Background
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype‐specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus ...dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first‐line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC‐STBSG) sites.
Methods
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression‐free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval‐censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
Results
Three hundred three patients from 18 EORTC‐STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score–matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval CI, 5.2‐9.7 months), 8.2 months (95% CI, 5.2‐10.1 months), and 4.8 months (95% CI, 2.3‐6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio HR, 0.72; 95% CI, 0.52‐0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9‐47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7‐33.4 months; HR, 0.65; 95% CI, 0.40‐1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0‐36.3 months; HR, 0.66; 95% CI, 0.43‐0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
Conclusions
This is the largest retrospective study of first‐line treatment for advanced leiomyosarcoma. In the propensity score–matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
In this propensity score‐adjusted, multi‐institutional series, doxorubicin and dacarbazine show better outcomes for the first‐line treatment of advanced leiomyosarcoma and warrant further studies. This series represents a benchmark for the future development of trials for leiomyosarcoma.
SummaryBackgroundDesmoid tumours are locally aggressive tumours associated with substantial morbidity. No systemic treatments are approved for this disease, with methotrexate–vinblastine the only ...chemotherapy regimen assessed in a clinical trial setting to date. VEGF overexpression is a common feature in aggressive desmoid tumours. Pazopanib is an oral antiangiogenic agent targeting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor-like protein (PDGFR) α and β, and c-KIT tyrosine kinases. We aimed to assess antitumour activity and safety of targeted therapy or combination chemotherapy in progressive desmoid tumours. MethodsDESMOPAZ was a non-comparative, randomised, open-label, phase 2 trial conducted at 12 centres from the French Sarcoma Group. We enrolled adults (≥18 years) with progressive desmoid tumours, normal organ function and centrally documented progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 based on two imaging assessments obtained within less than a 6-month interval. Participants were randomly assigned (2:1) to oral pazopanib 800 mg per day for up to 1 year or to an intravenous regimen combining vinblastine (5 mg/m 2 per dose) and methotrexate (30 mg/m 2 per dose), administered weekly for 6 months and then every other week for 6 months. Randomisation was stratified according to inclusion centre and tumour location. The primary endpoint was the proportion of patients who had not progressed at 6 months in the first 43 patients who had received one complete or two incomplete cycles of pazopanib. This endpoint was also assessed as a prespecified exploratory endpoint in all patients who had received one complete or two incomplete cycles of methotrexate–vinblastane. Safety analyses were done for all patients who received at least one dose of allocated treatment. This trial was registered with ClinicalTrials.gov, number NCT01876082. FindingsFrom Dec 4, 2012, to Aug 18, 2017, 72 patients were enrolled and randomly assigned (n=48 in the pazopanib group; n=24 in the methotrexate–vinblastine group). Median follow-up was 23·4 months (IQR 17·1–25·5). 46 patients in the pazopanib group and 20 patients in the methotrexate–vinblastine group were assessable for activity. In the first 43 patients assessable for the primary endpoint in the pazopanib group, the proportion of patients who had not progressed at 6 months was 83·7% (95% CI 69·3–93·2). The proportion of patients treated with methotrexate–vinblastine who had not progressed at 6 months was 45·0% (95% CI 23·1–68·5). The most common grade 3 or 4 adverse events in the pazopanib group were hypertension (n=10, 21%) and diarrhoea (n=7, 15%) and in the methotrexate–vinblastine group were neutropenia (n=10, 45%) and liver transaminitis (n=4, 18%). 11 patients (23%) had at least one serious adverse event related to study treatment in the pazopanib group, as did and six patients (27%) in the methotrexate–vinblastine group. InterpretationPazopanib has clinical activity in patients with progressive desmoid tumours and could be a valid treatment option in this rare and disabling disease. FundingGlaxoSmithKline and Novartis.
The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that ...included paclitaxel had greater antitumor activity and might improve survival.
We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.
From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio HR, 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001).
The addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.
Summary Background Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the ...humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com , number BO17705E. Findings 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52–0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 12% patients in the bevacizumab group vs 25 8% in the control group) and asthenia (34 10% vs 20 7%). Interpretation The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.
Summary Background Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve ...progression-free survival for patients with germ-cell tumours. Methods In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin 20 mg/m2 per day for 5 days, etoposide 100 mg/m2 per day for 5 days, and intramuscular or intravenous bleomycin 30 mg per day on days 1, 8, and 15), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18–21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m2 over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m2 over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m2 over 2 h on day 1), intravenous ifosfamide (2 g/m2 over 3 h on days 10, 12, and 14), plus mesna (500 mg/m2 at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10–14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov , number NCT00104676. Findings Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49–68) in the Unfav-dose-dense group versus 48% (38–59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44–1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57–81) in the Fav-BEP group (HR 0·66, 95% CI 0·49–0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (seven 7% vs one 1%) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1–2 febrile neutropenia (18 17% vs 18 18%) or toxic deaths (one 1% in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Interpretation Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Funding Institut National du Cancer (Programme Hospitalier de Recherche Clinique).
Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of ...colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis.
In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial.
Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3–97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders n=1, pruritus and toxidermia n=1, diarrhoea n=1, increased γ-glutamyl transferase concentration n=1, anorexia n=1, and increased headache n=1). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour n=1 and pilonidal cyst excision n=1).
More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted.
Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.
The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma.
Thirty patients were entered onto the ...study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles.
The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities.
Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
Summary Background Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or ...additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. Methods TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov , number NCT00619268. Findings Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29·5% (26 of 88 patients, 95% CI 20·0–39·1) in group A, 35·7% (15 of 42, 21·2–50·2) in group B, and 61·0% (25 of 41, 46·0–75·9) in group C. Median PFS was 8·2 months (95% CI 7·0–9·6) in group A, 8·2 months (5·5–11·7) in group B, and 16·8 months (6·0–26·0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. Interpretation The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. Funding French Ministry of Health and Wyeth Pharmaceuticals.
Summary Background The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is ...unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial. Methods In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle—ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov , number NCT00367861. Findings 434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33–38) after random assignment, 2-year progression-free survival was 80% (95% CI 58–91) in the continuation group and 16% (5–33) in the interruption group (p<0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups. Interpretation Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects. Funding Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.
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