High efficacy of gemcitabine and cisplatin plus trastuzumab in patients with HER2-overexpressing metastatic breast cancer: a phase II study

AimsEffective and tolerable regimens are sought specifically in women who have been pre-treated with anthracyclines and taxanes. Gemcitabine and cisplatin plus trastuzumab has shown synergistic activity in vitro, and provides a new mechanism of drug interaction. This multicentre phase II study aimed to evaluate the efficacy and tolerability of gemcitabine and cisplatin plus trastuzumab in previously treated patients with metastatic breast cancer (MBC).Materials and methodsPreviously treated patients with human epidermal growth factor receptor 2 (HER2) overexpressing MBC were enrolled in a multicentre phase II study (DAKO Hercep Test 3+). Treatment consisted of gemcitabine (750 mg/m²), cisplatin (30 mg/m²) given on days 1 and 8 every 3 weeks, and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly).ResultsTwenty patients were recruited, all of whom had previously received chemotherapy (12 pre-treated with taxanes, 18 pre-treated with anthracyclines seven pre-treated with taxanes and trastuzumab). A median of six cycles of the study treatment was delivered. There were eight partial responses, for an overall response rate of 40% (95% confidence interval 16.5–63.5%). The clinical benefit rate (complete response plus partial response plus stable disease) was 80% (95% CI 54.2–95.8%). The response rate in patients who had already received a trastuzumab-based regimen for MBC was 57.1% (95% CI 7.7–100%). Median time to progression was 10.2 months, and median overall survival was 18.8 months. Main toxicities were leukopenia (grade 3 in 55% of patients) and thrombocytopenia (grade 3 in 35% and grade 4 in 5% of patients). Non-haematological toxicity was rarely severe.ConclusionsCombination chemotherapy with gemcitabine and cisplatin plus trastuzumab is well tolerated and active in patients with HER2 overexpressing MBC, even after prior exposure to anthracyclines and taxanes.     

Phase II study of a gemcitabine and cisplatin combination regimen in taxane resistant metastatic breast cancer

Purpose: To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer. Patients and methods: Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m² IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m² by IV infusion over 1 h on day 1 in 21 day cycles. Results: Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1–8.9 months) and 15 months (95% CI 10.5–19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred. Conclusion: The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.     

Pooled Analysis of Phase II Trials Evaluating Weekly or Conventional Cisplatin as First-Line Therapy for Advanced Urothelial Carcinoma

BackgroundWeekly gemcitabine with GC every 3-4 weeks is considered conventional first-line chemotherapy for advanced urothelial carcinoma (UC). Weekly split-dose cisplatin with wGC might be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC and wGC to compare efficacy and safety.Patients and MethodsTwo trials of wGC and 3 trials of GC were identified. Because the data were not derived from randomized trials, GC and wGC were not formally compared, and exact 95% quasi-binomial confidence intervals (CI), for response rates and grade ≥ 3 toxicities were calculated.ResultsThe 95% CI overlapped, suggesting agreement between wGC and GC. No clear difference in response rates and grade ≥ 3 toxicities between GC and wGC were observed.ConclusionGemcitabine combined with day 1 cisplatin and wGC yielded similar responses and grade ≥ 3 toxicities in advanced UC in a hypothesis-generating pooled analysis of phase II trials. Considering the probable lower nephrotoxicity of fractionated cisplatin, prospective evaluation of wGC might be warranted across cisplatin-eligible and -ineligible patients to develop a single chemotherapy template for the development of combinations with biological agents in a broad population of patients.     

Cisplatin and carboplatin combination as second-line chemotherapy in dacarbazine-resistant melanoma patients

High-dose cisplatin regimens have been shown to be highly active in advanced melanoma patients but are associated with unacceptable side effects. In order to increase the platinum dose but avoid severe side effects, we treated 15 dacarbazine (DTIC)-resistant metastatic melanoma patients with a combination regimen of cisplatin (100 mg/m2) and carboplatin (200 mg/m2), two platinum analogues with a similar mode of action but a different toxicity pattern. After a mean follow-up period of 10.7 months (range 4-18 months), two patients (13.3%) achieved complete remission and two patients (13.3%) showed partial remission, giving an overall response rate of 26.4% (95% confidence interval [CI] 4.2-49%). Furthermore, three patients (20%; 95% CI 0-40.2%) experienced stable disease. The median duration of response was 7.1 months (95% CI 4.2-10.0 months), and the median overall survival was 12.5 months (95% CI 5.8-19.2 months), with eight patients still alive. The main side effects were haematological (leukopenia/thrombocytopenia World Health Organization [WHO] grade I-IV; anaemia WHO grade I-III), gastrointestinal (WHO grade I-III), neurological (WHO grade I-II) and renal (WHO grade I) toxicity. Nevertheless, except in one patient, side effects did not result in discontinuation of therapy. Despite the small number of patients treated in this preliminary study, we believe that combining cisplatin and carboplatin represents a novel, active and well-tolerated therapeutic option as second-line chemotherapy in DTIC-resistant advanced melanoma patients.     

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR)

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.BackgroundRandomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC).Patients and methodsPatients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m²/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points.ResultsA total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4–10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4–27.6 resp. 26.0–36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia.ConclusionThe combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.     

Delivery of perioperative chemotherapy for bladder cancer in routine clinical practice

BackgroundFew articles have documented regimens and timing of perioperative chemotherapy for bladder cancer in routine practice. Here, we describe practice patterns in the general population of Ontario, Canada.MethodsIn this retrospective cohort study, treatment and physician billing records were linked to the Ontario Cancer Registry to describe use of neoadjuvant (NACT) and adjuvant (ACT) chemotherapy among all patients with muscle-invasive bladder cancer treated with cystectomy in Ontario 1994–2008. Time to initiation of ACT (TTAC) was measured from cystectomy. Multivariate Cox regression was used to identify factors associated with overall (OS) and cancer-specific survival (CSS).ResultsOf 2944 patients undergoing cystectomy, 4% (129/2944) and 19% (571/2944) were treated with NACT and ACT, respectively. Five-year OS was 25% [95% confidence interval (CI) 17% to 34%] for NACT, 29% (95% CI 25% to 33%) for ACT cases. Among patients with identifiable drug regimens, cisplatin was used in 82% (253/308) and carboplatin in 14% (43/308). The most common regimens were gemcitabine–cisplatin (54%, 166/308) and methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) (21%, 66/308). Mean TTAC was 10 weeks; 23% of patients had TTAC >12 weeks. TTAC >12 weeks was associated with inferior OS [hazard ratio (HR) 1.28, 95% CI 1.00–1.62] and CSS (HR 1.30, 95% CI 1.00–1.69). In adjusted analyses, OS and CSS were lower among patients treated with carboplatin compared with those treated with cisplatin; OS HR 2.14 (95% CI 1.40–3.29) and CSS HR 2.06 (95% CI 1.26–3.37).ConclusionsMost patients in the general population receive cisplatin, and this may be associated with superior outcomes to carboplatin. Initiation of ACT beyond 12 weeks is associated with inferior survival. Patients should start ACT as soon as they are medically fit to do so.     

Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic breast cancer

This study was conducted to evaluate the response rate of gemcitabine and cisplatin as second-line combination chemotherapy in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Thirty-eight eligible women with measurable disease and anthracycline- and taxane-pretreated MBC were enrolled. The chemotherapy treatment consisted of gemcitabine (1,250 mg/m² by intravenous infusion over 30 min on days 1 and 8) and cisplatin (75 mg/m² by intravenous infusion over 1 h on day 1), which were administered every 21 days. Thirty-seven of 38 (97.4%) of patients were assessable for response. The objective response rate was 42.1% (95% CI, 26.4–57.8%) with 16 partial responses. The median time to progression (TTP) and overall survival (OS) for all patients were 5.4 months (95% CI, 2.7–8.1 months) and 13.9 months (95% CI, 9.4–18.4 months), respectively. The most frequent hematologic-related adverse events were grade 3/4 leucopenia and thrombocytopenia, observed in 10 patients (27.0%) and 11 (29.7%), respectively. Grade 3 stomatitis was observed in 3 (8.1%) patients. No grade 4 nonhematologic toxicity was observed in this study. No treatment-related deaths occurred during the study. In conclusion, the combination of gemcitabine and cisplatin is a safe and tolerable regimen as second-line combination for patients with anthracycline- and taxane-pretreated MBC.     

Gemcitabine plus carboplatin combination therapy as second-line treatment in patients with relapsed breast cancer

This study was designed to determine the safety and efficacy of the combination therapy of gemcitabine plus carboplatin when used as a second-line treatment in patients with metastatic breast cancer (MBC). From February 2002 to May 2003, 30 previously treated patients with adenocarcinoma of the breast received gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin to an area under the curve (AUC) of 5 on day 1. The carboplatin dose was changed to an AUC of 4.5 because of toxicity, with cycles repeated every 3 weeks. Among 30 patients enrolled, 25 were assessable for response rate (RR). There was no complete response; 9 patients (30%) had partial response, for an overall RR of 30%. The median time to progression for the study group was 20.47 weeks (range, 8-46 weeks). Treatment-related toxicities included grade 3/4 neutropenia in 50% of patients (20% of whom had febrile neutropenia), grade 3/4 anemia in 26.6% of patients, and grade 3/4 thrombocytopenia in 30%. Eleven patients (36.67%) had grade 1 alopecia, and 1 patient (3.33%) had grade 2 alopecia. Moderate nausea was observed in 8 patients (26.67%), and vomiting occurred in 7 patients. Four patients had asthenia and 3 (10%) experienced stomatitis. Three patients discontinued treatment because of hematologic toxicity (thrombocytopenia) and 2 patients are still receiving treatment. Carboplatin plus gemcitabine is an active combination for patients with MBC despite significant but manageable hematologic toxicity.     

Phase II study of continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of cisplatin) in patients with metastatic/locally advanced breast cancer (infusional ECarboF): a very active and well-tolerated outpatient regimen.

Infusional 5-fluorouracil (F) with cisplatin (C) and epirubicin (E), so-called infusional ECF, is a highly active new schedule against locally advanced or metastatic breast cancer. Cisplatin, however, is a major contributor to toxicity and usually requires inpatient treatment. In an attempt to overcome this, we have investigated the effect of substituting carboplatin for cisplatin in our original infusional ECF regimen. Fifty-two patients with metastatic (n = 36) or locally advanced/inflammatory (n = 16) breast cancer were treated with 5-fluorouracil 200 mg m-2 day-1 via a Hickman line using an ambulatory pump for for 6 months, with epirubicin 50 mg m-2 intravenously (i.v.) and carboplatin AUC5 i.v. every 4 weeks, for six courses (infusional ECarboF). The overall response rate (complete plus partial) was 81% (95% CI 67%-90%), with a complete response rate of 17% (95% CI 6-33%) in patients with metastatic disease and 56% (95% CI 30-80%) in patients with locally advanced disease. Median response duration and survival for metastatic disease was 8 and 14 months respectively, and two patients with locally advanced disease have relapsed. These results are very similar to those previously achieved with infusional ECF. Severe grade 3/4 toxicity was low. Infusional ECarboF is a highly active, well-tolerated, outpatient regimen effective against advanced/metastatic breast cancer and now warrants evaluation against conventional chemotherapy in high-risk early breast cancer.     

A Multicenter,Single-Arm Phase II Study of Pemetrexed Plus Doxorubicin Administered Every 21 Days in Patients With Advanced Breast Cancer

BackgroundDoxorubicin and pemetrexed have both shown single-agent activity in breast cancer. Preclinical and clinical evidence indicates that a combination of the 2 agents might have an additive or synergistic effect. A phase II trial was initiated to assess the antitumor activity and safety of pemetrexed plus doxorubicin in women with advanced breast cancer.Patients and MethodsAnthracycline-naive patients with advanced breast cancer received doxorubicin 50 mg/m² plus pemetrexed 500 mg/m² (both intravenously) on day 1 of 21-day cycles, as first-line therapy, with standard vitamin supplementation. Seventy-nine women were enrolled (median age, 55.3 years). Seventy-six patients (96.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1.ResultsAt baseline, 35 patients (44.3%) had visceral metastases. Three (4.2%) patients were HER2/neu positive, and 30 (42.3%) patients were HER2/neu negative. The objective response rate was 55.7% (95% exact CI, 44.1%-66.9%), including 2 (2.5%) complete responses. Median progression-free survival was 8 months (95% CI, 6.5-13.3 months). Two-year survival rate was 61.7% (95% CI, 49.7%-71.6%). Grade 3/4 drug-related toxicities in ≥ 10% patients included neutropenia (24.1%) and leukopenia (10.1%).ConclusionIn patients with advanced breast cancer, the combination of doxorubicin plus pemetrexed was well tolerated and showed promising antitumor activity that warrants further study.     

Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: A phase II clinical trial

Purpose: To determine the efficacy of gemcitabine and cisplatin combination therapy in patients with advanced and/or metastatic transitional cell urothelial carcinoma.Patients and methods: Forty-two chemonaïve patients with Karnofsky performance status (KPS) 70 were treated with cisplatin 35 mg/m² followed by gemcitabine 1000 mg/m² (30 min i.v. infusion) on days 1, 8, and 15 every twenty-eight days.Results: Thirty-eight patients were evaluable for efficacy. Half had visceral disease. There were seven complete (18%) and nine partial responses (24%), for a response rate of 42% (95% confidence interval (95% CI): 26%–59%). Responses were independently reviewed. Median response duration was 13.5 months (95% CI: 8.5–18.1 months), median time to progressive disease 7.2 months (95% CI: 4.0–9.1 months) and median survival 12.5 months (95% CI: 8.1–18.7 months); one-year survival was 52%. Laboratory toxicities included leucopenia (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4 symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no grade 4 infections and no toxic deaths.Conclusions: The combination of gemcitabine and cisplatin is active in patients with locally advanced and/or metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered inappropriate.     

A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer

PurposeThe purpose of this study was to evaluate the efficacy and toxicity of the combination of gemcitabine and carboplatin (and with trastuzumab in patients with HER2-positive disease) as first-line treatment for patients with metastatic breast cancer (MBC).Patients and MethodsSeventy-four patients who had received no previous chemotherapy for MBC were enrolled. Patients with HER2-negative breast cancer received treatment with gemcitabine 1000 mg/m² intravenously (I.V.) on days 1 and 8 and carboplatin area under the curve (AUC) 5 I.V. on day 1. Cycles were repeated every 21 days. Patients with HER2-positive disease also received trastuzumab 8-mg/kg I.V. loading dose, then 6 mg/kg I.V. every 21 days. After the first 29 patients were treated, the carboplatin dose was lowered to AUC 4. Patients were re-evaluated every 6 weeks; responses were measured using Response Evaluation Criteria in Solid Tumors criteria.ResultsIn patients with HER2-negative disease, gemcitabine/carboplatin produced a 34% major response rate; an additional 28% of patients had stable disease ≥ 6 months (overall disease control rate, 62%). Gemcitabine/carboplatin/trastuzumab produced an overall response rate of 66%, with a disease control rate of 77%. Grade 3/4 myelosuppression was common, even after reduction of the carboplatin dose. Only 3 patients treated with the lower dose regimen developed neutropenia and fever, but platelet and red blood cell transfusions were necessary in 24% and 40% of patients, respectively. Trastuzumab did not add to hematologic toxicity. Severe nonhematologic toxicity was uncommon.ConclusionGemcitabine/carboplatin and gemcitabine/carboplatin/trastuzumab are active first-line regimens for patients with MBC. The gemcitabine/carboplatin combination causes more grade 3/4 myelosuppression than other standard combination regimens for MBC; however, severe nonhematologic toxicity is minimal.     

Randomized,multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer

BACKGROUND: We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to GP (gemcitabine 1200 mg/m(2), days 1 and 8 plus cisplatin 80 mg/m(2) day 2) or GC (gemcitabine 1200 mg/m(2), days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks. RESULTS: Sixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6-54.2%) for GP and 31.0% (95% C.I., 18.2-42.8%) for GC (P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm (P<0.005). CONCLUSIONS: GC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.     

Neuroendocrine Carcinoma of the Urinary Bladder: A Large,Retrospective Study From the French Genito-Urinary Tumor Group

BackgroundNeuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.Materials and MethodsWe retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.ResultsFrom 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.ConclusionsIn early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.     

Cisplatin plus Gemcitabine as Adjuvant Chemotherapy for Radically Resected Non–Small-Cell Lung Cancer: A Pilot Study

BackgroundThe combination cisplatin/gemcitabine is one of the most active and well-tolerated regimens in advanced non–small-cell lung cancer (NSCLC). We undertook this pilot study to evaluate postoperative drug delivery and toxicity of cisplatin plus gemcitabine in patients with radically resected stage IB-III NSCLC.Patients and MethodsTwenty-two consecutive patients were treated with cisplatin 80 mg/m² on day 1 and gemcitabine 1200 mg/m² on days 1 and 8 every 3 weeks for 4 planned courses. Most patients (50%) had pathologic stage IIIA disease; all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. The median age was 63 years (range, 56-73 years). Six out of 22 patients (27.3%) had undergone pneumonectomy.ResultsA total of 85 courses of chemotherapy were administered, and the median number of courses was 4 (range, 1-4 courses); twenty-one out of 22 patients received the planned 4 courses of chemotherapy. Chemotherapy caused grade 3 anemia in 1 patient, grade 3 thrombocytopenia in another patient, and grade 3/4 neutropenia in 4 patients; grade 3 vomiting was observed in 3 patients, and grade 3 anorexia and grade 3 asthenia were both observed in 1 patient. No treatment-related deaths occurred. The median delivered dose intensities of cisplatin and gemcitabine were 24.3 mg/m²/week (97.2%) and 700.9 mg/m² weekly (87.5%), respectively.ConclusionThe combination of cisplatin/gemcitabine is a feasible and well-tolerated regimen in the adjuvant setting. Future trials should better define the best strategy in terms of efficacy, toxicity, and quality of life between this combination and the standard regimen, cisplatin plus vinorelbine.     

Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial

PurposeThis single centre, open labelled, randomised non-inferiority trial compared concurrent chemoradiotherapy with carboplatin versus standard concurrent chemoradiotherapy with cisplatin in patients with locoregionally advanced nasopharyngeal cancer (NPC).Patients and methodsFrom August 1999 to December 2004, 206 patients with locally advanced NPC were randomised with 101 to cisplatin arm and 105 to carboplatin arm. Planned radiotherapy was the same in both groups. All the patients were evaluated for toxicity and survival according to the as-treated principle.ResultsWith a median follow-up of 26.3 months (range 3–74.6 months), 59% of patients in the cisplatin arm completed the planned concurrent chemoradiation treatment, compared to 73% in the carboplatin arm. Forty-two percent of cisplatin patients completed the 3 cycles of adjuvant therapy compared to 70% in the carboplatin group. There were more renal toxicity, leucopenia, and anaemia in the cisplatin group, and more thrombocytopenia in the carboplatin arm. The 3 year disease free survival rates were 63.4% for the cisplatin group and 60.9% for the carboplatin group (p = 0.9613) (HR 0.70, 95% confidence interval (CI): 0.50–0.98). The 3 year overall survival rates were 77.7% and 79.2% for cisplatin and carboplatin groups, respectively (p = 0.9884) (HR 0.83, 95% CI: 0.63–1.010).ConclusionWe concluded that the tolerability of carboplatin based regimen is better than that of the cisplatin regimen. Moreover, the treatment efficacy of carboplatin arm is not different from the standard regimen in the treatment of locoregional advanced stage NPC.     

Efficacy and safety of gemcitabine plus doxorubicin in patients with renal medullary carcinoma

IntroductionRenal medullary carcinoma (RMC) is a rare and lethal renal cell carcinoma characterized by the loss of tumor suppressor SMARCB1. Molecular profiling studies have suggested that RMC cells may be vulnerable to therapies that generate DNA damage, such as the combination of the nucleoside analog gemcitabine, and topoisomerase inhibitor doxorubicin.Patients and MethodsWe retrospectively analyzed the records of patients with RMC treated with gemcitabine plus doxorubicin at our institution between January 2005 and September 2020. Best radiographic response and disease progression (RECIST v1.1) were assessed by a blinded radiologist.ResultsSixteen patients were included in the study. All but 1 patient (93.8%) received prior platinum-based chemotherapy. Gemcitabine was given intravenously at 900-1200 mg/m² and doxorubicin at 40-50 mg/m² intravenously every 2 weeks. Three patients (18.8%) achieved partial response and 7 (43.8%) patients achieved stable disease. The median progression-free survival was 2.8 months (95% CI, 0-6.0). Median overall survival (OS) from gemcitabine plus doxorubicin initiation was 8.1 months (95% CI, 4.6-11.7) and OS from diagnosis was 15.5 months (95% CI, 4.2-26.8 months). There were no grade ≥ 4 AEs; grade 3 AEs were cytopenias (18.8%), nausea (12.5%), fatigue (12.5%), and cardiotoxicity (6.2%). No somatic alterations were detected in the 9 patients tested by targeted next generation sequencing assays.ConclusionGemcitabine plus doxorubicin was well tolerated and demonstrated clinical activity in patients with platinum-refractory RMC, with a subset of patients experiencing durable responses lasting longer than 6 months. Further investigation is warranted to determine biomarkers of sensitivity and target mechanisms of resistance.     

A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer

BackgroundIniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine–cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.Patients and methodsPatients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m², days 1/8) and cisplatin (75 mg/m², day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.ResultsOne hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%–42.1%] with GC versus 20.0% (95% CI 11.9%–30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8–5.6) months with GC and 5.7 (95% CI 4.6–6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56–1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9–17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48–1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3–4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).ConclusionsAddition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.Trial RegistrationClinicalTrial.gov Identifier NCT01086254.     

A Randomized Phase II Study of Pemetrexed in Combination With Cisplatin or Carboplatin as First-Line Therapy for Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

BackgroundPemetrexed plus cisplatin was approved for first-line treatment of non–small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.Patients and MethodsThe patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or pemetrexed (500 mg/m²) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety.ResultsSixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]).ConclusionsBoth the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.     

Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer

Background:This phase II study was initiated to determine theefficacy and safety of gemcitabine plus cisplatin in patients with pancreaticcancer. Patients and methods:Gemcitabine 1000 mg/m² was givenon days 1, 8, and 15 of a 28-day schedule, and cisplatin 50 mg/m²on days 1 and 15 to chemonaive patients with locally advanced or metastaticpancreatic cancer. Results:Of the 41 patients enrolled (median age 57, and61% male), median Karnofsky performance status was 80%. Patientsreceived a median of 4.2 cycles (range 1–11). In 35 evaluable patients,one complete response (CR) and three partial responses (PR) were observed, foran overall response rate of 11% (95% confidence interval(95% CI): 3.2%–26.7%). Stable disease (SD) >3months occurred in 20 (57%) patients; 6 survived 1 year. Mediantime to progressive disease was 4.3 months (95% CI: 3.0–5.7months). For all patients, median survival was 8.2 months (95% CI:6.1–10.6 months) with a one-year survival rate of 27%. Therapywas well tolerated. Grade 3–4 neutropenia (no grade 3–4infection), thrombocytopenia (no bleeding), nausea/vomiting, and alopecia werereported in 29%, 13%, and 2.6% of patients, respectively. Conclusions:The combination of gemcitabine and cisplatin is amoderately active treatment for patients with locally advanced and metastaticpancreatic cancer without compromising tolerability.