Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin

This 10-year follow-up study of 91 patients with disseminated testicular nonseminomatous cancer, treated with cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy and vinblastine plus bleomycin maintenance chemotherapy for a planned period of 2 years, shows a 63% cure rate. The predominant long-term sequelae are neurological and sexual dysfunction in 68% and 40% of patients, respectively. Two patients died of myocardial infarction. Sixteen percent of patients developed hypertension, 23% Raynaud's phenomenon, and 25% ototoxicity. Despite the long-term side effects, 90% of the patients who responded to a questionnaire are fully employed. This study shows that the maintenance chemotherapy has contributed to the incidence and/or degree of neurotoxicity, hypertension, and renal function disturbance.     

Five-year survival of patients with disseminated nonseminomatous testicular cancer treated with cisplatin, vinblastine, and bleomycin

Ninety-one patients with disseminated testicular non-seminomas were treated with 3 to 4 cycles of cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy followed by cisplatin and vinblastine maintenance therapy for 1 year. The follow-up of these patients ranges from 24 to 66 months. Forty-nine (54%) patients achieved complete remission by chemotherapy alone and 14 (15%) were rendered free of tumor by surgery after chemotherapy, for a total complete remission rate of 69%. Three complete responders relapsed within 13 months, and two died. One additional complete responder died of a noncancer-related cause. One of the surgical complete responders relapsed and died. Overall, 58 (64%) patients remain free of disease. The 5-year survival is 95% for complete responders, 32% for partial responders, and 72% overall. This combination regimen has significantly improved the survival of disseminated testicular cancer patients, equaling that of Stage II patients in older literature.     

Second cancer in patients treated for testicular seminoma.

The exact risk of developing a second primary cancer following radiotherapy for testicular seminoma is not known. At the Northern Israel Oncology Center, between the years 1968-1988, 75 patients with early stage (I,IIA) testicular seminoma were treated by orchiectomy followed by radiation therapy. The overall 10- and 20-year survival probability was 95% and 90%, respectively. Eight patients (11%) developed nine second cancers, with a cumulative rate of one case per 1,000 years of follow-up. The second primary cancers were: two bronchogenic carcinomas, one contralateral seminoma, one thymoma, one papillary carcinoma of the thyroid, one carcinoma of the stomach, one transitional cell carcinoma of the urinary bladder, one carcinoma of the colon, and one malignant melanoma. Three of these tumors developed within the irradiated field. Five of these eight patients are alive with no evidence of recurrent cancer. We conclude that patients treated for seminoma have an increased risk of developing a second cancer. There is a need for greater awareness of this possibility. The overall prognosis remains favorable.     

Fertility in patients treated for testicular cancer

Introduction  

Testicular cancer affects men mostly in their reproductive age with a cure rate over 90% and fertility is one of the main concerns of survivors. To further elucidate the question of fertility after treatment for testicular cancer, we performed a survey in patients treated in our institution.     

Peri-operative care in patients treated for testicular cancer

The success of combination chemotherapy in treating advanced metastatic germ cell tumors has led to new challenges for the genitourinary oncologic surgeon in the peri-operative care of patients. Surgery remains an integral part of the management of patients with advanced germ cell tumors. Retroperitoneal node dissections following chemotherapy or radiation, or both, are technically more demanding and subject to higher rates of peri-operative complications. Overall post-therapy surgical complication rates range from 33% to 75%, with the highest rates among patients who receive both radiation and chemotherapy. Although most patients with testicular cancer are young and healthy, residual pulmonary, renal, vascular, and neurologic toxicities from chemotherapy can increase the risk of peri-operative complications. In addition, the volume and location of tumor can increase the technical demands, especially when there is a tremendous soft tissue reaction to the chemotherapy. Identification of pre-operative risk factors for peri-operative complications is imperative and the first step in pre-operative planning. Pulmonary toxicity and vascular (cardiac or peripheral) events are the two most immediately life-threatening complications that can occur in the peri-operative period. Due to the high incidence of subclinical pulmonary toxicity, one must consider all patients who have received bleomycin pre-operatively at risk to develop postoperative pulmonary problems. Pre-operative evaluation and judicious fluid management have been shown to reduce the risk of life-threatening respiratory complications in the postoperative period.     

Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin

In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program, a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease, and a laparotomy was not performed to assess response), 31 (43%) responded, including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate), based on duration of CFI, were 5 to 12 months, 27% (5%); 13 to 24 months, 33% (11%); and more than 24 months, 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion, secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.     

Compliance with follow-up of patients treated for non-seminomatous testicular cancer

Many patients with Stage 1 non-seminomas are now treated by orchidectomy and close follow-up along. Chart review indicated that a group of such patients, compared with patients treated with chemotherapy, tended to be less compliant with follow-up. A questionnaire given to a second sample of patients confirmed that surgical patients underestimated the dangers of the disease and chances of relapse, and doubted the value of follow-up.     

Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines

Purpose:To assess the antitumor efficacy and safety of avinorelbine and cisplatin combination in patients with metastatic breastcancer previously treated with anthracyclines. Patients and methods:Fifty-three patients with assessablemetastatic breast cancer with previous exposure to anthracyclines (adjuvantn= 6, palliative n= 47) were studied. Cisplatin 75mg/m² on day 1 was given followed by 25 mg/m²vinorelbine (VNR) on days 1 + 8, in a five-min i.v. infusion. Courses wererepeated every three weeks on an outpatient basis. Treatment continued untildisease progression, excess toxicity or patient refusal. Patients wereclassified according to their response to anthracyclines: anthracyclinerefractory patients were patients who had never responded under ananthracycline regimen. Anthracycline resistant patients were either metastaticpatients who progressed within four months of completing anthracycline-basedchemotherapy or patients who progressed within six months of completion of ananthracycline adjuvant treatment. Patients who progressed four months afterthe end of an anthracycline regimen in metastatic setting or six months afterthe end of an anthracycline regimen in adjuvant setting were considered aspatients previously treated with anthracyclines and were called `relapsed'. Results:Four patients (8%) achieved a complete response(CR) and twenty-two patients (41%) achieved a partial response (PR)with an overall response rate (OR) of 49% (95% confidenceinterval (CI): 35–63). Stable disease (SD) was observed infive patients (9%), twenty-two patients had progressive disease (PD).Responses according to previous sensitivity to anthracycline were as follow:5 refractory patients achieved a PR from 14 patients (36%). Seven ofsixteen resistant patients responded (44%), six with PR and one withCR. Among 23 `relapsed' patients, 14 responses were observed (61%),with 3 CR and 11 PR. There was no statistical difference in RR among the threegroups. The median duration of response for all patients was 7 months, themedian time to progression (TTP) 5 months and median overall survival 12months.All patients were assessed for toxicity. The main toxicity was neutropeniagrade 3 and 4 in 49% of patients. Febrile neutropenia requiringhospitalization was uncommon (2 patients). There were no treatment relateddeaths. Despite potential overlapping neurologic toxicities of the two drugs,only eight patients (15%) developed neuropathy, which was, however,mild (grades 1 and 2). Conclusions:This cisplatin–VNR regimen is well toleratedand active in patients who failed anthracyclines. The response rate, TTP andsurvival data are engouranging and indicate that cisplatin–VNR may havea place as second-line treatment alternative to taxanes or other less activeregimens. If these results can be verified in multi-institution trials, thiscombination of drugs would merit investigation as first-line therapy in thispatient population.     

Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer.

PURPOSE: To evaluate the dose, toxicity, and efficacy of paclitaxel in combination with ifosfamide and cisplatin as salvage therapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS: Thirty patients with previously treated GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. All had favorable prognostic features for response (testis primary tumor site and prior complete response to first-line chemotherapy program). Four cycles of paclitaxel, ifosfamide 5 g/m(2), and cisplatin 100 mg/m(2) were given 21 days apart with granulocyte colony-stimulating factor support, followed by resection of radiographic residua. The dose of paclitaxel was increased among cohorts with dose levels of 175, 215, and 250 mg/m(2); the largest dose was selected for the phase II part of the trial. RESULTS: Twenty-three (77%) of 30 patients achieved a complete response to chemotherapy alone, and one patient achieved a durable partial response with normal tumor markers. Therefore, 24 (80%) achieved a favorable response. Eleven patients with normalized markers after chemotherapy underwent resection of residual tissue, with only necrosis found in 10 and mature teratoma in one. Two patients relapsed, and 22 (73%) of the favorable responses remain durable at a median follow-up duration of 33 months. Myelosuppression was the major toxicity, and two patients had grade 3 neurotoxicity. CONCLUSION: Four cycles of TIP was associated with a high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing salvage regimen for testicular GCTs. The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors for a favorable outcome to conventional-dose salvage therapy.     

Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer.

To date, the prevalence and nature of the late toxicity of cisplatin-based combination chemotherapy for advanced testicular cancer has been poorly documented. Thirty men with a median age of 35 years (range, 23 to 63), who had undergone such treatment were assessed with detailed investigation to determine the type and frequency of chronic toxicity. The median follow-up from the time of commencement of chemotherapy was 75 months (range, 48 to 126). The most common late toxic effects were high tone hearing loss in 23 men (77%) and electrophysiological evidence of peripheral nerve damage in 15 (50%). Both the hearing and nerve abnormalities were predominantly asymptomatic. In addition, elevation of serum cholesterol, noted in 20 patients (67%), was significant (P = .014) when compared with a control population. Hyperuricemia was present in nine patients (30%). Only one patient, with other risk factors (smoking, family history), had evidence of ischaemic heart disease while 20% (all with a smoking history) had a diminished single breath diffusing capacity for carbon monoxide (DLCO). Cisplatin-based chemotherapy is relatively free of major long-term side effects and should not be withheld for fear of late toxicity.     

Incidence of neuropathy in 395 patients with ovarian cancer treated with or without cisplatin

In two consecutive trials, a total of 395 patients with ovarian cancer were treated with a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapeutic regimens including cisplatin or without this drug. With respect to neurotoxicity, 387 patients were fully eligible. The median follow-up for survival was 45 months. Neurotoxicity in any grade of severity developed in 47% of the patients treated with a cisplatin-containing regimen and in 25% of those treated with the non-cisplatin-containing regimen. The severity of neurotoxicity was much higher, however, in the cisplatin-treated patients. Neurotoxicity-free survival decreased below 50% at cumulative doses of cisplatin between 500 and 600 mg/m2. No additional effect of hexamethylmelamine on the incidence or severity of neurotoxicity could be demonstrated. In patients who survived for more than 5 years, the incidence of cisplatin neuropathy was 61%. Prognostic variables (age, International Federation of Gynecology and Obstetrics [FIGO] stage, performance status, and others) possibly associated with high-risk subgroups could not be identified. The only consistent factor correlated with neurotoxicity was the total dose of cisplatin received.     

Long-term platinum excretion in patients treated with cisplatin

The purpose of this study was to determine long-term renal platinum excretion after chemotherapy with cisplatin. We examined urinary platinum concentrations in 23 men at 150–3022 days after anticancer treatment for testicular neoplasm. Spot urine samples were analyzed by voltammetry. This new, subtle method with a detection limit of 2 pg platinum allows determination of even the natural background level. Urinary platinum concentrations in our patients ranged between 0.74 and 77.24 g/g creatinine, depending on the total delivered dose and follow-up period. Regression analysis of the data showed two phases of long-term renal platinum excretion, one occurring at between 150 and 900 days of follow-up and the other with an onset at 900 days after cisplatin administration (r ₁ ²=0.82,r ₂ ²=0.88). Two biological half-lives of 160 and 720 days were calculated. Our results show that urinary platinum concentrations determined at 8 years after cisplatin therapy are 40 times higher than the background level (up to 0.02 g/g creatinine). Our findings on the long-term pharmacolinetics of this anticancer agent may facilitate further studies on sites of platinum storage in the human body as well as clinical studies on the late adverse effects of cisplatin.     

Hyperzincuria and hypozincemia in patients treated with cisplatin

The effect of cis-diamminedichloroplatinum (DDP) on plasma and urinary zinc was studied in fifteen patients with squamous cell carcinoma. A decrease in plasma zinc accompanied by an increase in urinary zinc excretion was observed. Pretreatment plasma or urinary zinc did not correlate with tumor size or site, nor was there a correlation between changes in these measurements and a response to therapy. The enhanced excretion of urinary zinc may be related to a decrease in amino acid resorption in the proximal tubule. It is concluded that DDP administration may result in hyperzincuria and could potentially precipitate a symptomatic zinc deficiency state.     

吉西他滨联合顺铂治疗晚期乳腺癌的临床观察

目的观察吉西他滨联合顺铂治疗晚期乳腺癌的疗效及不良反应。方法47例晚期乳腺癌患者采用吉西他滨1000mg/m^2,静脉滴注30min,d1,d8;顺铂25～40mg/m^2,d2～4。21d一周期,治疗2周期后评价疗效及不良反应。结果47例均可评价疗效,共完成周期数为206个。完全缓解（CR）4例,部分缓解（PR）17例,稳定（SD）15例,进展（PD）11例,总有效率（CR＋PR）44.7%,疾病控制率（CR＋PR＋SD）76.6%,中位疾病进展时间8.7个月,中位生存期为12.3个月（2.0～52.5个月）。主要不良反应为骨髓抑制、胃肠道反应。结论吉西他滨联合顺铂治疗晚期乳腺癌疗效较好,毒副反应轻,耐受性好,是晚期乳腺癌的有效治疗方案。     

Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer.

PURPOSE: After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS: In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS: Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION: In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.     

Gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients.

PURPOSE: To determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed adenocarcinoma of the breast. PATIENTS AND METHODS: Previously treated patients with adenocarcinoma of the breast received cisplatin (30 mg/m(2)) plus gemcitabine (1,000 mg/m(2)) on days 1, 8, and 15 of each 28-day cycle, which was changed after patient no. 12 to cisplatin (30 mg/m(2)) plus gemcitabine (750 mg/m(2)) days 1 and 8 of each 21-day cycle. RESULTS: Of 30 patients, three (10%) had complete and 12 (40%) had partial responses, for an overall response rate of 50%. Two objective responses were observed among the four patients accrued after relapse that followed high-dose/stem-cell therapies. The median time to progression was 14 weeks. The median time to progression for objective responders was 23.5 weeks, with a range of 8 to 68 weeks. Toxicities included grades III and IV neutropenia in 13%, anemia in 6%, thrombocytopenia in 31%, grade III nausea in 4%, and grade II peripheral neuropathy in 2% of 151 treatment cycles. Moderate alopecia occurred in four patients. There were no treatment-related deaths. CONCLUSION: Cisplatin plus gemcitabine is active and tolerable for patients with relapsed breast cancer. Responses observed in previously treated patients, including high-dose/stem-cell failures, indicate activity in otherwise drug-refractory patients.     

Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer.

PURPOSE: Despite generally high cure rates in patients with metastatic testicular germ cell tumors, patients with incomplete response to cisplatin-based first-line therapy or with relapsed disease after high-dose salvage chemotherapy have a very poor prognosis. This phase II study evaluates the use of gemcitabine in patients with intensively pretreated or cisplatin-refractory testicular germ cell cancers. PATIENTS AND METHODS: Thirty-five patients (median age, 33 years) were enrolled; 31 patients were fully assessable. All patients had metastatic nonseminomatous germ cell tumors; eight patients had extragonadal primary tumors. Twenty patients (63%) had lung metastases, and 12 patients (39%) had liver metastases. The median number of prior cisplatin-based chemotherapy cycles was seven; 22 patients (71%) had received high-dose chemotherapy with autologous stem-cell transplantation, and 19 patients (61%) had received treatment with paclitaxel. Seventeen patients (54%) were considered refractory or absolutely refractory to chemotherapy. RESULTS: Six of 31 assessable patients (19%) responded favorably to gemcitabine, 11 patients (35%) displayed no change, and 14 patients (45%) had disease progression. The median time to treatment failure was 4 months (range, 2 to 9+ months), and the median survival was 6 months (range, 2 to 23 months). Patients received a median of six gemcitabine applications. Ten patients (32%) required dose reductions, mainly owing to hematologic toxicity. Grade 3/4 granulocytopenia occurred in four patients (13%) and grade 3/4 thrombocytopenia in seven patients (22%). One case of severe sepsis was observed. CONCLUSION: Gemcitabine displays antitumor activity in intensively pretreated and refractory germ cell tumors. Responses were observed in approximately 20% of patients, including three of 22 patients after previous high-dose chemotherapy and one of four patients with mediastinal tumors. Gemcitabine may be a reasonable palliative option for intensively pretreated patients and should be further investigated to define its role in the risk-adapted treatment strategies for germ cell tumors.     

Long-term effects of chemotherapy in patients with testicular cancer.

PURPOSE: Combination chemotherapy regimens that include cisplatin (CDDP) and bleomycin (BLE) result in the cure of the majority of patients with malignant germ cell tumors of the testis. We investigated the long-term damage of such chemotherapy to renal, pulmonary, and hearing function. PATIENTS AND METHODS: Forty-three patients with disseminated testicular carcinoma were studied 1.5 to 9.3 years (median, 4.1 years) after completion of chemotherapy. All 43 patients received CDDP; of these, 39 also received BLE, 27 vinblastine (VLB), and 27 etoposide (VP-16). Mean cumulative doses of individual cytotoxic drugs administered were CDDP 483 mg/m2 (range, 189 to 1,173 mg/m2), BLE 160 mg/m2 (range, 81 to 311 mg/m2), VLB 31 mg/m2 (range, 19 to 158 mg/m2), and VP-16 667 mg/m2 (range, 242 to 1,455 mg/m2). RESULTS: In the majority of cases, values of renal, pulmonary, and hearing function were within the normal range before treatment. An initial decrease in renal, pulmonary, and hearing function was observed, with recovery of pulmonary function at late follow-up. On average, a decrease of 15% in creatinine clearance rates was observed at late follow-up. Long-term effect on audiometric function was considerable, but frequencies affected were outside the range of conversational speech. With multivariate analysis, no overall relation between the cumulative doses of the individual drugs and the loss in organ function was found; the cumulative doses of CDDP and BLE only contributed approximately 30% to the loss in renal function and vital capacity, respectively. CONCLUSION: Chemotherapy-induced pulmonary toxicity is reversible, whereas nephrotoxicity and ototoxicity are not. However, the long-term effects of chemotherapy in testicular cancer patients were minor and not invalidating.     

Chemotherapy of testicular cancer, with special reference to cisplatin therapy

Our statistical study revealed that testicular neoplasms seemed to increase in incidence during a 28-year-period from 1950 to 1977 in Japan. Annual deaths from testicular neoplasm were approximately 50 in the first 4 years of the period and increased to approximately 200 in the last 3 years. Age-adjusted mortality rate increased from 1.2 per million to 3.3 per million during the period. Untoward effects of CDDP were surveyed among 47 patients with urogenital malignancy who received anticancerous chemotherapies of CDDP alone or in combination with other drugs at the Kyoto University Hospital or its affiliates in the recent 3 years. About 95% of the patients suffered from such gastro-intestinal ailments as loss of appetite and vomiting. Bone marrow suppression was confirmed by laboratory studies among a third of the patients. Nephrotoxicity indicated by 25 to 50% reduction in creatinine clearance was induced in 6 patients-transitory in 4 and permanent in the remaining. Fifty percent survival rate was 18 months and 5 survived more than 2 years with NED among 21 patients with stage II or stage III testicular cancer treated at the Hospital or its affiliates since 1975, while the rate was 6 months among 10 patients during the period from 1965 to 1974. These improvements was thought to be brought in by adopation of VAB or PVB chemotherapy.