Months For Best Supportive Care Research Articles

Real-World Treatment Patterns and Clinical Outcomes in Canadian Patients with AML Unfit for First-Line Intensive Chemotherapy.

Acute myeloid leukemia (AML) is a hematological malignancy that predominantly affects the elderly. Prognosis declines with age. For those who cannot tolerate intensive chemotherapy, historically established treatment options have been hypomethylating agents (HMAs), low dose cytarabine (LDAC), and best supportive care (BSC). As the standard of care evolves for those unfit for intensive chemotherapy, there is a need to understand established treatment pathways, clinical outcomes and healthcare resource utilization in Canada. The CURRENT study was a retrospective chart review of AML patients not eligible for intensive chemotherapy who initiated first-line treatment between 1 January 2015 and 31 December 2018. Data were collected from 170 Canadian patients treated at six hematology centers, of whom 118 received systemic therapy and 52 received BSC as first-line treatment. Median overall survival was 8.58 months and varied from 2.96 months for BSC to 13.31 months for HMAs. Over 80% of patients had at least one outpatient visit, and 67% of patients receiving systemic therapy and 71% of those receiving BSC had at least one admission to hospital, during their first line of therapy. A total of 96 (81.4%) patients receiving first line systemic therapy and 39 (75.0%) of those receiving first line BSC had at least one red blood cell or platelet transfusion. These findings highlight the unmet need for novel therapies for patients ineligible for intensive chemotherapy.

P-44 Impact of regorafenib dose optimization on clinical outcomes compared to best supportive care and TAS-102 in the treatment of relapsed/refractory metastatic colorectal cancer

In a randomized controlled trial (RCT) ReDOS of relapsed/refractory metastatic colorectal cancer (mCRC) patients, regorafenib dose optimization (rego 80+), starting at 80 mg/day with 40 mg weekly increments to the standard dose of 160 mg/day, was found to improve tolerability and clinical outcomes compared to regorafenib at standard dose (rego 160), 160 mg/day for 21 days of a 28-day cycle. This network meta-analysis (NMA) aims to further investigate the impact of rego 80+ on efficacy and safety compared to best supportive care (BSC) and trifluridine/tipiracil (TAS-102). RCTs included in the NMA were identified via a systematic literature review conducted in April 2021. A feasibility assessment was performed to ensure that the included trials did not differ significantly with respect to treatment effect modifiers. Bayesian fixed effect NMAs were performed to simultaneously synthesize hazard ratios (HRs) for overall survival (OS) and progression-free survival (PSF) and odds ratios for safety endpoints of interest, and their respective 95% credible intervals (Crl). The HRs from the NMA were applied to the rego 80+ OS and PFS Kaplan Meier Curves from the ReDOS trial to estimate predicted median OS and PFS for each treatment. Three global or US-only RCTs (ReDOS, CORRECT, RECOURSE) and three Asian-only RCTs (TERRA, Yoshino 2012, and CONCUR) were included in the NMA. When all trials were analyzed, rego 80+ was associated with statistically significant improvements in OS and PFS vs. BSC (HR [95% CrI]: 0.49 [0.33, 0.73] and 0.35 [0.24, 0.53], respectively) and numerically favorable improvements in OS and PFS vs. rego 160 (0.72 [0.49, 1.05] and 0.84 [0.56,1.25]), and TAS-102 (0.71 [0.47, 1.08] and 0.78 [0.52, 1.18]). Median OS (95% confidence interval [CI]) was estimated to be 9.8 (7.5, 11.9) months for rego 80+, 7.5 (4.6, 11.9) months for rego 160, 7.5 (4.4, 11.9) months for TAS-102, and 6.4 (2.5, 10.3) months for BSC. Median PFS (95% CI) was 2.80 (2.0, 2.5) months for rego 80+, 2.07 (1.89, 5.85) months for rego 160, 1.98 (1.8, 5.76) months for TAS-102, and 1.89 (1.17, 2.16) months for BSC. For grade 3+ adverse events (AEs), BSC was the most favorable, with the exception of increased aspartate transaminase (AST). Compared to rego 160, rego 80+ was numerically favorable in all AEs analyzed including hand-foot skin reactions (HSFR), diarrhea, fatigue, hypertension, and increased AST. Compared to TAS-102, rego 80+ had higher incidence of HSFR, comparable fatigue and hypertension, and numerically lower incidence of diarrhea, increased AST, neutropenia, febrile neutropenia, leukopenia, and anemia. All NMA findings were consistent when Asian-only trials were excluded from the analyses. Findings from this NMA indicate that rego 80+ provides additional survival benefits (over standard dose rego 160) when compared to BSC and TAS-102; with gains of median OS of 3.4 months (∼50% risk reduction), and 2.3 months (∼30% risk reduction), respectively. Results also suggest that rego 80+ delays disease progression in comparison. With its more favorable safety profile, rego 80+ should be considered a preferred option for optimizing clinical outcomes in patients with relapsed/refractory mCRC.

Effects of liver metastases on efficacy of immune checkpoint blockade in treatment refractory, metastatic colorectal cancer (CRC): CCTG CO.26.

3600 Background: Immune checkpoint blockade has limited activity in microsatellite-stable (MSS) or mis-match repair proficient (pMMR) CRC. Recent findings suggest that immunotherapy efficacy may be modulated by the presence of liver metastases. We conducted a retrospective analysis of the Canadian Cancer Trials Group (CCTG) CO.26 study to investigate the relationship between the presence of liver metastases and activity of immune checkpoint blockade. Methods: The CCTG CO.26 study was a randomized phase II study (NCT02870920). Pts with treatment refractory CRC were randomized to durvalumab, tremelimumab and best supportive care (BSC) or BSC alone in a 2:1 fashion. Treatment consisted of durvalumab (1500 mg) q 28 days and tremelimumab (75 mg) q 28 days for the first 4 cycles. The primary endpoint was overall survival (OS) and a two-sided p-value <0.10 was considered significant. Results: Between 08/20106-06/2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced between groups. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 months and 1.9 months respectively (HR 1.01, 90% CI: 0.76 – 1.34). Disease control rate (DCR) was 22.6% for durvalumab and tremelimumab and 6.6% for BSC (p = 0.006). At study entry, liver metastases were absent in 29.4% pts. Pts without liver metastases had improved OS compared to those with liver metastases, irrespective of treatments. PFS was significantly longer in those without liver metastases on durvalumab and tremelimumab (HR: 0.55, 90% CI: 0.31 – 0.97, p = 0.08, interaction p = 0.02). DCR was 49% in patients without liver metastases with durvalumab and tremelimumab, compared to 10% in those with liver metastases (Odds Ratio: 0.12, 90% CI: 0.05 – 0.26). Conclusions: Pts without liver metastases had improved OS and PFS, and higher DCR. Absence of liver metastases may be an indicator for improved efficacy of immune checkpoint blockade and should be investigated in future studies. [Table: see text]

A Population-based Study of Treatment Patterns and Survival of Patients With De Novo Stage IV Non-Small Cell Lung Cancer.

Treatment strategies for metastatic non-small cell lung cancer (NSCLC) are evolving rapidly and can be highly variable. Real-world evidence of treatment patterns and outcomes can provide an understanding of our current practice and offer insights on ways to incorporate emerging therapies into our treatment paradigm. In this population-based study, we investigated treatments and outcomes of stage IV NSCLC patients from a large Canadian province. Patients diagnosed with de novo stage IV NSCLC from April 1, 2010 to March 31, 2015 were identified. Data for baseline characteristics, treatments, and outcomes were obtained from provincial data sources, including the cancer registry and electronic medical records. We classified systemic treatments as chemotherapy, targeted therapy (anti-epidermal growth factor receptor, and anti-anaplastic lymphoma kinase) and immunotherapy (checkpoint inhibitors) and characterized clinical outcomes by treatment type. A total of 6438 patients were identified with NSCLC, of whom 3606 (56%) had de novo stage IV disease. The median age of diagnosis was 69 (range: 20 to 100) years and 52.4% were men. First-line palliative treatments included: chemotherapy in 19.5% (n=703), targeted agents in 5.7% (n=204), immunotherapy in 1% (n=1), radiotherapy in 6.8% (n=246), and best supportive care in 74.8% (n=2,698). Median overall survival (mOS) from diagnosis for the whole cohort was 3.8 months. Within subgroups, mOS was 18.0 months for targeted therapies, 9.4 months for chemotherapy, and 2.5 months for best supportive care. Only 1.0% of patients (n=34) received immunotherapy at any line. Survival benefit was dependent on type of treatment received, with significantly better mOS observed with the use of small-molecule targeted therapy against epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements, as compared with best supportive care.

Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non–Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial

BackgroundWe evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non–small-cell lung cancer. Patients and MethodsPatients with treatment-naive squamous non–small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). ResultsOverall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator’s discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). ConclusionsThe results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.

Cytoreductive nephrectomy in metastatic renal cell carcinoma: outcome of patients treated with a multidisciplinary, algorithm-driven approach.

Metastatic renal cell carcinoma (mRCC) represents a significant and rising burden of disease, with rapidly evolving treatment modalities. The role of cytoreductive nephrectomy (CN) is controversial in this setting. As such, London Cancer has pursued a multidisciplinary team (MDT) approach when assessing suitability for surgery. A retrospective analysis of treatment-naive synchronous mRCC patients, managed via a renal-specialist MDT, was conducted between January 2015 and December 2018. An MDT selection algorithm for CN-using theInternational Metastatic Renal Cell Carcinoma Database Consortium score (IMDC), performance status and metastatic disease burden-was developed. 87 treatment-naive synchronous mRCC patients received either CN (n = 18), Systemic therapy (ST) alone (n = 43) or Best supportive care (BSC) (n = 26). Progression free survival (PFS) and overall survival (OS) were assessed. 51% and 39% were IMDC intermediate and poor risk. Median PFS was 28.6months and 4.5months in the CN group and ST alone group, respectively, Hazard Ratio for death was 3.63 [(95% CI 1.68-7.83) p < 0.05]. OS remains immature for the CN group, but a median OS of 12.8months was observed in the ST group and 5.0months for BSC. 1-year OS rate for CN, ST and BSC groups was 77.8%, 55.8% and 23.10%, respectively. Thesefindingsdescribe outcomes of an unselected series of patients treated via an MDT-driven, protocolised treatment pathway. MDT pathway-based decision making may improve patient selection for CN. Further research is needed to evaluate the role of CN amongst a growing landscape of treatment strategies, including immune checkpoint inhibitors and combination therapies. Multi-disciplinary team, pathway-based treatment strategy may improve patient selection for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma.

PB1728 CLINICAL CHARACTERISTICS AND THERAPEUTIC RESULTS OF PRIMARY REFRACTORY ACUTE MYELOID LEUKEMIA IN OLDER PATIENTS. A STUDY ON 118 CONSECUTIVE PATIENTS.

Background:There is no universally agreed definition of primary refractory acute myeloid leukemia (AML) and optimal treatment modalities are still ill defined, particularly in older patient population.Aims:We describe clinical characteristics and therapeutic results from a series of 118 consecutive elderly patients with AML classified as primary refractory on the basis of achievement of less than partial response according to ELN criteria following administration of intensive induction chemotherapy aimed at complete remission (CR) achievement.Methods:There were 72 males and 46 females, with a median age of 68 years (range: 61‐79). In 40patients (34%), a previously diagnosed myelodysplastic syndrome preceded the onset of AML. Sixty‐six patients (56%) had adverse karyotype, 52 normal (43%) and 1 (1%) AML with t(8;21) translocation. In the group with normal karyotype, 38 patients were classified as intermediate and 14 as adverse risk category according to European LeukemiaNet criteria. Induction treatment included anthracyclines and cytarabine in 74 cases, and fludarabine based regimens in the remaining 44. In all patients, more than 50 % of blasts were found at bone marrow evaluation after induction. Subsequent therapy included salvage intensive chemotherapy (ISC) based on intermediate‐high dose cytarabine in 74 patients (63%), hypomethylating agents (HMAs) in 26 (22%), 22 azacitidine and 4 decitabine, and best supportive care (BSC) in 18 (15%). Therapeutic choice was mainly based on eligibility to allogeneic stem cell transplantation (SCT), ECOG performance status, logistic reasons and personal physician attitude.Results:Following intensive salvage chemotherapy, CR was achieved in 28 patients out of 74 intensively treated (38%) and 16 of them did actually receive SCT. No CR was observed with HMAs, but 2 patients had a reduction of bone marrow blasts at less than 10 % and received SCT. The median survival for the whole patient population was 7.7 months and there were no significant difference according to different treatments (9 months for ISC, 8 for HMAs and 5 months for BSC, p.0.3). The outcome was also similar for patients with normal karyotype (8 months) vs unfavorable karyotype (7 months),p:0.23 and patients with previous MDS (7 months) vs. de novo AML (8 months), p:0.43. Achievement of CR and SCT were the only factors significantly related to a better outcome in univariate and multivariate analysis (median survival for patients achieving CR or not: 18 months vs 7 months, respectively, p: &lt; 0.001; 18 months for allografted patients vs. 6 for not allografted, p:0.001).Summary/Conclusion:We conclude that primary refractory AML in older patients is characterized by an extremely poor outcome; SCT represents the only chance for long‐term survival and ISC should be considered only in transplant eligible patients (figure). HMAs represent a reasonable option and, occasionally, a bridge to SCT. The possibility of administration of new molecularly targeted new agents is expected to lead to significant improvement of clinical outcome in this prognostic adverse patient category.image

Randomized phase 3 study of maintenance therapy with S-1 plus best supportive care (BSC) versus BSC alone after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell lung carcinoma (WJOG7512L).

e20531 Background: Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however. Methods: WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival. Results: Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC ( n = 67) or BSC alone ( n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference ( P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients. Conclusions: Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC. Clinical trial information: UMIN000010396.

452P - Pemetrexed versus best supportive care following platinum-based doublet chemotherapy for patients with advanced nonsmall cell nonsquamous lung cancer

Background: From very beginning optimal treatment strategy for advanced disease ca lung (Stage IIIB or IV) was, four to six cycles platinum based combined (doublet) regimen then observation and subsequently administration of second line chemotherapy with the progression of disease. Maintenance therapy in ca lung is a latest growing idea, improving quality of life. The advantage of using switch maintenance therapy over continuation therapy that a valuable number of tumor cells responds to different active agent when resistant to the first-line treatment. On the basis of this, we conducted a reterospectivev study compare pemetrexed versus best supportive care (BSC) as switch maintenance therapy. Methods: Between July 2012 and January 2014, newly diagnosed patients with Stage IIIB/IV NSCLC (nonsquamous) received six cycles of carboplatin AUC 6 or 7 (day1) and paclitaxel (175 mg/m2 day 1) every 3 weeks, nonprogressores and patients with stable disease were randomized 1:1 to receive maintenance pemetrexed 500 mg/m2 IV infusion over 10 minutes on day 1 of each 21-day cycle or BSC alone untill progression of disease. Vitamin B12, Folic acid and dexamethasone added to pemetrexed according to standard protocol. The primary endpoint was a comparison of overall survival (OS) between pemetrexed and BSC group, and the secondary endpoint was progression-free survival (PFS). Results: Initially total of 128 patients were enrolled in this study. Patients characteristics were as follows (stage IV disease 54%, ECOG performance status 0-1: 71.2s%, median age 54 years, male 81%,). These all patients received 6 cycles of initial therap. Further 71.09% (91 patients) nonprogessors randomly distributed for Pemetrexed (n = 46) and BSC group (n = 45). The median OS for Pemetrexed group was 13.2 months and 10.6 months for BSC, with a hazard ratio (HR) 0.77 (95% CI: 0.61–0.93, P = 0.003). The median PFS was 6.4 months for pemetrexed versus 4.8 months for BSC, with a HR 0.66 (95% CI: 0.48–0.84, P = 0.007). Hematological toxicities were the main toxicities specially grade 3/4 neutropenia and anemia Conclusions: Switch maintenance therapy with Pemetrexed, after doublet chemotherapy specially platinum based in advanced nonsquamous NSCLC has produced appreciable longer OS and PFS compared to BSC alone at the cost of higher grade 3/4 hematological toxicities. Legal entity responsible for the study: sp medical college radiotherapy department bikaner rajasthan Funding: None Disclosure: All authors have declared no conflicts of interest.

Outcomes after the diagnosis of brain metastases in Brazilian NSCLC patients.

e20568 Background: Brain metastases (BM) are common and affects near half of patients with non-small-cell lung cancer (NSCLC), with poor prognosis. Few data is available about this group of patients and Brazilian are underrepresented. Methods: Patients with NSCLC that developed BM between January 05 and December 15 at Hospital de Clinicas de Porto Alegre were identified and medical records were reviewed. OS and PFS were estimated by Kaplan-Meier curves. Multivariate analysis was performed to identify factors associated with survival. Statistical analysis was performed with SPSS 22.0. Results: 113 patients were identified. Mean age was 60.1 ± 8.7 years, 50% were female, 84% were Caucasian, 87% had a positive smoking history, 71% had adenocarcinoma histology and 72% had stage IV disease at presentation. BM was present at initial diagnosis in 38% of patients. At diagnosis of BM, 39% of patients had a Karnofsky performance status &lt; 70, 20% had systemic disease under control, 31% had more than 3 brain lesions and 81% had a GPA score ≤2. 35 patients (31%) were submitted to either surgery or stereotaxic radiotherapy (SRDT), 52 (46%) to whole brain radiation (WBRT) and 26 (23%) to best supportive care (BSC). With a median follow-up of 11.2 months, 96% of patients have died. The OS was 11.2 months (95% IC, 9.4 to 13.1). The median survival time following diagnosis of BM was 4.9 months and survival according to treatment was 16.3 months for resection, 8.9 months for SRDT, 3.8 months for WBRT and 0.7 months for BSC. A Karnofsky performance status &lt; 70 at diagnosis of BM and palliative treatment to BM (WBRT or BSC) were associated with worse outcome in multivariate analysis. The GPA score wasn't statically associated with prognosis. A longer survival of patients submitted to WBRT was seen when compare to BSC, HR of 0.38. There is a trend for longer survival in patients submitted to BM resection when compared to SRDT, but without statically significance. Conclusions: To our knowledge this is the largest report of NSCLC patients with BM from Latin America. Our data is in line with previous reports. A poor Karnofsky performance status and palliative treatment to BM are associated with poor survival. WBRT is associated with longer survival when compared to BSC in all the GPA score stratus.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009. Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma. The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016;122:2206-15. © 2016 American Cancer Society.

Impact of rechallenge with imatinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib and sunitinib.

Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patient's choice after discussion with his or her physician. The primary endpoint was overall survival, and secondary endpoints were time to treatment failure, clinical response rate assessed by Choi criteria, and safety. Results. Fourteen patients were treated with imatinib plus BSC and 12 received BSC alone. Median overall survival was greatly improved for the imatinib group, although differences were not significant (22 months for imatinib plus BSC versus 4 months for BSC; P = 0.058). Three patients (21%) had a clinical response in the imatinib group, and one had a clinical response in the BSC alone group. Imatinib was well tolerated. Conclusions. Rechallenge with imatinib may be associated with improvement in overall survival without deteriorating performance status in patients who failed imatinib and sunitinib. A prospective study should be considered to confirm the efficacy of rechallenge with imatinib.

Tolerance and benefits of treatment for elderly patients with limited small-cell lung cancer

Over 20% of all newly diagnosed Dutch patients with small-cell lung cancer (SCLC) are aged ≥75 years. Uncertainties still exist about safety and efficacy of chemotherapy and chemoradiation in elderly patients. We evaluated the association between patient characteristics and (completion of) treatment and also evaluated toxicity, response and survival in elderly patients with SCLC. Population-based data from patients aged 75 years or older and diagnosed with limited SCLC in 1997-2004 in The Netherlands were used (N = 368). Additional data on co-morbidity, motive for deviating from guidelines, grades 3-5 toxicity, response and survival were gathered from medical records. Although only relatively fit elderly were selected for chemotherapy, almost 70% developed toxicity, leading to early termination of chemotherapy in over half of all patients. Median survival time was 6.7 months, but differed strongly according to type and completion of treatment (13.5 months for chemoradiation, 7.1 months for chemotherapy, 2.9 months for best supportive care, 11.5 months for patients receiving at least 4 cycles of chemotherapy and 3.6 months for less than 4 cycles). Although toxicity rate was high and many patients could not complete the full chemotherapy, those who received chemotherapy or chemoradiation had a significantly better survival. We hypothesize that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm.

Maintenance erlotinib in advanced nonsmall cell lung cancer: cost-effectiveness in EGFR wild-type across Europe

BackgroundFirst-line maintenance erlotinib in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) has demonstrated significant overall survival and progression-free survival benefits compared with best supportive care plus placebo, irrespective of epidermal growth factor receptor (EGFR) status (SATURN trial). The cost-effectiveness of first-line maintenance erlotinib in the overall SATURN population has been assessed and published recently, but analyses according to EGFR mutation status have not been performed yet, which was the rationale for assessing the cost-effectiveness of first-line maintenance erlotinib specifically in EGFR wild-type metastatic NSCLC.MethodsThe incremental cost per life-year gained of first-line maintenance erlotinib compared with best supportive care in patients with EGFR wild-type stable metastatic NSCLC was assessed for five European countries (the United Kingdom, Germany, France, Spain, and Italy) with an area-under-the-curve model consisting of three health states (progression-free survival, progressive disease, death). Log-logistic survival functions were fitted to Phase III patient-level data (SATURN) to model progression-free survival and overall survival. The first-line maintenance erlotinib therapy cost (modeled for time to treatment cessation), medication cost in later lines, and cost for the treatment of adverse events were included. Deterministic and probabilistic sensitivity analyses using Monte Carlo simulation (1000 iterations) were performed.ResultsAccording to the model simulations, first-line maintenance erlotinib compared with best supportive care in EGFR wild-type stable metastatic NSCLC resulted in 4.57 months of life gained (17.82 months for erlotinib versus 13.24 months for best supportive care) and 1.14 months of life without progression gained (erlotinib 4.29 versus best supportive care 3.15), and incremental total costs of erlotinib from €7897 (UK) to €9580 (Germany). The corresponding mean incremental cost per life-year gained of erlotinib ranged between €20,711 (UK) and €25,124 (Germany). Sensitivity analyses confirmed these results.ConclusionFirst-line erlotinib maintenance treatment is cost-effective compared with best supportive care in EGFR wild-type stable metastatic NSCLC, irrespective of the country setting.

Stage III Non–Small-Cell Lung Cancer: Population-Based Patterns of Treatment in British Columbia, Canada

Management of Stage III non-small-cell lung cancer (NSCLC) involves surgery, radiotherapy (RT), chemotherapy, and best supportive care. The aims were to describe the patterns of treatment in a population-based cohort of patients, and compare utilization of RT and chemotherapy to model estimates of need. Patients diagnosed with Stage III NSCLC between January 1, 2000, to December 31, 2007, were identified from the British Columbia Cancer Agency database. Patients who had prior or concomitant malignancy were excluded. Patient demographics, tumor characteristics, and initial treatment were extracted. Survival data were derived from the British Columbia Vital Statistics Death Listings. 2365 patients with Stage III NSCLC were referred, of which 212 patients were excluded, leaving 2153 patients in the study population. Median age was 69 years. Disease stage was IIIA in 49% and IIIB in 51%. Histologies were squamous-cell carcinoma (31%), adenocarcinoma (27%), NSCLC not otherwise specified (31%), and other pathology (11%). Initial treatment included surgery in 12%, RT in 78%, and chemotherapy in 31%. Predicted RT utilization was 77% to 87% and chemotherapy 78%. From 2000 to 2007, curative-intent treatment increased from 21% to 35%, chemoradiotherapy from 8% to 18.6%, and concurrent chemoradiotherapy from 5.1% to 17.6%. Median survival was 30 months for patients who had curative surgery, 21 months for curative RT, 8 months for palliative treatment, and 5 months for best supportive care (p < 0.001). RT utilization was similar to that predicted by models whereas chemotherapy utilization was less. During the study period, the proportion of patients receiving curative chemoradiotherapy doubled and of those receiving concurrent chemoradiotherapy trebled.

BEVATEM: Phase II single-center study of bevacizumab in combination with temozolomide in patients (pts) with first-line metastatic uveal melanoma (MUM): First-step results.

8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.

5-Azacytidine Versus Intensive Chemotherapy or BSC in Elderly (>60 years) Acute Myeloid Leukemia Patients. A Retrospective Analysis

Abstract 2612 BACKGROUND:5-Azacytidine (AZA) has proven to prolong overall survival (OS) in higher-risk MDS patients and elderly patients with WHO-defined AML and low bone marrow blast count (20–30%) compared to conventional care regimens. These exciting results have prompted us to seek the potential role of AZA on the treatment of elderly (> 60 years) patients with AML compared to best-supportive care (BSC) or intensive chemotherapy (ICT). PATIENTS & METHODS:We have performed a retrospective analysis in 182 elderly AML patients, median age: 70y (60–84). Out of them, 67 patients from 9 Spanish centers diagnosed between Jan/07 to Feb/11 and not eligible for ICT, received 5-AZA as first line therapy by compassionate use. AZA was administered subcutaneously (75–100 mg/m2/d) for 7 days of every 28d. Patients received a median of 6 AZA cycles (1–24). For comparisons, historical cohort (N= 115) diagnosed at same period from University Hospital Reina Sofia was used. Among them, 68 patients unfit for ICT had received only BSC consisting on oral chemotherapy agents, blood product transfusions and antibiotics with granulocyte colony-stimulating factor for neutropenic infection. In this historical cohort 47 patients had received ICT consisted of induction with cytarabine (100–200 mg/m2/d by continuous infusion) for 7 days plus idarubicin (9–12 mg/m2/d) for 3 days followed by Autologous (N=9) or Allogeneic (N=4) Transplant. Outcome measures were performed according to the International Working Group criteria (AML-IWG-2006). RESULTS:Clinical characteristics of patients are detailed in Table 1. Meaningfully, patients in ICT group were significantly younger than those in BSC or AZA arms and also had significantly better ECOG scores. By contrast, patients in AZA group had significantly lower WBC and bone marrow blast count than those receiving ICT. There were not statistical differences in the presence of MDS features or gender distribution (M/F) comparing three arms. Most importantly the percentage of patients with intermediate-adverse cytogenetics was comparable between three arms.Median follow-up for surviving patients from the start of therapy was 5, 13 and 7.4 months for BSC, ICT and AZA groups respectively. The 12 months Overall Survival (OS) was 9%, 52% and 43% for BSC, ICT and AZA groups respectively. The 2y-OS was 0%, 20% and 18% for BSC, ICT and AZA groups respectively. Median OS months for BSC were 2.03 whereas for ICT and AZA groups were significantly longer: 11.2 and 13.7 respectively (Figure 1). We found statistical differences when comparing OS in BSC group with either ICT or AZA, but there was not statistical differences comparing ICT with AZA groups (p=0,75, HR=0,13; 95% CI=0,2–1,2). In multivariable Cox regression analysis, considering variables such as cytogenetic risk group, % BM Blasts and type of treatment AZA vs ICT, only high ECOG scores (p=0,01, HR=2,76; 95% CI=1,2–6) were associated with inferior survival. CONCLUSIONS:These retrospective data suggest that AZA can be an effective alternative option for elderly AML patients unfit for ICT. In our experience, these patients can achieve comparable OS at 2 years than those suitable for ICT, although ECOG score remained the most independent significant variable impacting on outcome. There is a need for prospective clinical trials in order to determine the place of this approach within the growing therapeutic opportunities for elderly patients with AML.Table 1:Clinical characteristics of 182 elderly AML patients.BSC N=68Intensive CT N=475-AZA N=67PMedian age, y (Range)76 (62–89)65 (60–75)*71 (60–84)*0.04 <0,01*Sex (M/F)37/3130/1748/190.11Median leucocyte count x109/L (range)17.6 (0.4–211)28.6 (0.8–166)*4.4 (0.2–17.5)*0.01 <0,01*Median BM Blasts count (%) (range)47 (21–90)64 (24–93)34 (20–84)0.003 <0,01*ECOG ≥ 260 (88%)7 (15%)45 (67%)<0.01 <0,01*Cytogenetic Risk*, N (%)0.67Intermediate39 (57.3)32 (68)46 (68.6)0.86*Adverse12 (17.6)12 (25.5)15 (22.3)NT1736MDS features, N (%)37 (54.4)21 (44.6)34 (50.7)0.16Patients alive, N (%)10 (14.7)9 (19.1)26 (38.8)0.004 0,06*Median,follow-up of survivors, months5 (0–10)13 (2–46)7.4 (1–28,3)0.03 0,06*Median Overall Survival, months2,0311,2*13,7*<0.001 0,75*OS at 1 year9%52%*43%*<0.001 0,75*OS at 2 years0%20%*18%* [Display omitted] Disclosures:Off Label Use: Azacitidine in AML.

A multicenter, randomized phase III trial comparing second-line chemotherapy (SLC) plus best supportive care (BSC) with BSC alone for pretreated advanced gastric cancer (AGC).

4004 Background: Currently no evidence that SLC in AGC patients will result in substantial prolongation of survival when compared to BSC exists, and there is potential for toxicity from the treatment. The efficacy and safety of SLC using either single-agent docetaxel or irinotecan was evaluated in a randomized phase III trial. Methods: Two-hundreds two patients with AGC, one or two prior chemotherapy regimen(s) involving both fluoropyrimidines and platinum, and an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned 2:1 to SLC or BSC. Choice of SLC, either docetaxel 60 mg/m2 every 3 weeks or irinotecan 150 mg/m2 every 2 weeks, was left to the discretion of investigators. Randomization was stratified by PS and the number of prior chemotherapy. All patients received standard BSC regimen a priori defined in the study protocol. Primary endpoint was the overall survival (OS). Results: Between Sep 2008 and Sep 2010, 193 eligible patients, 74% with one prior chemotherapy and 54% with PS 0, were enrolled: SLC (n=128) or BSC (n=65). SLC was generally well tolerated, with all-cause deaths within 30 days of random assignment of 3% and 4%, respectively, on SLC and BSC arm. As of current analysis, 128 (66%) patients died. In the intent-to-treat population, a significant difference in OS (5.1 months for SLC v 3.8 months for BSC) was observed (hazard ratio, 0.63; 95% confidence interval, 0.47-0.86; P=0.004). The OS benefit for SLC was relevant in most of the prospectively defined subgroups including age, gender, PS, number of prior treatments, number of metastatic sites, hemoglobin levels, and response to prior chemotherapy. Significantly more patients on SLC arm received further salvage chemotherapy than those on BSC arm (40% v 22%, respectively; P=0.011). Conclusions: This is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

Vinflunine

Vinflunine is a novel bifluorinated vinca alkaloid that appears to differ from other class members in terms of its tubulin-binding properties and inhibitory effects on microtubule dynamics. Notably, it demonstrated superior in vivo antitumour activity to that of vinorelbine in a range of transplantable murine and human tumours. In a randomized, open-label, multicentre phase III trial in adult patients with advanced transitional cell carcinoma of the urothelium who experienced progression after first-line platinum-containing chemotherapy (n = 370), median overall survival (OS; primary endpoint) was 6.9 months for intravenous vinflunine plus best supportive care (BSC) recipients versus 4.6 months for BSC alone recipients in the intent to treat (ITT) population. The difference in OS between treatment groups was not significant in the ITT population; however, there was a significant improvement in OS for vinflunine plus BSC recipients in the ITT population after adjusting for prespecified prognostic factors, and in the analysis of the eligible population (ITT population excluding baseline protocol violations). In the latter, median OS was 6.9 months with vinflunine plus BSC versus 4.3 months with BSC alone after a median follow-up of approximately 1.8 years and again after a median follow-up of approximately 3.6 years. Progression-free survival, objective response rate and disease control rate were significantly improved with vinflunine plus BSC versus BSC alone. The most frequent treatment-related adverse events in vinflunine recipients included myelosuppression (e.g. neutropenia) and gastrointestinal symptoms (e.g. constipation). In general, adverse events with vinflunine were noncumulative and medically manageable.

Phase III Trial of Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract

Vinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen. The study was designed to compare overall survival (OS) between patients receiving VFL + BSC (performance status [PS] = 0: 320 mg/m(2), every 3 weeks; PS = 0 with previous pelvic radiation and PS = 1: 280 mg/m(2) subsequently escalated to 320 mg/m(2)) or BSC. Three hundred seventy patients were randomly assigned (VFL + BSC, n =253; BSC, n = 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL + BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL + BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P = .287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P = .036), reducing the death risk by 23% (HR = 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n = 357), the median OS was significantly longer for VFL + BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P = .040). Overall response rate, disease control, and progression-free survival were all statistically significant favoring VFL + BSC (P = .006, P = .002, and P = .001, respectively). VFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy.