chemistries were performed three times per week during chemotherapy. The observed toxicities during the induction chemotherapy were graded according to CTCAE v3.0. All episodes of hypocalcemia (albumin-corrected serum calcium level <8.5 mg/dl), hyponatremia (<136 mEq/l) and hypochloraemia (<97 mEq/l) during chemotherapy were recorded. For post-chemotherapy pulmonary function assessment, the diffusion capacity (DLCO) was measured by the single-breath method. The observed DLCO was corrected for hemoglobin (Hb) level using the following equation: Corrected DLCO = observed DLCO/0.06965 Hb (18). The corrected DLCO is expressed as a percentage of the predicted value according to reference values based on height and age.
CALCULATION OF RDI FOR BEP
The RDI of each drug during the induction chemotherapy was calculated by dividing the actually given drug intensity by the planned dose intensity and was expressed as a decimal, with a value of 1.0 indicating that the patient received 100% of the planned dose.
STATISTICAL ANALYSIS
The influence of different predictive factors on bone marrow suppression was estimated using the Fisher's exact test. Survival curves were constructed by the Kaplan–Meier method and compared using the log-lank test. In both analyses, the level of significance was set at P < 0.05. Statistical analysis was performed using JMP software (version 5.1; SAS Institute Inc., Cary, NC, USA) (19), and Microsoft Excel (Microsoft Corp. Redmond, WA, USA) was employed for graphic presentation.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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COMPLETION AND RDI OF INDUCTION CHEMOTHERAPY
As shown in Table 1, 30 patients received three cycles of BEP, while 5 patients received four cycles of BEP as the planned induction chemotherapy. Three patients, who had marker normalization after three cycles of BEP, did not have surgery for the minimal residual RPLN mass and received one additional course of EP. One patient with active asthma underwent four cycles of EP. Therefore, 39 patients received the planned induction chemotherapy. Of the remaining three patients, two required discontinuation of bleomycin during induction chemotherapy due to adverse effects, bleomycin-induced pneumonitis (BIP) and scratch dermatitis. Another patient, who had complicated psychiatric disorders, refused any further treatment after one course of BEP, for a reason not related to chemotherapy. Therefore, the patient was not included for the subsequent RDI analysis.
Besides the elimination of bleomycin, there was only one patient who needed a dose reduction during induction chemotherapy. The patient received BEP with a 70% dose of each drug at the first cycle due to renal dysfunction from hydronephrosis. After the renal function had improved, the patient received full dose BEP in the subsequent cycles.
RDI was calculated in 41 patients, taking cycle postponements as well as dose reduction and drug elimination from the planned chemotherapy into considerations. Cycles were postponed in 23 patients for 33 cycles of the 93 subsequent treatment cycles (35%), but the duration was only 1 day in 16 of 33 cases. Most of the frequent reasons for one-day postponement were not related to chemotherapy. Postponements of more than 3 days occurred in 11 treatment cycles for 7 patients. The major reason was patient compliance, followed by bone marrow suppression. The RDI of the agents for all cycles are listed in Table 2. The average RDI of bleomycin was 0.95, while that of etoposide and cisplatin was 0.97. Treatment with RDI over 0.9 was performed in 88% of patients for bleomycin and 90% of patients for etoposide and cisplatin.
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TOXICITIES OF INDUCTION CHEMOTHERAPY
There was no toxic death due to induction chemotherapy. Table 3 lists the worst chemotherapy-induced toxicities throughout all cycles of induction chemotherapy.
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Hematologic toxicities
The most frequent toxicity was leukopenia (grade 3 in 44% and grade 4 in 55%), followed by anemia and thrombocytopenia. Nineteen patients (45%) experienced neutropenic fever, all of whom were successfully treated with empiric broad-spectrum antibiotics. Table 4 shows the details of hematologic toxicities according to the treatment cycle. In the first three cycles of the induction chemotherapy, the median leukocyte nadir was 1200/mm3 to 1800/mm3, which occurred at median 13–15 days after treatment. The median platelet nadir was 8.6 x 104/mm3 to 7.5 x 104/mm3 at median days 14 to 15 after treatment. There was no clear tendency in both nadir counts during the first three courses; however, both leukocyte and platelet counts were significantly decreased at the fourth cycle: 700/mm3 and 2.3 x 104/mm3, respectively. In contrast, the nadir hemoglobin levels were observed following the treatment cycles: 10.5 g/dl after the first cycle to 7.7 g/dl after the fourth cycle. There was no significant tendency in the incidence and duration of neutropenic fever among the treatment cycles.
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Non-hematologic toxicity
The most frequent gastrointestinal toxicity was vomiting, which was observed at grade 1 in 48% and grade 2 in 7%. Of note, a moderate degree of diarrhea and stomatitis were not rare. Diarrhea and stomatitis of grades 2 or 3 occurred in 20 and 26%, respectively. Of other non-hematologic toxicities, electrolyte imbalance was commonly observed. The overall incidences of hypochloraemia, hyponatremia and hypocalcemia were 60, 38, and 17%, respectively. Elevations of serum creatinine, liver enzymes and total bilirubin of grade 2 were observed in
10% of patients. One patient, who had massive liver metastases, developed grade 4 hepatotoxicity at the first course of BEP. As other non-hematologic toxicities, electrolyte imbalance was frequently seen. Most of the imbalance was transient, thus might be related to hydration or vomiting during chemotherapy. However, some patients who developed hypocalcemia needed calcium replacement for persistent hypocalcemia. As a principle, we measured DLCO after the last course of BEP for patients planning post-chemotherapy surgery. DLCO was also checked after completion of the planned chemotherapy. As a result, DLCO was measured in 33 patients after the completion of BEP. DLCO decreased below 70% of the predicted value in 10 patients. The median percentage of the measured DLCO of these patients was 62% (range 45–61%). Of them, two patients developed clinically evident BIP with hypoxia or fine crepitations during 2 and 3 courses of BEP. A 66-year-old man developed BIP with mild hypoxemia and fine crepitations at the second course of BEP (total bleomycin dose of 120 mg). Chest computed tomography (CT) revealed fibrotic change in bilateral lung fields. Bleomycin was discontinued, and the patient received additional two cycles of EP without further progress of BIP. The other patient, a 38-year-old man, developed mild hypoxemia with a PaO2 of 72 mmHg during the planned third course of BEP. Plain chest x-ray revealed interstitial infiltrates. Because the DLCO was 41% of the predicted value, the last injection of bleomycin was stopped (total 240 mg). Chest CT at 2 weeks later revealed mild fibrotic change, and blood gas analysis showed improvement of hypoxemia. Three additional patients, although lacking signs and symptoms, were revealed by chest CT to have abnormalities suggesting BIP. There was no significant difference in DLCO between older (over 31 years: n = 20) and younger patients (n = 14). However, it is of note that all five patients who developed clinically or radiologically diagnosed BIP were over 31 years of age. The median age of these patients was 43 years (range: 37–66 years).
In this series, no clinically evident neuropathy was noted in the medical records.
PRETREATMENT PREDICTIVE FACTORS FOR LEUKOPENIA AND THROMBOCYTOPENIA
To identify predictive factors for leukopenia and thrombocytopenia at the first cycle of the induction chemotherapy, we evaluated the five pretreatment variables. These included age (
40 years, <40 years), performance status (PS) (1, 0), IGCCC criteria (good, intermediate or poor risk), creatinine clearance (90 ml/min, <90 ml/min) and serum albumin level (3.8 g/dl, <3.8 g/dl). Each potential predictor was examined by univariate analyses, and subgroups of patients were compared using the Fisher's exact test. As shown in Table 5, the patients with PS > 0 had a somewhat higher incidence of a leukocyte nadir below 1000/mm3, but the difference was not significant (P = 0.051). Also, other variables were not significant predictors for the leukocyte nadir. In contrast, patients with an unfavorable PS or lower serum albumin level had a significantly high risk for developing thrombocytopenia below 5 x 104/mm3.
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SURVIVAL OF PATIENTS
In addition to the induction chemotherapy, 16 patients received second-line or salvage chemotherapy for refractory or relapsed disease. Twenty-one patients underwent surgery for post-chemotherapy residual mass. The overall 5-year cause-specific survival rate was 85%. Figure 1 represents the cause-specific survival curve according to IGCCC criteria. Eighteen patients (54%) were classified as good-prognosis, 15 patients (27%) as intermediate-prognosis and 9 patients (19%) as poor-prognosis. The patients classified into the good-prognosis group had a 5 year survival rate of 94%; the intermediate- and poor-prognosis groups had 5 year survival rates of 84 and 73%, respectively. The difference between the three groups was not statistically significant. In addition, the survival was compared by RDI of the induction chemotherapy. The 5 year survival rates of patients with RDI
0.95(n = 34) and <0.95 (n = 7) were 84 and 86%, respectively. There was no statistical difference. When the 5-year survival rate compared RDI with a cut-off of 0.9, the survival rates of patients with RDI 0.9 (n = 37) and <0.9 (n = 4) were 86 and 75%, respectively. The survival of patients with RDI < 0.9 was somewhat lower, but the difference was not statistically significant.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The present retrospective review shows that planned induction chemotherapy is possible in most Japanese testicular cancer patients. Overall, the subsequent chemotherapy could be started within 3 days of postponement in 83 of 93 treatment cycles (89%). Dose reduction or drug elimination was needed in only three patients. As a result, treatment with an RDI over 0.9 was performed in 88% of patients. The average RDI of bleomycin was 0.95 and that of etoposide and cisplatin was 0.97. This is in accordance with our previous analysis of RDI for PVB, where RDI increased from 0.87 to 0.98 with use of G-CSF. A similar improvement of RDI in BEP or EP was reported in a prospective study in which subjects were randomized to receive or not to receive G-CSF (20). The randomized study showed that the routine use of G-CSF significantly improved the delivery of the planned treatment schedule. The median RDI for cisplatin, etoposide and bleomycin was 1.00, 0.99 and 0.98, respectively (20).
The present investigation, as well as those published previously (5,6), suggests that the RDI of BEP plays an important role, but its definite significance in the treatment outcome was not demonstrated. The survival of patients with RDI < 0.9 was somewhat lower, but the difference was not statistically significant. This is partly due to the limited number of patients with RDI < 0.9. As another possible reason, at least, it is conceivable that elimination of bleomycin is effectively compensated for by the addition of one or more courses of EP or the ifosfamide-containing regimen. Recently, in germ cell tumor chemotherapy, there is increasing evidence which suggests that institutional experience is associated with treatment outcome (21,22). Collette et al. (22) reported worse outcomes in institutions entering fewer than five patients to clinical trials for ‘poor-prognosis’ germ cell tumor compared with institutions entering five or more patients. Although a combination of factors may be involved in the institutional difference, the authors pointed out that the RDI of cisplatin and etoposide was statistically significantly lower in institutions that had treated fewer than five patients than in the institutions that treated more patients (22). In this investigation, the linkage between our institutional experience and treatment outcome is not clear; therefore, it is likely that high RDI might be directly associated with the favorable outcomes of our patients.
Bone marrow suppression is the most common toxic manifestation of BEP. Overall, 55% of patients had leukocyte counts below 1000/mm3, and 34% had platelet counts below 5 x 104/mm3. Clinical hemorrhage was not seen, but 12 patients (29%) needed platelet transfusion at some time during treatment. Forty-five percent of patients experienced neutropenic fever. In all these patients, the neurtopenic fever was manageable with prompt antibiotic use. Indeed, most neutropenic fever during BEP was manageable; however, it is necessary to keep in mind that neutropenic sepsis is still the second leading cause of treatment-related death with BEP. The incidence was 1.6% in the original BEP report (2), and a similar incidence was noted in patients who belonged to the non-G-CSF arm of the G-CSF randomized study (20). Our analysis suggests that lower PS and serum albumin levels might be the possible risk factors for severe bone marrow suppression at the first cycle of BEP.
Although not life-threatening, vomiting and nausea are still important for the patient's quality of life and affect compliance in spite of the use of 5-HT3 inhibitor for acute emesis. Further prevention of delayed nausea and vomiting is an important issue in supportive care of BEP. Stomatitis is unpleasant and can compromise quality of life and sometimes nutritional intake. Although many pharmacologic interventions have been tested, there is no standard therapy to prevent stomatitis (23).
Bleomycin is an essential component of induction chemotherapy for testicular cancer (24), but its application is characterized by the development of sometimes fatal complications. BIP is the leading cause of treatment-related death of BEP. The reported incidence of fatal BIP is 0.8–2.8% (2,20,25). In this retrospective review, five patients with clinically or radiologically evident BIP were identified, all of whom recovered. The median age of these patients was 43 years. The risk of BIP is known to be closely related to the cumulative bleomysin dose (26). In addition, recent investigations indicate that impaired renal function and relatively higher age are important risk factors for developing BIP during testicular cancer chemotherapy (25–27). Simpson et al. (25) reported a high incidence of fatal BIP, 10%, in testicular cancer patients over 40 years with a mean cumulative bleomycin dose of 180–210 mg.
A decrease in DLCO is not necessarily a specific indicator of BIP (28), but the DLCO assessment is easy and useful for screening subclinical lung toxicity. We identified a significant decrease in DLCO in 30% of post-chemotherapy patients. Based on the result above, we recommend pulmonary function assessment in high-risk patients, especially when post-chemotherapy surgery is planned. Alternatively, to avoid fatal bleomycin toxicity, BEP can be replaced by other suitable regimens (i.e. four courses of EP for good-risk patients or four courses of VIP for intermediate- or poor-risk patients) in patients with unacceptable risks.
Finally, the prognosis of our patients is somewhat better than the original IGCCCG data (11). This is partly due to the lack of poor-risk extragonadal cases in the present analysis. In addition, it is likely that the high completion rate of BEP along with the introduction of the modern second-line chemotherapy contributed to the improvement of treatment outcome. We believe that optimal assessment and management of toxicity based on cumulative treatment experience are essential for performing BEP with high RDI.
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References |
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