Cisplatin-based Combination Therapy Research Articles

Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO).

298 Background: Neoadjuvant chemotherapy (NC) for the treatment of MIBC remains underutilized in the United States despite evidence supporting its use. The aim of this project is to examine the current management of MIBC by MO to move towards standardization of practice. Methods: An electronic 26 question survey was emailed to 92 MO belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology, and posted on the US Oncology portal for 8 wks. The study was approved by the Office of Management and Budget (0925-0046). Percentages are based on the fraction that responded to a given question. Results: Of the 83 respondents: 48% were non-academic. 51% were general oncologists and 45% focused on GU malignancies. The majority of MIBC referrals came from urologists (79%). Initial CT staging with abd/pelvis was required by 88%, CT chest by only 72% and PET by 21%. NC is offered by 79% of MO to all MIBC pts and by 45% to all pts with high grade upper tract urothelial carcinoma. Adjuvant chemotherapy (AC) was offered by 46% to all MIBC pts and by 41% to pts with upper tract disease. NC was not offered if ECOG performance status (PS) was >3 (49%), in T2 disease without lymphovascular invasion (29%), or with GFR of <50 ml/min (35%). Chemotherapy regimens used for NC included gemcitabine/cisplatin (90%); methotrexate/vinblastine/adriamycin/cisplatin (MVAC) (30%), dose dense MVAC (20%); gemcitabine/carboplatin (36%); single-agent gemcitabine (10%), other regimens described include carboplatin/paclitaxel and ifosfamide/doxorubicin/gemcitabine. Response to NC was assessed by CT abd/pelvis (82%), CT chest (39%), cystoscopy (30%) and PET (12%). Pts with pathologic residual disease (>pT2 or positive LN) after NC were generally observed (74%). Conclusions: The majority of MO do offer perioperative chemotherapy for MIBC pts with a trend towards increased use of NC over AC, which follows best evidence. The main reason for not offering perioperative chemotherapy was poor PS. The majority offer cisplatin-based combination therapy by preference. Increasing the rate of referrals of MIBC pts to MO, will result in more pts receiving perioperative cisplatin-based chemotherapy and may lead to better outcomes in this disease.

Surgical management of pancreatic neuroendocrine tumors

This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.

Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of topotecan in combination with cisplatin for the treatment of recurrent and stage IVB carcinoma of the cervix, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes measured were overall survival, progression-free survival, response rates, adverse effects of treatment, health-related quality of life (HRQoL) and quality-adjusted life-years (QALYs) gained. The manufacturer stated that topotecan plus cisplatin is the only combination regimen to date to have demonstrated a statistically significant survival advantage compared to cisplatin monotherapy in the licensed population. The clinical evidence came from three clinical trials comparing topotecan plus cisplatin with cisplatin monotherapy (GOG-0179), topotecan plus cisplatin with paclitaxel plus cisplatin (GOG-0169), and four cisplatin-based combination therapies: topotecan plus cisplatin, paclitaxel plus cisplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin (GOG-0204). Results from GOG-0179 showed greater median overall survival with topotecan plus cisplatin than with cisplatin monotherapy: 9.4 months versus 6.5 months. Similar results were also reported for median progression-free survival. Response rates also showed an advantage with topotecan plus cisplatin compared with cisplatin monotherapy. The response rates in patients receiving cisplatin monotherapy were very low, but the potential reasons for this were not discussed in the manufacturer’s submission. Patients receiving topotecan plus cisplatin experienced a greater number of adverse events and the ERG was concerned with some of the assumptions related to HRQoL. In the base-case direct comparison, the incremental cost-effectiveness ratio (ICER) of topotecan plus cisplatin versus cisplatin monotherapy was £17,974 per QALY in the main licensed population, £10,928 per QALY in the cisplatin-naive population (including stage IVB patients) and £32,463 per QALY in sustained cisplatin-free interval patients. In response to the point for clarification raised by the ERG, the manufacturer submitted a revised indirect comparison incorporating HRQoL and a longer time horizon. Where the hazard ratio derived from GOG-0169 was employed, paclitaxel plus cisplatin was dominated by topotecan plus cisplatin, but, where the hazard ratio from GOG-0204 was adopted, paclitaxel plus cisplatin was found to have an ICER of £13,260 per QALY versus topotecan plus cisplatin. At present there is a paucity of evidence available on the clinical effects of topotecan plus cisplatin and the effects of palliative treatment in general for women with advanced and recurrent carcinoma of the cervix. Further trials, or the implementation of registries, are required to establish the efficacy and safety of topotecan plus cisplatin. The guidance issued by NICE in September 2009 as a result of the STA states that topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer, only if they have not previously received cisplatin. Women who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for the treatment of cervical cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of topotecan in combination with cisplatin for the treatment of recurrent and stage IVB carcinoma of the cervix, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes measured were overall survival, progression-free survival, response rates, adverse effects of treatment, health-related quality of life (HRQoL) and quality-adjusted life-years (QALYs) gained. The manufacturer stated that topotecan plus cisplatin is the only combination regimen to date to have demonstrated a statistically significant survival advantage compared to cisplatin monotherapy in the licensed population. The clinical evidence came from three clinical trials comparing topotecan plus cisplatin with cisplatin monotherapy (GOG-0179), topotecan plus cisplatin with paclitaxel plus cisplatin (GOG-0169), and four cisplatin-based combination therapies: topotecan plus cisplatin, paclitaxel plus cisplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin (GOG-0204). Results from GOG-0179 showed greater median overall survival with topotecan plus cisplatin than with cisplatin monotherapy: 9.4 months versus 6.5 months. Similar results were also reported for median progression-free survival. Response rates also showed an advantage with topotecan plus cisplatin compared with cisplatin monotherapy. The response rates in patients receiving cisplatin monotherapy were very low, but the potential reasons for this were not discussed in the manufacturer's submission. Patients receiving topotecan plus cisplatin experienced a greater number of adverse events and the ERG was concerned with some of the assumptions related to HRQoL. In the base-case direct comparison, the incremental cost-effectiveness ratio (ICER) of topotecan plus cisplatin versus cisplatin monotherapy was 17,974 pounds per QALY in the main licensed population, 10,928 pounds per QALY in the cisplatin-naive population (including stage IVB patients) and 32,463 pounds per QALY in sustained cisplatin-free interval patients. In response to the point for clarification raised by the ERG, the manufacturer submitted a revised indirect comparison incorporating HRQoL and a longer time horizon. Where the hazard ratio derived from GOG-0169 was employed, paclitaxel plus cisplatin was dominated by topotecan plus cisplatin, but, where the hazard ratio from GOG-0204 was adopted, paclitaxel plus cisplatin was found to have an ICER of 13,260 pounds per QALY versus topotecan plus cisplatin. At present there is a paucity of evidence available on the clinical effects of topotecan plus cisplatin and the effects of palliative treatment in general for women with advanced and recurrent carcinoma of the cervix. Further trials, or the implementation of registries, are required to establish the efficacy and safety of topotecan plus cisplatin. The guidance issued by NICE on 28 October 2009 as a result of the STA states that topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer, only if they have not previously received cisplatin. Women who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for the treatment of cervical cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Is neoadjuvant chemotherapy with gemcitabine plus cisplatin beneficial in patients with muscle-invasive bladder cancer?

Evaluation of: Weight CJ, Garcia JA, Hansel DE et al. Lack of pathologic down-staging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder. Cancer 115, 792–799 (2009).This study by the Glickman Urological Institute fails to show a beneficial role for neoadjuvant chemotherapy in muscle-invasive bladder cancer. The poor outcomes in the study could be attributed to the use of non-methotrexate, vinblastine, doxorubicin and cisplatin regimens and to excessive delays in performing cystectomy. Randomized trials of neoadjuvant chemotherapy have shown improved survival and increased rates of pathologic complete response when using cisplatin-based combination therapies compared with local therapy alone. A regimen consisting of gemcitabine plus cisplatin has shown similar efficacy and less toxicity in the metastatic setting and further research is warranted before its efficacy can be extrapolated to the neoadjuvant setting.

A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer

Cisplatin-based combination therapy produces higher response rates and improved survival, in comparison to single-agent cisplatin in the treatment of cervical cancer. Cisplatin and paclitaxel (PT) requires a prolonged infusion and is less convenient and more toxic than the combination of carboplatin and paclitaxel (CT) leading to more widespread use of CT. The objective of this study was to compare response rate and survival in patients with cervical cancer treated with PT or CT. A retrospective search of databases at the University of Oklahoma, Washington University-Barnes Jewish Christian Hospitals, Johns Hopkins University, and University of Alabama at Birmingham identified patients with stage IVB, recurrent or persistent cervical cancer who were treated with PT or CT. A total of 62 patients were identified. 14 were treated with PT and 48 with CT. There were no statistical differences between the groups in terms of demographics, prior radiation therapy, or median number of cycles. There was a trend toward a larger number of patients in the CT arm having received prior cisplatin/radiation (p=0.07). Objective responses occurred in 29% of patients receiving PT vs. 53% of patients receiving CT. With a median follow-up of 9 months, survival was not different with a median survival of 14 and 11 months, respectively. In this retrospective evaluation, CT compares favorably with PT and demonstrates a superior overall response rate. Because of its ease of administration and improved toxicity profile, CT should be considered in the treatment of advanced, recurrent or progressive cervical cancer.

The lack of long-term effect of Cisplatin based combination chemotherapy on serum cholesterol for treatment of testicular cancer.

Cisplatin based combination therapy is curative in most patients with advanced testicular cancer. Previous reports have suggested that hypercholesterolemia is a common complication in this patient group. We performed a cross-sectional study to assess further the relationship of cisplatin based chemotherapy and serum cholesterol in long-term survivors of testicular cancer. Fasting lipid profiles were obtained from 106 men previously treated for testicular cancer, of whom 34 had received cisplatin based combination chemotherapy and 72 were chemotherapy naive. Mean total cholesterol in the chemotherapy and nonchemotherapy groups was 5.50 +/- 0.20 and 5.36 +/- 0.13 mmol./l., respectively (p = 0.55). Mean high density lipoprotein cholesterol in the chemotherapy and nonchemotherapy groups was 1.09 +/- 0.04 and 1.09 +/- 0.03 mmol./l., (p = 0.94), while mean low density lipoprotein cholesterol was 3.49 +/- 0.17 and 3.40 +/- 0.11 mmol./l. (p = 0.67) respectively. The mean total-to-high density lipoprotein cholesterol ratio was 5.26 +/- 0.27 in the chemotherapy group and 5.12 +/- 0.16 in the nonchemotherapy group (p = 0.67). Body mass index was not significantly different in the 2 groups. Administering cisplatin based chemotherapy was unrelated to lipid profiles in long-term survivors of testicular cancer. Chemotherapy treated and chemotherapy naive patients had mean cholesterol levels in the borderline elevated range and body mass index in the overweight range. These potentially reversible cardiovascular risk factors have considerable importance in the overall testicular cancer population.

Recent updates in the clinical use of platinum compounds for the treatment of gynecologic cancers

Platinum compounds have long played a role in the treatment of gynecologic cancers. Single-agent cisplatin and carboplatin have shown activity in endometrial cancer, and more recent studies have begun to investigate a variety of new platinum-based combinations. In cervical cancer, chemotherapy is used primarily to treat advanced or recurrent disease. Agents with proven single-agent activity in this setting include cisplatin, ifosfamide, and doxorubicin, and a number of cisplatin-based combination therapies are under clinical investigation. A variety of cisplatin-based combinations have also been used in ovarian cancer chemotherapy, with more recent studies investigating the substitution of carboplatin or oxaliplatin for cisplatin and the addition of paclitaxel. This review will examine recent clinical data on the use of platinum-based chemotherapies for the treatment of these gynecologic cancers.

The Lack of Long-Term Effect of Cisplatin Based Combination Chemotherapy on Serum Cholesterol for Treatment of Testicular Cancer

Cisplatin based combination therapy is curative in most patients with advanced testicular cancer. Previous reports have suggested that hypercholesterolemia is a common complication in this patient group. We performed a cross-sectional study to assess further the relationship of cisplatin based chemotherapy and serum cholesterol in long-term survivors of testicular cancer. Fasting lipid profiles were obtained from 106 men previously treated for testicular cancer, of whom 34 had received cisplatin based combination chemotherapy and 72 were chemotherapy naive. Mean total cholesterol in the chemotherapy and nonchemotherapy groups was 5.50 +/- 0.20 and 5.36 +/- 0.13 mmol./l., respectively (p = 0.55). Mean high density lipoprotein cholesterol in the chemotherapy and nonchemotherapy groups was 1.09 +/- 0.04 and 1.09 +/- 0.03 mmol./l., (p = 0.94), while mean low density lipoprotein cholesterol was 3.49 +/- 0.17 and 3.40 +/- 0.11 mmol./l. (p = 0.67) respectively. The mean total-to-high density lipoprotein cholesterol ratio was 5.26 +/- 0.27 in the chemotherapy group and 5.12 +/- 0.16 in the nonchemotherapy group (p = 0.67). Body mass index was not significantly different in the 2 groups. Administering cisplatin based chemotherapy was unrelated to lipid profiles in long-term survivors of testicular cancer. Chemotherapy treated and chemotherapy naive patients had mean cholesterol levels in the borderline elevated range and body mass index in the overweight range. These potentially reversible cardiovascular risk factors have considerable importance in the overall testicular cancer population.

EFFICIENT CARBOPLATIN SINGLE THERAPY IN A MOUSE MODEL OF HUMAN TESTICULAR NONSEMINOMATOUS GERM CELL TUMOR

Cisplatin based combination therapy has shown excellent clinical results in patients with testicular nonseminomatous germ cell tumor but chemotherapy induced morbidity and reduced patient compliance are limiting factors in this regimen. To decrease cisplatin based combination therapy induced morbidity we examined carboplatin versus etoposide single therapy in an animal model. A total of 180 SCID mice bearing testicular nonseminomatous germ cell tumor xenografts received 120 mg./kg. carboplatin as a single cycle, 60 or 30 mg./kg. carboplatin cycled twice, 80, 50 or 30 mg./kg. etoposide cycled twice, or Ringer solution as the control. An additional 20 sham treated and 20 untreated mice also served as controls. Histological and immunocytochemical testing, in vivo microscopy, vascular corrosion casting, serum tumor markers, complete blood count and real-time polymerase chain reaction were used to monitor therapy efficacy. Carboplatin at 60 mg./kg. cycled twice eradicated the tumor and significantly reduced vascular density and vascular endothelial growth factor-A messenger RNA (p <0.05). Elevated tumor markers returned to baseline after carboplatin administration. Therapy was well tolerated, resulting thrombocytopenia disappeared 6 weeks after therapy and the animals were tumor-free 6 months after treatment. Although 120 mg./kg. carboplatin eradicated the tumor, it resulted in extensive mortality and morbidity. Single treatment 30, 50 and 80 mg./kg. etoposide failed. Carboplatin single therapy was highly effective in our nonseminomatous germ cell tumor model and it may be examined in future clinical trials in patients with high risk stage I nonseminomatous germ cell cancer for reducing cisplatin based combination therapy induced morbidity. Vascular density and vascular endothelial growth factor messenger RNA were elevated in our animal model and deserve further study in nonseminomatous germ cell tumor cases as potential risk factors.

Do all patients with advanced non-small-cell lung cancer benefit from cisplatin-based combination therapy?

Platinum-based chemotherapy has been shown to be effective in improving survival and quality of life in advanced non-small-cell lung cancer (NSCLC) patients. The objective of this study was to identify patients more likely to benefit from chemotherapy in order to avoid the indiscriminate treatment of all patients. A multivariate analysis of survival was performed using the database of the European randomized phase III trial that compared vinorelbine (navelbine) (NVB), vinorelbine-cisplatin (NVB-P) and vindesine-cisplatin (VDS-P) in 612 patients with inoperable NSCLC (stage III or IV). Interactions between treatment and the prognostic factors singled out by the Cox procedure were specifically tested. The performance status (PS) was the only significant interaction among the selected prognostic factors and treatment. Subgroup analysis showed that the advantage obtained with NVB-P predominantly concerned PS 0-1 patients, whose median survival lasted 43 weeks (95% confidence interval (95% CI): 39-50 weeks) with a one-year survival rate of 38% (95% CI: 31%-46%) versus 36 weeks (95%, CI: 30-40 weeks) and 34% (95% CI: 27%-42%) for NVB alone, and 33 weeks (95% CI: 30-39 weeks) and 29% (95% CI: 22%-36%) for VDS-P. In sharp contrast, survival in PS 2 patients was similar (median 18 weeks) (NVB-P 95% CI: 11-34 weeks; NVB 95% CI: 11-35 weeks; VDS-P 95% CI: 14-32 weeks) whatever the treatment. PS 2 patients with advanced NSCLC might not benefit from cisplatin combination therapy.

ANTITUMOR-ACTIVITY AND TOXICITY OF CONTINUOUS-INFUSION VERSUS BOLUS ADMINISTRATION OF BLEOMYCIN IN 2 HETEROTRANSPLANTED HUMAN TESTICULAR CANCER CELL-LINES

The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity.

Long-term follow-up of patients with advanced ovarian carcinoma treated with chemotherapy

The evolution of the management of advanced ovarian carcinoma over the last fifteen years has resulted from a number of well-designed randomized trials involving large numbers of patients. A critical review of long-term follow-up of patients entered onto eleven major randomized trials of advanced ovarian carcinoma has been performed. In the pre-platinum era no long-term survival benefit was obtained with combination compared with single agent chemotherapy. When adding cisplatin to front-line therapy at least a short-term gain in terms of superior response rate and progression-free intervals is obtained compared with non-cisplatin combination chemotherapy. Survival data are more difficult to assess due to the use of cisplatin-containing salvage therapy. Cisplatin-based combination therapy also offers enhanced patient benefit when compared with cisplatin alone. A slight advantage favouring anthracycline-containing therapy is observed, whereas no advantage is obtained with alternating cisplatin and non-cisplatin regimens or by adding BCG. Platinum-based combination chemotherapy is clearly associated with improved response rates and progression-free survival and, at least in some studies, better overall survival. At least six cycles of therapy should be given. Such approaches should yield long-term survival rates of 10% or better for patients with large-volume disease and 20% or better for small-volume disease.

Results of chemotherapy in advanced carcinoma of the fallopian tube

Forty-six patients with measurable disease received chemotherapy for advanced primary or recurrent carcinoma of the fallopian tube. The response rate was 9% with single-agent therapy, 29% with multiagent therapy without cisplatin, and 81% with cisplatin-containing combination therapy. Survival was significantly improved in Stage III/IV with the addition of cisplatin-based combination therapy.

Failure of hexamethylmelamine as salvage therapy in ovarian epithelial adenocarcinoma resistant to combination chemotherapy

Favorable responses to hexamethylmelamine (HMM) have been documented in untreated as well as in alkylating agent-resistant ovarian epithelial adenocarcinoma (OvCa). Platinum-based combination therapy for OvCa has been used since 1976. Eighteen patients with OvCa were treated with HMM as salvage therapy between February 1979 and October 1981. All patients had histologically confirmed OvCa. Eleven tumors were grade III III and seven tumors were grade II III . Sixteen patients had received cisplati-based combination therapy, whereas two had received doxorubicin/cyclophosphamide because of other medical conditions. HMM was used alone in 16 patients and in combination with other drugs in two patients. The initial dose of HMM was 300 mg/m 2/day × 14 days when used alone and 130 mg/ m 2/day × 14 days when used in combination with other drugs. Six patients were treated at a reduced initial dose because of prior marrow toxicity. Adverse effects were tolerable, with 14 patients experiencing hematologic toxicity (5 mild, 5 moderate, 3 severe, 1 life threatening) and 15 patients experiencing GI toxicity (5 mild, 7 moderate, 3 severe). Only 2 patients experienced no toxicity. No objective tumor responses were observed. Four patients had progression of tumor within 4 weeks of starting therapy and 14 patients had stable disease with a mean progression-free interval of 21 weeks. Although HMM is an active drug in untreated and alkylating agent-resistant OvCa, experience suggests that HMM at the dose and schedule tested has insignificant activity in patients who have failed cisplatin-based combination therapy.