Months Of Platinum-based Chemotherapy Research Articles

Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis

ObjectivePlatinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. MethodsIn this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. ResultsOf 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 μg/ml (range 0.4–3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46–1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). ConclusionsMetabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors.

Poly(ADP-ribose) polymerase inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.

Abstract CT234: A Phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2

Abstract Background: PARP inhibitors have activity in multiple BRCA-related malignancies and have recently demonstrated dramatic efficacy as a maintenance strategy for platinum-sensitive ovarian cancer. Between 5-8% of patients with pancreatic cancer (PC) have a pathogenic mutation in BRCA1, BRCA2 or PALB2. Therefore, we initiated a single arm phase II clinical trial of maintenance monotherapy rucaparib in patients with advanced PC and a pathogenic germline or somatic BRCA or PALB2 mutation, whose cancer had not progressed following at least four months of platinum-based chemotherapy (NCT 03140670). Methods: Patients were enrolled and treated with rucaparib 600mg PO BID until disease progression or unacceptable toxicity. The primary endpoint is progression free survival (PFS). Patients have previously received &amp;gt;4 months of platinum-based chemotherapy without evidence of disease progression. However, patients with a medical contraindication to receiving the full four months of platinum have been permitted to enroll at the discretion of the primary investigator. Responses were determined using RECIST v1.1. Results: As of December 31st, 2018, we have enrolled 24 of the planned 42 patients, of which 19 are evaluable for PFS at the time of this interim analysis. For these patients, the mutational distribution includes: 13 germline BRCA2, 3 germline BRCA1, 2 germline PALB2, 1 somatic BRCA2. Patients were predominantly female (84.2%) with a median age of 61 years (range: 35-81). Patients had received a median of four months (range 0.5-32 months) of prior platinum therapy for advanced disease. All patients were evaluable for toxicity. Overall, treatment with rucaparib was well tolerated without dose limiting toxicities. The most common adverse events that were at least possibly related to treatment included nausea (grade 1, 41.6%; grade 2, 4.2%), dysgeusia (grade 1, 33.3%) and fatigue (grade 1, 25%). One patient required dose reduction for nausea. The median PFS was 9.1 months from the start of rucaparib therapy with an ORR of 36.8% (six PRs; one CR). Disease control rate (CR + PR + SD) was 89.5% for at least eight weeks. Two patients (10.5%) had progressive disease at first follow-up scan two months after beginning treatment. Eight patients have been on rucaparib for &amp;gt;6 months and two patients remain on treatment for &amp;gt;1 year (13 months and 15 months). The seven responding patients include those with germline BRCA2 mutations (4 patients), germline PALB2 mutations (2 patients) and somatic BRCA2 mutation (1 patient). Conclusions: Based on these early data, maintenance rucaparib following induction with platinum-based chemotherapy shows encouraging disease control with minimal toxicity in patients with platinum-sensitive advanced PC and a pathogenic mutation in BRCA1, BRCA2 or PALB2. Citation Format: Kim A. Reiss Binder, Rosemarie Mick, Mark O'Hara, Ursina Teitelbaum, Thomas Karasic, Charles Schneider, Peter J. O'Dwyer, Erica Carpenter, Austin Pantel, Mehran Makvandi, David Mankoff, Katherine Nathanson, Kara Maxwell, Stacy Cowden, Mary Jane Fuhrer, Janae Romeo, Gregory L. Beatty, Susan Domchek. A Phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT234.

Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer

BackgroundStage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.MethodsIn this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.ResultsOf the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.ConclusionsChemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.)

A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy

There is no standard second line therapy for relapsed oesophago-gastric (O-G) cancer. We recruited 29 eligible patients with relapsed O-G cancer who had progressed during or within 3 months of prior chemotherapy to assess the efficacy and toxicity of capecitabine [2,000 mg/(m(2) day) on days 1-14] and irinotecan (250 mg/m(2)) given every 3 weeks. Five patients (17%) demonstrated objective response, while a further seven patients (24%) achieved disease stabilisation. Median progression-free survival and overall survival were 3.1 months (95% CI = 2.2-4.1 months) and 6.5 months (95%CI = 6-7.1 months), respectively. Among symptomatic patients, palliation of tumour-related symptoms included resolution of reflux (5/12 pts), dysphagia (3/9 pts) and weight loss (4/9 pts), improvements in anorexia (4/10 pts), nausea (3/4 pts), vomiting (4/6 pts) and pain (4/16 pts). Grade 3-4 toxicities were diarrhoea (15%), nausea and vomiting (7%), lethargy (31%), neutropenia (31%), anemia (14%) and thrombocytopenia (7%). Capecitabine and irinotecan has anti-tumour activity as second line treatment for relapsed O-G cancer, and provides an important improvement in disease related symptoms.

Phase II trial evaluating capecitabine and irinotecan in patients (pts) with esophago-gastric (E-G) carcinoma having progressed or relapsed within 3 months of platinum-based chemotherapy

4170 Background: To assess the efficacy and toxicity of a 3-weekly regimen containing capecitabine combined with irinotecan (CapeIri) in refractory or relapsed E-G carcinomas. Primary endpoints were response rate (RR) and disease free survival (DFS) with secondary endpoints of overall survival (OS) and toxicity. Methods: 29 pts with locally advanced or metastatic E-G carcinoma (27 adenocarcinoma, 2 squamous carcinoma) with documented progression during or within 3 months of completion of chemotherapy were recruited between January 2003 and November 2004. Capecitabine (2000mg/m2/day Day 1–14) and Irinotecan (250mg/m2 Day 1) (CapeIri) was given every 3 weeks. CT response was assessed at 12 and 24 weeks. Results: Four pts were ineligible due to no measurable disease (number, n=3) and progression > 3 months since platinum therapy (n=1). Median age of the 25 eligible pts was 59 years and 21 pts (84%) had metastatic disease. All pts had previously received platinum although one pt had capecitabine alone immediately prior to study entry. 19/25 (76%) received a 3-drug ECF-like regimen. At present, with a median follow up of 4.3 months, 21 pts are assessable for response. 3 pts responded, RR 14.3% (95% CI 3.1–36.3%) and 3 pts (14.3%) had stable disease. Improvement in the following tumor-related symptoms occurred: dysphagia 43% (3/7 pts), reflux 50% (5/10), anorexia 44% (4/9), weight loss 43% (3/7), vomiting 60% (3/5) and pain 29% (4/14). 8 pts (32%) had grade 3/4 neutropenia and 1 pt (4%) had febrile neutropenia. There were no toxic deaths. Median DFS was 2.8 months and median survival was 6.3 months. Conclusions: Second-line chemotherapy with CapeIri in primary refractory and relapsed esophago-gastric carcinoma is effective, tolerable palliative treatment and warrants further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, sanofi-aventis Roche, sanofi-aventis Roche-educational grant and free drug. Money to research fund, sanofi-aventis towards drug costs, to research fund not myself.