Bleomycin, Etoposide And Cisplatin Regimen Research Articles

P-088 Bleomycin, etoposide and cisplatin (BEP) chemotherapy-induced testicular toxicity: ameliorative effect of sodium alginate by inhibiting oxidative stress, apoptosis and inflammation

Abstract Study question Is there a potential for sodium alginate (NaAL) to alleviate the damage induced by BEP chemotherapy in testicular cells and the spermatogenesis process? Summary answer Administering NaAL at doses of 25 and 50 mg/kg demonstrates protective effects against BEP-evoked toxicity damage through the modulation of nitro-oxidative stress, inflammation, and apoptosis. What is known already Testicular tumours are a prevalent malignancy affecting young males aged 20 to 35 years. The globally accepted chemotherapy for testicular cancer involves administering the bleomycin, etoposide, and cisplatin (BEP) regimen in three to four cycles. Unfortunately, the BEP regimen poses a substantial risk of reproductive system toxicity, presenting a significant concern and one of the most challenging long-term complications for young cancer survivors. Sodium alginate (NaAL), an anionic polysaccharide abundant in nature, offers potential solutions with its inherent antioxidant, anti-inflammatory, anti-apoptotic, and anti-proliferative properties. Study design, size, duration Sixty adult male Wistar rats were randomly assigned to six groups (n = 10/group). Groups 1, 3, and 4 received a vehicle, 25 mg/kg, and 50 mg/kg of NaAL, respectively. The remaining groups underwent a three-week cycle of bleomycin, etoposide, and cisplatin (BEP) with or without NaAL. NaAL administration began one week before BEP initiation, continued on days 2, 9, and 16, and extended for one week post the BEP cycle. Participants/materials, setting, methods At the end of the study (day 42), various parameters, including body and testes weight, sperm parameters (count, motility, viability, and morphology), testosterone hormone levels, testicular histopathology, stereological parameters of the testes, and levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), were assessed. Additionally, the expression of Bcl-2, Bax, caspase-3, p53, and TNF-α was evaluated using real-time PCR and immunohistochemistry. Main results and the role of chance NaAL treatment resulted in a significant improvement in both body weight and testis weight in animals injected with BEP compared to the BEP group (P < 0.05). Stereological procedures, QRT-PCR examination, and immunohistochemical (IHC) staining for quantitative testis analysis indicated that NaAL reversed the impaired spermatogenesis induced by BEP (P < 0.05). Additionally, NaAL restored the disturbance caused by BEP in sperm count, motility, viability, and morphology. The testosterone level significantly decreased in the BEP-treated group compared to the control group (P < 0.05). However, co-administration of 50 mg/kg of NaAL significantly increased the serum testosterone level (P < 0.05). Furthermore, NaAL improved the antioxidant status of the testis by increasing TAC and ameliorating MDA and NO levels. Notably, QRT-PCR examination revealed that NaAL treatment suppressed BEP-induced apoptosis and inflammation by modulating genes such as Bcl-2, Bax, Caspase-3, and p53 in the testis (P < 0.05). Co-administration of 25 and 50 mg/kg of NaAL with the BEP regimen significantly reduced the number of p53 and TNF-α-positive cells compared to the BEP group. Further, NaAL at low and high doses increased the expression of Bcl-2 protein in spermatogenic cells compared to the BEP-treated group. Limitations, reasons for caution Due to limitations in our laboratory resources, we were unable to pursue further studies to validate the mechanism of sodium alginate on specific targets using more advanced techniques such as transfection and transgenic methodologies. Wider implications of the findings These findings illuminate the potential clinical applications of sodium alginate, suggesting its promising role as a beneficial supplement in medical contexts, particularly in addressing fertility issues. Additionally, this antioxidant could accelerate the fertility recovery period in young patients undergoing the BEP chemotherapy regimen, ultimately enhancing their overall quality of life. Trial registration number N/A

Therapeutic effect of sodium alginate on bleomycin, etoposide and cisplatin (BEP)-induced reproductive toxicity by inhibiting nitro-oxidative stress, inflammation and apoptosis

Impaired spermatogenesis and male infertility are common consequences of chemotherapy drugs used in patients with testicular cancer. The present study investigated the effects of sodium alginate (NaAL) on testicular toxicity caused by bleomycin, etoposide, and cisplatin (BEP). Rats in group 1 received normal saline, while groups 2 and 3 were treated with 25 and 50 mg/kg of NaAL, respectively. Group 4 was treated with a 21-day cycle of BEP (0.5 mg/kg bleomycin, 5 mg/kg etoposide, and 1 mg/kg cisplatin), and groups 5 and 6 received BEP regimen plus 25 and 50 mg/kg of NaAL, respectively. Then, sperm parameters, testosterone levels, testicular histopathology and stereological parameters, testicular levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), and the expression of apoptosis-associated genes including Bcl2, Bax, Caspase3, p53, and TNF-α were evaluated. Our findings revealed that NaAL improved sperm parameters, testosterone levels, histopathology, and stereology parameters in BEP-administrated rats. NaAL also improved testis antioxidant status by enhancing TAC and ameliorating MDA and NO. Further, modifications to the expression of Bcl2, Bax, Caspase3, p53, and TNF-α suggested that NaAL alleviated BEP-induced apoptosis and inflammation. Collectively, NaAL protects rats’ testes against BEP-evoked toxicity damage through the modulation of nitro-oxidative stress, apoptosis, and inflammation.

Antiemetic Efficacy and Safety of Palonosetron on Days 1 and 5 with Aprepitant and Dexamethasone during Bleomycin, Etoposide, and Cisplatin Chemotherapy in Patients with Germ Cell Tumor: A Prospective Study

Objective. BEP (bleomycin, etoposide, and cisplatin) chemotherapy is a standard regimen for germ cell tumors (GCTs); however, their high emetogenicity is problematic. The control of chemotherapy‐induced nausea and vomiting (CINV) is crucial to complete the treatment. We conducted this study to explore the efficacy and safety of antiemetic therapy with dexamethasone and aprepitant for 5 days in combination with palonosetron 0.75 mg on days 1 and 5 in BEP. Methods. This open‐label single‐arm study was prospectively conducted in 4 hospitals. Chemotherapy‐naïve men with GCT who were scheduled to receive the BEP regimen were eligible. The primary endpoint was the complete response (CR) rate of CINV. Results. A total of 19 patients were enrolled. Overall, 16 (84.2%) patients experienced some nausea, whereas only 4 (21.1%) patients had grade 1 emetic events. Overall CR of CINV was achieved in 9 (47.4%) patients. Although 14 (73.7%) patients experienced 22 adverse events after palonosetron administration, severe adverse events (grade 3 or more) attributable to it did not occur. Conclusion. The results suggest that aprepitant, palonosetron, and dexamethasone antiemetic therapy for patients with GCT receiving BEP is safe, whereas the efficacy of additional palonosetron administration on day 5 for prevention of delayed CINV remains unclear. This trial is registered with UMIN000008110.

Administration of standard-dose BEP regimen (bleomycin + etoposide + cisplatin) is essential for treatment of ovarian yolk sac tumour

AimThe aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome. MethodsA multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated. ResultsThere were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age⩾22, alpha-fetoprotein⩾33,000ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P=0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and<50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P=0.02 and 62.5% versus 96.9%, P=0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively. ConclusionsThe results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function.

Outcome of 3-day bleomycin, etoposide and cisplatin chemotherapeutic regimen for patients with malignant ovarian germ cell tumours: A Taiwanese Gynecologic Oncology Group study

BackgroundThe combination of bleomycin, etoposide and cisplatin (BEP) is currently the most widely used treatment for malignant ovarian germ cell tumours (MOGCTs). The aim of this study was to evaluate the efficacy and adverse effects of the 3-day BEP regimen in Taiwan. The prognostic factors of the MOGCT patients were also analysed. Patients and methodsTwo hundred and thirty-nine cases of MOGCTs were identified from the Taiwanese Gynecologic Oncology Group database, and 204 of those who received postoperative BEP chemotherapy were then analysed. ResultsThe estimated rate of no evidence of disease was 94.0% for 204 patients with adjuvant BEP regimen. Seven grade 3/4 haematological adverse effects including four subjects with neutropenia, one with pancytopenia and two with neutropenic fever were recorded in the 853 total courses of chemotherapeutic cycles. The rates of haematological and non-haematological adverse effects were 0.82% and 2.3%, respectively. No treatment-related mortality was noted. In the analysis of prognostic factors, only tumour stage had a significant impact on disease recurrence (95% confidence interval (CI), 4.2–94.4, p<0.001) and disease-related mortality (95% CI, 2.2–163.9, p=0.007). ConclusionsThe current 3-day adjuvant BEP regimen was effective and safe for patients with MOGCTs.

900P - Prognostic Significance of Serum Alphafoetoprotein Early Decline in Ovarian Yolk Sac Tumor

ABSTRACT Aim: Ovarian yolk sac tumor (OYST) is a very rare malignancy arising in young women. Due to the rarity of this tumor, only few retrospective series have been published. We recently reported one of the largest series on outcome in OYSTs pts. Here, we aimed to evaluate the serum alphafoetoprotein (AFP) early decline which might help to make appropriate risk-based decision about therapy. Methods: This retrospective study is based on prospectively recorded OYST cases at the Institut Gustave-Roussy (IGR). Pediatric cases were excluded. Survival curves were estimated by the Kaplan-Meier method. Serum AFP decline was calculated with the formula applied at IGR in poor prognosis germ cell tumor. Pts were classified in either favorable or unfavorable decline. Univariate analysis using the log-rank test tested possible associations between survival and patient or disease covariates. Multivariate analysis was performed using a model of logistic regression. Results: Between 1976 and 2006, 84 pts were registered. Data on AFP were available to calculate AFP early decline for 57 pts. Median post-operative AFP was 1040 (2 - 116 539) ng/mL. Most of the pts (48/57) have undergone fertility-sparing surgery. Cisplatin-based chemotherapy was given 56/57 pts and 42/57 pts received bleomycin, etoposide and cisplatin (BEP) regimen. Overall 5-year and event-free survival rates were 82% and 81%, respectively. The disease stage, presence of ascites at presentation, BEP regimen, serum AFP half-life and early AFP decline were significantly predictive factors. Overall survival in pts with favorable AFP decline was 96% whereas it was 49% in pts with unfavorable decline (p Conclusions: Serum AFP early decline help to identify poor prognosis ovarian YSTs pts. This may be relevant for the management of OYSTs since it has been shown in a phase III study (GETUG 13) in testicular poor prognosis germ cell tumor that early switch to a dose dense chemotherapy regimen for pts with slow tumor marker decline reduces the risk of progression or death. Disclosure: All authors have declared no conflicts of interest.

Sertoli‐Leydig cell tumor of the ovary: Analysis of a single institution database

To evaluate the clinicopathological features, management, survival and prognostic factors of patients with Sertoli-Leydig cell tumors of the ovary (SLCT) managed at a single institution. The clinical records of patients with Sertoli-Leydig cell tumors of the ovary managed at the KK Women's and Children's Hospital, Singapore, between October 1998 and December 2008 were reviewed. Data of pathological features, treatment given and progress on follow-up was studied. Sertoli-Leydig cell tumor of the ovary accounted for 1.3% of malignant ovarian neoplasms. The median age of the patient was 30 years. The most common mode of presentation was with hormonal-related symptoms (80%) in the form of secondary amenorrhea, irregular menses and features of virilization. Thirteen of the 15 patients underwent surgical staging and all were found to have stage-I disease at the time of diagnosis. Ten patients with intermediate and poorly differentiated tumors received adjuvant bleomycin, etoposide and cisplatin (BEP) chemotherapy. Recurrent disease was detected in two patients (13.3%) during a median follow-up of 63 months, both of whom had poorly differentiated type of tumor. Both these patients underwent optimal debulking surgery followed by postoperative chemotherapy (BEP regimen). There were no disease -elated deaths and all patients were under complete remission at the last follow-up. As most Sertoli-Leydig cell tumors of the ovary are seen in young women and detected while still in the early stages, a favorable outcome can be achieved by conservative surgery. Patients with moderate and poorly differentiated types of tumors benefit from adjuvant chemotherapy. Recurrences tend to occur early and are commonly seen in patients with poorly differentiated tumors.

Management of good risk germ‐cell tumours

Following the implementation of cisplatin-containing combined chemotherapy, patients with good-risk metastatic germ-cell cancer have an excellent prognosis. Since the 1980s, bleomycin, etoposide and cisplatin (BEP) have become the standard chemotherapy regimen for these patients. In view of both the high curative potential of BEP chemotherapy and the treatment-related side-effects, trials were carried out in patients with the greatest chance of cure to develop regimens with an improved toxicity profile while maintaining efficacy. Following the results of these trials, the standard chemotherapy in good-risk disease has been reduced from four cycles of BEP (4BEP) to three cycles of BEP (3BEP). Four cycles of etoposide and cisplatin (4EP) is an alternative treatment regimen, with similar efficacy. Studies that explored additional adjustments in the BEP regimen to further decrease toxicity have shown that the lower threshold of efficacy has been reached, and that the efficacy of the chemotherapy is compromised. Especially during the last decade, important long-term side-effects after the treatment of germ-cell cancers have been recognized. Chemotherapy in patients with germ-cell cancer increases the risk of developing cardiovascular disease and second malignant neoplasms. Whether 3BEP or 4EP is the optimal chemotherapy regimen for the future remains to be identified. Possibly differences in acute and late toxicities attributed to chemotherapy might eventually identify the best strategy.

Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Outcome and reproductive function after cumulative high-dose combination chemotherapy with bleomycin, etoposide and cisplatin (BEP) for patients with ovarian endodermal sinus tumor

Objective The aim of this study was to investigate the outcome and reproductive function of patients with ovarian endodermal sinus tumor (EST) after cumulative high-dose combination chemotherapy with bleomycin, etoposide and cisplatin (BEP). Methods Between 1995 and 2006, 1034 patients with the diagnosis of ovarian cancer were treated at a single institution. Among these patients, 51 had a confirmed diagnosis of malignant ovarian germ cell tumor (MOGCT) including 20 cases of EST. We retrospectively reviewed those patients with EST, who received BEP as adjuvant chemotherapy. The doses were 15 mg/day of bleomycin on days 1 to 3, 100 mg/m 2/day IV of etoposide on days 1 to 3 and 20 mg/m 2/day of cisplatin on days 1 to 5. The median number of total cycles was six (range between three and nine). Results The median age of the patients with EST was 18 years (range 5 to 36). All except two were nulliparous. The overall survival rate was 90% at a median follow-up of 70 months. Two patients (10%) had disease recurrence in the pelvis. Of the 15 patients who were treated with fertility-sparing surgery, all had regular menstruation following the completion of adjuvant chemotherapy, and two of these patients had pregnancies with live birth deliveries and no complications. Conclusion In patients with EST, the cumulative high-dose BEP regimen resulted in excellent overall survival and did not seem to impair ovarian function.

Long‐term results of first‐line sequential high‐dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor

Standard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor (GCT). First-line high-dose chemotherapy (HD-CT) may improve the result. High-dose carboplatin, etoposide, ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) was investigated as first-line chemotherapy in patients with advanced testicular GCT. Fifty-five previously untreated testicular GCT patients with Indiana 'advanced disease' criteria received three cycles of bleomycin, etoposide and cisplatin (BEP) followed by one cycle of HD-CT plus PBSCT, if elevated serum tumor markers were observed after three cycles of the BEP regimen. Thirty patients were treated with BEP alone, because the tumor marker(s) declined to normal range. Twenty-five patients received BEP and HD-CT. One patient died of rhabdomyolysis due to HD-CT. Three and six (13% and 25%) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses, respectively. The other patients achieved no change. Fifteen (63%) are alive and 14 (58%) are free of disease at a median follow-up time of 54 months. Severe toxicity included treatment-related death (4%). HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting. HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated. This regimen might be examined for further investigation in randomized trials in first-line chemotherapy for patients with poor-risk testicular GCT.

The management and survival of patients with advanced germ-cell tumours: improving outcome in intermediate and poor prognosis patients.

The survival of germ-cell tumours (GCT) was transformed after the introduction of cisplatin-based therapy. Previous trials have indicated BEP (bleomycin, etoposide and cisplatin) as the optimum treatment, although some centres including our own advocate the use of the alternating regimen POMB-ACE (cisplatin, vincristine, methotrexate, bleomycin and dactinomycin, cyclophosphamide and etoposide) for men with intermediate or poor prognosis disease. We analysed the survival and management of GCT patients treated at a specialist cancer centre in relation to internationally recognised prognostic groupings. We retrieved patient information using the Trent Testicular Tumour Registry and supplemented it with information from patient notes. This included all patients with Royal Marsden Hospital Stage II, III and IV disease and patients with stage I disease at diagnosis with raised markers or subsequent relapse. We compared the efficacy and toxicity of the BEP and POMB-ACE chemotherapy regimens, and assessed relapse-free and overall survival. We identified 178 non-seminomatous germ cell tumours (NSGCT) and 71 seminoma patients. Overall survival was similar to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification for the good (95% vs 92%) and intermediate groups (82% vs 80%). The outcome for the poor prognosis group was better than expected in our series (57% vs 48%). There was a higher proportion of both immediate and late side-effects with POMB-ACE. Survival and disease progression rates at this single institution were at least as good as reported by the IGCCCG and somewhat better for the poor-prognosis group. This may reflect use of the POMB-ACE chemotherapy regimen as opposed to standard BEP regimen. However, a randomised comparison of BEP and POMB-ACE would be required to validate this.

Chemotherapy of Testis Cancer.

BACKGROUND: Prior to the use of cisplatin, durable complete remissions of metastatic testis cancer were rare. In 1977, a treatment program including a chemotherapy program of cisplatin, vinblastine, and bleomycin (PVB) led to high response rates and acceptable toxicities in patients with disseminated testis cancer. Since then, the BEP (bleomycin, etoposide, and cisplatin) regimen has been established as standard therapy for good- and poor-risk disease and ifosfamide-based regimens or high-dose chemotherapy with stem cell rescue as salvage therapy. METHODS: The results of those prospective, randomized clinical trials that have markedly improved the outlook of patients with this type of cancer have been reviewed. RESULTS: Categories of risk have been defined. Standard therapy for both good-risk and poor-risk disease remains BEP therapy. High-dose chemotherapy with autologous bone marrow or peripheral stem cell rescue transplantation is being investigated to overcome chemotherapy resistance. CONCLUSIONS: While the present state of the art for treating metastatic testicular cancer is promising, approximately one third of patients with "poor-risk" disease will not achieve a remission. Trials of new agents and approaches are needed to increase patient survival.

Testicular cancer

The rising rate of germ cell cancer of the testis over the past decade has been demonstrated to be occurring predominantly in the younger age group (15 to 19 years) in association with earlier onset of puberty and earlier onset of regular sexual activity. Chemicals and viruses, with their atrophogenic effect, remain the main candidates for inducing the final common pathway of tumor development and clonal evolution, ie, gonadotropin-driven mitosis in spermatogonia. The possibility of different genetic mechanisms regulating susceptibility and resistance to these two extreme causes of gonadal atrophy in families is raised by the failure of a genome screen in a series of sibling pairs with testicular cancer to identify a single significant linkage group. Studies demonstrating high levels of non-mutated p53 protein and rapid induction of apoptosis by chemotherapy provide a new insight into the cause of the exquisite chemosensitivity of these tumors. Durable responses to paclitaxel and in vitro activity in response to temezolamide provide further evidence of the plethora of agents that work against these tumors, although no new first-line therapeutic approaches have been reported recently. The most important clinical trial studied good-risk patients and demonstrated that to gain the benefit of reducing treatment time from 12 to 9 weeks it is essential to retain bleomycin in the BEP (bleomycin, etoposide, and cisplatin) regimen. The final new idea to emerge recently comes from a series of papers on management of primary tumors in patients with a solitary testis and the possible use of organ-conserving surgery plus postoperative radiation. Another study did suggest it might be possible to use preoperative chemotherapy in those wishing to retain spermatogenesis.