Bleomycin Combination Chemotherapy Research Articles

Bleomycin-induced Flagellate Dermatitis: a Case Report

Abstract Flagellate dermatitis represents a unique cutaneous eruption associated with several causes, including treatment with certain chemotherapeutic agents, ingestion of toxins and rheumatologic conditions like adult-onset Still’s disease and dermatomyositis. We present the case of a 35-year-old woman with stage IIA Hodgkin lymphoma who was treated with the ABVD chemotherapy regimen (doxorubicin, bleomycin, vinblastine and dacarbazine). During the third cycle of chemotherapy, she developed multiple linear erythematous macules and hyperpigmentation in a striking flagellate-like pattern localized on the upper chest, submammary folds, neck and upper part of the back. The lesions resolved completely within three months after the withdrawal of bleomycin. Clinicians should be aware of this distinctive cutaneous toxicity in patients receiving bleomycin combination chemotherapy.

Acute inferior st segment elevation myocardial infarction due to chemotherapy in a young man with testicular cancer

SUMMARY Testicular cancer is the most common malignancy in men between 15 and 29 years of age. cisplatin, etoposide and bleomycin combination chemotherapy remains the mainstay of testicular cancer treatment. Acute myocardial infarction is a rare complication of these chemotherapeutics. In this case report, we present a case of 36-year-old male with acute inferior ST-segment elevation myocardial infarction after bleomycin injection. Because the patient had no significant risk factors for coronary artery disease, the infarction was likely caused by the chemotherapy regimen. Keywords: Testicular Cancer, Acute Myocardial Infarction, Cisplatin, Bleomycin, Etoposide

Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients

BackgroundBleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. MethodsIn 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. ResultsBIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. ConclusionWe observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity.

Outcomes after bleomycin, etoposide and cisplatin combination chemotherapy in patients with ovarian yolk sac tumor

Objective: The aim of this study was to evaluate the oncologic and reproductive outcomes of patients with ovarian yolk sac tumor after bleomycin, etoposide, cisplatin (BEP) chemotherapy following surgery. Methods: Of 145 patients with histologically confirmed malignant ovarian germ cell tumor, 43 had yolk sac tumor and received BEP chemotherapy after surgery. A retrospective analysis of these patients was performed. Results: The mean age of 43 patients was 24.8 years (range, 7 to 59 years). Thirty eight patients were iparous. Of 179 BEP chemotherapy cycles, grade 1~2 hematologic and non-hematologic adverse events occurred in 46 cycles in 21 patients. Thirty nine patients showed complete remission, 1 patient showed partial remission, and 3 patient had progressive disease during BEP chemotherapy. After median follow-up time of 57 months (range, 3 to 153 months), 5 patients had recurrent disease and three of them died of disease. The 5-year recurrence free survival rate and overall survival rate were 86% and 94%, respectively. After chemotherapy, all but one premenarchal patients had normal menstruation. Of them 5 patients tried to conceive and 3 of them succeeded in pregnancy. Conclusion: BEP chemotherapy was very safe and effective in patients with ovarian yolk sac tumor. Survival outcomes are excellent and reproductive outcomes are promising after BEP chemotherapy.

Short- and Long-Term Outcomes After Large Pulmonary Resection for Germ Cell Tumors After Bleomycin-Combination Chemotherapy

Abstract Background Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy. Methods Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; right=9, left=10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy. Results There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n=2; bilobectomy, n=2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up. Conclusions Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.

Short- and Long-Term Outcomes after Large Pulmonary Resection for Germ Cell Tumors After Bleomycin-Combination Chemotherapy

Background Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy. Methods Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; right = 9, left = 10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy. Results There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n = 2; bilobectomy, n = 2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up. Conclusions Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. METHODS: For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. RESULTS: Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16-64; median cumulative bleomycin dose 270 mg, range 60-360; median pretreatment creatinine clearance 122 ml/min, range 64-202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11-2.51). Patients with BIP had a lower creatinine clearance. CONCLUSIONS: Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. Methods:For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. Results:Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16–64; median cumulative bleomycin dose 270 mg, range 60–360; median pretreatment creatinine clearance 122 ml/min, range 64–202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11–2.51). Patients with BIP had a lower creatinine clearance. Conclusions:Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.

Second-Line Chemotherapy with Bleomycin, Methotrexate, and Vinorelbine (BMV) for Patients with Squamous Cell Carcinoma of the Head, Neck and Esophagus (SCC-HN&E) Pretreated with a Cisplatin-Containing Regimen: A Phase II Study

We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m2, and vinorelbine 30 mg/m2) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) [27%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.

Long-term complications of chemotherapy for germ cell tumours.

Testicular cancer is the most common solid tumour among young males aged 15-35 years. Cisplatin-based combination chemotherapy has changed the outlook of this disease. Disseminated testicular cancer, once uniformly fatal, now has a cure rate of more than 80% with combination chemotherapy. Systematic randomised trials have shown that cisplatin, etoposide and bleomycin (PEB) combination chemotherapy remains the mainstay of treatment. While there is a high cure rate with chemotherapy in patients with this disease, some long-term complications from chemotherapy have now been recognised, including secondary leukaemia, therapy-related solid tumours, nephrotoxicity, neurotoxicity, pulmonary toxicity, vascular toxicity and infertility. Etoposide, a DNA topoisomerase II inhibitor, is a significant risk factor for developing leukaemia; the risk appears to be correlated with the total dose given. Patients receiving cisplatin-based combination chemotherapy for testicular cancer also appear to have a higher relative risk for developing second non-germ cell malignancies; the greatest risks for therapy-related solid tumours were seen with a combination of radiation therapy plus chemotherapy. Long-term vascular toxicities associated with chemotherapy include Raynaud's phenomenon, acute myocardial infarction and cerebrovascular events. Bleomycin is thought to be the most important drug in the pathogenesis of Raynaud's phenomenon, while cisplatin is the most likely agent involved in myocardial infarction. Peripheral neuropathy is the most common form of neurotoxicity observed with cisplatin-based chemotherapy. Risk factors for the development of neural damage include a high cumulative dose of cisplatin, the use of vinblastine and the concomitant development of Raynaud's phenomenon. Cisplatin is also well known to cause significant nephrotoxicity. Approximately 25% of patients present with azoospermia after undergoing combination chemotherapy with a follow up of 2-5 years. Physician awareness of complications associated with chemotherapy is vital to maximise efficacy, minimise toxicity, and preserve quality of life after treatment. Sperm cryopreservation should be considered for patients who desire children. Close monitoring during therapy allows for the early diagnosis of complications, and close follow up of patients after the completion of therapy is necessary to monitor for relapse and development of long-term complications such as myelodysplastic syndrome and leukaemia. Despite these complications, given the potential for cure rates in this young group of patients, the benefits far outweigh the risks.

Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer

Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer

COMBINATION CHEMOTHERAPY FOR METASTATIC OR LOCALLY ADVANCED GENITOURINARY SQUAMOUS CELL CARCINOMA: A PHASE II STUDY OF METHOTREXATE, CISPLATIN AND BLEOMYCIN

Purpose The prognosis of patients with advanced squamous cell carcinoma of genitourinary origin is poor. While single agent chemotherapy results mainly in partial responses of short duration, data on the efficacy of combination chemotherapy are extremely limited. We determined the response rate and toxicity of a combination of 3 of the most active agents, methotrexate, cisplatin and bleomycin, in patients with advanced genitourinary squamous cell carcinoma. Materials and Methods Patients with metastatic or locally advanced genitourinary squamous cell carcinoma were eligible for study. Treatment consisted of 200 mg./m. 2 methotrexate on days m, 15 and 22, and 20 mg./m. 2 cisplatin and 10 mg./m. 2 bleomycin on days 2 through 6 during a 28-day cycle. Results Of the 30 patients who enrolled in the trial 29 were evaluable for response. Objective response was achieved in 16 patients (55%, 95% confidence interval 36 to 72), 4 of whom achieved a complete response (14%). Median objective response duration was 4.7 months (range 1.9 to 39.5). Median survival of the entire group was 11.5 months (range 1.5 to 87.0). Of the patients 9 achieved disease-free status, including 6 following consolidation surgery or radiation therapy. Median survival of these 9 patients (34.4 months, range 9.6 to 87.0) was significantly greater (p = 0.0003) than that of patients who did not become disease-free (7.0 months, range 1.5 to 38.6). Grade III or IV hematological toxicity in 116 courses included neutropenia (13%) and thrombocytopenia (6%). Among 30 patients evaluable for toxicity serious nonhematological toxic effects included stomatitis (3%) and renal toxicity (7%). There was 1 death from neutropenic sepsis. Conclusions Methotrexate, cisplatin and bleomycin combination chemotherapy for genitourinary squamous cell carcinoma results in a high but short lived overall response rate, and a low complete response rate with manageable toxicity. A multidisciplinary approach to achieve disease-free status may provide the best opportunity to effect survival and should be the focus of future trials.

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An EORTC Gynecologic Cancer Coop. Group (GCCG) study

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An EORTC Gynecologic Cancer Coop. Group (GCCG) study

Combined approach (chemotherapy plus surgery) in advanced testis tumours

Eight consecutive patients with stage III or bulky stage II germ cell tumors were treated with 4 cycles of cisplatin, etoposide and bleomycin combination chemotherapy (PEB). 3 patients were in complete remission (CR) after surgery of residual masses. 5 patients received 2–4 additional courses of P.V.I. (cisplatin, vinblastine and iphosphamide) chemotherapy and had complete remission (3 cases after surgery of residual masses). No residual tumor was found in 2 cases at surgery (25%). In the present series 3 patients had extrapulmonary disease, 2 retroperitoneal lymphnodes larger than 10 cm. and pulmonary disease. 1 patient had previous incomplete RPND. After a median follow-up period of 30 months (15–37) all the patients are disease-free with normal levels of AFP and beta HCG. In conclusion we repeat that intensive combination chemotherapy is the key for successful surgery of residual malignancy in patients with disseminated testicular cancer. Second-line of chemotherapy is more favourable than early surgery, in our opinion, for treatment of far-advanced disease.

Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in good-prognosis metastatic testicular nonseminomatous germ cell tumors.

The combination of carboplatin, etoposide, and bleomycin (CEB) was evaluated as initial chemotherapy in 76 patients with good-prognosis metastatic nonseminomatous germ cell tumors (NSGCT) between 1984 and 1988. The classification of eligible patients included Royal Marsden Hospital (RMH) stages IM, IIA, IIB, IIC, IIIA, IIIB, IV0ABCL1, and IV0ABL2. Four courses of combination chemotherapy were administered in a 21-day cycle, and surgical excision of residual mass was performed in 27 cases (23 laparotomies and four thoracotomies). At the time of analysis, median follow-up was 24 months from start of chemotherapy (range, 6 to 54 months). The 2-year cause-specific survival probability was 98.5%, the single cause-related mortality being caused by bleomycin pneumonitis. Five patients failed CEB chemotherapy, but all have been successfully salvaged with a combination of surgery and intensive chemotherapy, follow-up from completion of all treatment being 35 to 44 months. The toxicity of CEB included bone marrow suppression and alopecia in all patients but no significant neurotoxicity or ototoxicity, and minimal renal toxicity. Only four (5%) patients had a decrease in the glomerular filtration rate greater than 15%. In 51% of patients, the hemoglobin fell below 10 g/dL. The WBC count nadir was less than 1,500/microL in 11% of treatment cycles and in 16% the platelet nadir fell below 50,000/microL. Decreases in the WBC and platelet counts were of very brief duration. Only one of 310 CEB cycles was complicated by neutropenic sepsis, and there were no episodes of thrombocytopenic purpura or bleeding. We conclude that the CEB combination represents an effective alternative to cisplatin-based chemotherapy in good-prognosis NSGCT and that the replacement of cisplatin by carboplatin leads to reduced toxicity.

The prognostic value of a response to chemotherapy given before radiotherapy in advanced cancer of cervix

Forty patients with stage III and 15 patients with stage IVa carcinoma of cervix have been treated with two pulses of cisplatin, vincristine and bleomycin combination chemotherapy before full dose radical radiotherapy. Twenty-seven of 51 (53%, 95% confidence interval 40-67%) had an objective response to chemotherapy and all chemotherapy responders had a complete response to radiotherapy. The actuarial survival at 24 months of responders to chemotherapy is 71% against 37% for non-responders. The responding patients had an estimated reduction in mortality to 36% (P = 0.014, 95% CI 15-81%) of that of the non-responders to chemotherapy. The incidence of tumour recurrence or distant metastases showed a similar reduction to 34% (P = 0.006, 95% CI 14-73%) of that of the non-responders. The data strongly suggest that response to chemotherapy in the initial treatment of advanced cervical cancer is associated with an improvement in survival following subsequent radical radiotherapy.

Hemolytic Uremic Syndrome Following Cisplatin, Bleomycin, and Vincristine Chemotherapy

This report describes a patient who developed the hemolytic uremic syndrome while undergoing chemotherapy with cisplatin, bleomycin, and vincristine, for metastatic squamous cell cancer of the floor of the mouth. In spite of dialysis and plasmapheresis, the patient died. This complication has rarely been reported in association with cisplatin, bleomycin, or vincristine therapy. The etiology of this syndrome is uncertain but may be related to scleroderma-like endothelial injury and vasospasm caused by bleomycin combination chemotherapy. It is notable that the development of the hemolytic uremic syndrome in conjunction with this combination of agents has been fatal in all patients over the age of 50 with squamous cell cancers.

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An eortc gynecology cancer cooperative group study

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An eortc gynecology cancer cooperative group study

Pulmonary Nodules Simulating Metastasis of Germ Cell Tumor after Aggressive Chemotherapy

We describe a patient in whom pulmonary nodules developed without infectious symptoms during treatment with bleomycin, cis-platinum, vinblastine and etoposide combination chemotherapy for metastatic extra-gonadal germ cell tumor. At thoracotomy only fibrosis was found. In this case, false-positive elevation of alpha-fetoprotein and the CT scan appearance made us interpret the pulmonary nodules as new metastatic lesions.

Vindesine, cisplatin, and bleomycin combination chemotherapy in non-small cell lung cancer: Survival and quality of life

Vindesine, cisplatin, and bleomycin combination chemotherapy in non-small cell lung cancer: Survival and quality of life