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Introduction: Objective assessment of treatment effectiveness using real-world claims data is challenging. This study assessed treatment-free intervals (TFI) as a proxy for treatment effectiveness, and all-cause healthcare costs among adult patients with irritable bowel syndrome with diarrhea (IBS-D) treated with rifaximin or eluxadoline in the USA. Methods: Adult patients (18–64 years) with IBS-D and ≥ 1 rifaximin or eluxadoline prescription were identified in the IQVIA PharMetrics® Plus database (10/01/2015–12/31/2021) and classified into two mutually exclusive cohorts (i.e., rifaximin and eluxadoline). Index date was the date of rifaximin or eluxadoline initiation. Entropy-balanced baseline characteristics, TFI (periods of ≥ 30 consecutive days without IBS-D treatment), and healthcare costs were reported. Healthcare costs were compared between cohorts using mean cost differences. Results: There were 7094 and 2161 patients in the rifaximin and eluxadoline cohorts, respectively. After balancing, baseline characteristics (mean age 44.1 years; female 72.4%) were similar between cohorts. A higher proportion of patients treated with rifaximin achieved a TFI of ≥ 30 days (76.2% vs. 66.7%), ≥ 60 days (67.0% vs. 47.0%), ≥ 90 days (61.0% vs. 38.7%), ≥ 180 days (51.7% vs. 31.0%), and ≥ 240 days (47.7% vs. 27.9%) compared to eluxadoline. Among patients with a TFI ≥ 30 days, mean TFI durations were 8.3 and 6.0 months for the rifaximin and eluxadoline cohorts. Mean all-cause healthcare costs were lower for rifaximin vs. eluxadoline ($18,316 vs. $23,437; p = 0.008), primarily driven by pharmacy costs ($7348 vs. $10,250; p < 0.001). In a simulated health plan of one million commercially insured lives, initiating 50% of patients on rifaximin instead of eluxadoline resulted in total cost savings of $2.1 million per year or $0.18 per-member-per-month. Conclusions: This real-world study suggests that TFI is a meaningful surrogate measure of treatment effectiveness in IBS-D. Patients treated with rifaximin had longer treatment-free periods and lower healthcare costs than patients treated with eluxadoline. [ABSTRACT FROM AUTHOR]

Objective: Central nervous system (CNS) metastasis originating from gynecological cancer is a very rare and late manifestation of the disease. Therefore, there is still limited data on prognostic factors for survival. The objective of the present study is to identify prognostic factors for survival in patients with CNS metastasis originating from gynecological cancer. Study Design: The present retrospective study analyzed the patients with gynecological cancers who were treated due to CNS metastases between January 1999 and December 2019 at Istanbul University Hospital. Results: Forty-seven patients with CNS metastasis of gynecological origin were included in the study. The median age at the time of CNS metastasis was 59 (range 34–93). The median time from initial cancer diagnosis to CNS metastasis was 24.9 (range: 0–108.2) months. Most patients had epithelial ovarian cancer (EOC) (76.6%), followed by endometrial cancer (EC) (14.8%), cervical cancer (CC) (4.3%), and vulvar cancer (VC) (4.3%). By multivariate analysis, the presence of extracranial metastasis (HR: 5.10; 95% CI: 1.71-15.18), Eastern Cooperative Oncology Group (ECOG) performance status ≥3 (HR: 2.92; 95% CI: 1.36-6.26), palliative care only for the treatment of CNS metastasis (HR: 1.47; 95% CI: 0.58-4.11), and treatment-free interval (TFI) <6 months (HR: 2.74; 95% CI: 1.23-6.08) were independent factors that associated with worse survival. Conclusion: Patients with CNS metastasis who have favorable prognostic factors are considered to be appropriate candidates for aggressive and long-term treatment strategies. Extracranial metastasis, ECOG performance status, treatment history of CNS metastasis, and TFI were determined as independent prognostic factors that improved survival. TFI might be taken into account as a prognostic factor for patients with CNS metastasis in gynecological cancer. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of multiple myeloma (MM) is rising and there are fewer Indian studies; a comprehensive research of MM patients' survival data in a real-world population is needed. This study aims to analyze the survival status of MM patients with different treatment regimens along with its correlation to other parameters such as treatment-free interval (TFI) and time-to-next treatment (TTNT). Materials and Methods: This was a retrospective observational study, done in the department of oncology, at a tertiary care hospital in Kerala, from August 2019 to July 2020, to analyze the survival data in patients diagnosed with MM from 2015 to 2019. The effectiveness endpoints include time-to-event analyses such as TTNT and TFI. After receiving various therapy regimens, the survival rates were analyzed; the Kaplan--Meier estimator was used to determine the cumulative survival. The correlations between overall survival (OS) and duration of therapy, TFI, TTNT, and other parameters were calculated using the Karl Pearson's correlation coefficient. Results: 72 (82.80%) of the patients survived to the end of the study (OS), with a mean survival time of 4.02 ± 2.81 years. 52 (59.80%) patients had progression-free survival (PFS), while the remaining 35 (40.22%) had no significant disease prognosis. Both OS and PFS showed a significant positive correlation (P > 0.05) with TTNT and TFI. Conclusions: Completely adherent chemotherapy for 1 year can promise a survival time not <2 years. Longer TFI resulted in better OS and PFS. Extending the duration of the second LOT correlated with the better OS and PFS. [ABSTRACT FROM AUTHOR]

This study was carried out to assess the prognostic power of low CD49d expression (≥10%) in newly diagnosed CLL patients using a previously described cohort. Eighty‐five patients were included. Median age at diagnosis; 70 years (43–88); CD49d was expressed in 33/85 (38.8%); 23/33 (69.7%) at ≥30% referred to as 'HiCD49d' and 10/33 (30.3%) between 10 and 30% with a bimodal pattern on scatterplot analysis referred to as 'LoCD49d'. Eleven patients (12.9%) presented as Binet stage B, of whom 8 (72.7%) were CD49d+ (HiCD49d 7/8; LoCD49d 1/8). Seven of 81 patients (8.6%) were NOTCH1 mutated and all were CD49d+ (p ≤.01). IgVH analysis was performed on 29 (87.8%) of the CD49d+ cases, of whom 21 (72.4%) were unmutated and 8 (27.6%) were mutated. CD38+/CD49d+ accounted for 11/20 (55%) (CD38+/HiCD49D: 9/11; CD38+/LoCD49D: 2/11). At 42 months, treatment had been initiated in 18/85 (21%) patients, of these 10/33 (30.3%) were CD49d+ versus 8/52 (15.4%) of the CD49d− group. The median treatment free interval for the CD49d+ group was 11 months (HiCD49d; 14.5 months, LoCD49d; 11 months) compared to 21.5 months for the CD49d− group. These findings suggest that the predictive value of CD49d expression is retained at expression levels down to 10%. [ABSTRACT FROM AUTHOR]

Introduction: The combination of ipilimumab/nivolumab is approved for patients with treatment-naïve, intermediate-, and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of reinduction at progression is unknown. A phase II trial of intermittent ipilimumab/nivolumab with reinduction at progression was conducted (NCT03126331)., Patients and Methods: Patients with treatment-naïve mRCC were treated with induction ipilimumab/nivolumab followed by up to 24 weeks of maintenance nivolumab. Patients who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Patients were restaged every 12 weeks. Patients with no disease progression (PD) remained off therapy. Upon PD, patients were re-challenged with 2 doses of ipilimumab/nivolumab every 3 weeks. Study objectives were to estimate success rate of observation in patients who achieve a CR/PR, and to assess toxicity in patients undergoing reinduction. The study accrued slower than expected and was closed prior to the anticipated accrual goal of 20 patients., Results: Nine patients were included; 89% male, median age 57, 67% clear-cell histology, and 78% intermediate-risk by IMDC criteria. Response to ipilimumab/nivolumab followed by nivolumab maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). Two patients had PD off therapy and received 2 cycles of reinduction ipilimumab and nivolumab. No grade 3 or greater toxicities occurred with reinduction. Both patients developed PD at their first scans after reinduction., Conclusion: This prospective study demonstrates that patients with a radiographic response to ipilimumab/nivolumab can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted., Trial Registration: NCT03126331 [Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331]., Competing Interests: Disclosure MCO has served in consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, Astra-Zeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. AB receives consulting fees from EMD-Serono, Bristol Myers Squibb, Eisai; honoraria from Eisai, Natera, Aveo Pharmaceuticals; research support from Natera, Aveo, Merck, Pfizer, Rubius Therapeutics, Roche, BMS. KEB receives research funding to the institution for preclinical research from Aravive, Arsenal, BMS-LCFA-IASLC, and Pionyr; and has received consulting fees from Alpine Bioscience, Aravive, Aveo, Astrazeneca, BMS, Exelixis, Eisai, Merck, Nimbus, Seagen, Sanofi. AM receives consulting fees from AVEO; honoraria from Integrity CME, Targeted Oncology, Cleveland Clinic, Aptitude Health. SG Reports fees for consulting from Merck, BMS, Gilead, Seattle Genetics, EMD Sorono, Bayer, Foundation Medicine, Astellas; speaker's bureau fees from Gilead, Seattle Genetics, BMS; research funding to institution from Merck, Roche, Novartis, Pfizer, QED, Seattle Genetics, Acrivion, EMD Sorono, Exelixis; owns stock in BionTech, Moderna, Nektar Therapeutics. BIR declares institutional funding from Exelixis, AVEO, Genentech, BMS, Arcus, Merck, Dragonfly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics, Dracen Pharmaceuticals, Janssen, Adela, AstraZeneca, Pionyr, Tempus, VasGene Therapeutics, Gilead, POINT Biopharma, Pfizer, Daiichi Sankyo, Arrowhead Pharmaceuticals, Exelixis, Surface Oncology, and Aravive; has received consulting fees from BMS, Genentech, AVEO and Exelixis, Pfizer, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Eisai, Nikang Therapeutics, EUSA, Athenex, Debiopharm, and HiberCell., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract Background Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. Methods Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered “feasible” if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. Results Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16–53) off therapy. No patients developed RECIST PD while off therapy. Conclusions This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. Trial registration NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331).

Small cell lung cancer (SCLC) is characterized by high initial responses to platinum-based chemotherapy plus immune checkpoint inhibitors; however, most patients quickly relapse and require subsequent treatment. Second-line treatment options in SCLC remain limited, and treatment algorithms are not completely consistent across the available guidelines in this setting. This review highlights key considerations regarding selection of second-line treatment for patients with relapsed SCLC. In particular, the role of lurbinectedin, which was first approved in 2020, representing the first significant addition to treatment algorithms in this setting for decades, is summarized. Future directions, including the identification of SCLC subtypes and the need for predictive biomarkers to guide patient selection and targeted therapy, are also discussed., Competing Interests: Declaration of competing interest FB reports to be the primary investigator on the Jazz EMERGE trial and is a speaker for Jazz., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This analysis evaluated the relationship between treatment-free interval (TFI, in PALOMA-2)/disease-free interval (DFI, in PALOMA-3) and progression-free survival (PFS) and overall survival (OS, in PALOMA-3), treatment effect in patients with bone-only disease, and whether intrinsic subtype affects PFS in patients receiving palbociclib. Methods: Data were from phase 3, randomized PALOMA-2 and PALOMA-3 clinical studies of hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+ /HER2−) advanced breast cancer (ABC) patients receiving endocrine therapy plus palbociclib or placebo. Subpopulation treatment effect pattern plot (STEPP) analysis evaluated the association between DFI and PFS and OS. PFS by luminal subtype and cyclin-dependent kinase (CDK) 4/6 or endocrine pathway gene expression levels were evaluated in patients with bone-only disease; median PFS and OS were estimated by the Kaplan–Meier method. Results: Median durations of TFI were 37.1 and 30.9 months (PALOMA-2) and DFI were 49.2 and 52.0 months (PALOMA-3) in the palbociclib and placebo groups, respectively. Among the PALOMA-2 biomarker population (n = 454), 23% had bone-only disease; median PFS was longer with palbociclib versus placebo (31.3 vs 11.2 months; hazard ratio, 0.41; 95% CI 0.25‒0.69). The interaction effect of bone-only versus visceral disease subgroups on median PFS with palbociclib was not significant (P = 0.262). Among the PALOMA-3 biomarker population (n = 302), 27% had bone-only disease. STEPP analyses showed that palbociclib PFS benefit was not affected by DFI, and that palbociclib OS effect may be smaller in patients with short DFIs. Among patients who provided metastatic tumor tissues (n = 142), regardless of luminal A (hazard ratio, 0.23; 95% CI 0.11‒0.47; P = 0.0000158) or luminal B (hazard ratio, 0.26; 95% CI 0.12‒0.56; P = 0.000269) subtype, palbociclib improved PFS versus placebo. Conclusions: These findings support palbociclib plus endocrine therapy as standard of care for HR+ /HER2− ABC patients, regardless of baseline TFI/DFI or intrinsic molecular subtype, including patients with bone-only disease. Trial registration: Pfizer (clinicaltrials.gov:NCT01740427, NCT01942135). [ABSTRACT FROM AUTHOR]

Introduction: Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy. Objective: To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma. Methods: We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated. Results: Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8–107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2–7.5) months and 12.9 (95% CI, 7.8–16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1–10.5) months in the <180 days group and 16.4 (95% CI, 13.1–130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10–0.66), respectively. Conclusion: The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval. [ABSTRACT FROM AUTHOR]

Background: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. Methods: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. Results: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16--53) off therapy. No patients developed RECIST PD while off therapy. Conclusions: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. [ABSTRACT FROM AUTHOR]

Aims: The goal of this study was to analyze persistence and the treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany. Methods: Patients who received a first prescription of biological drugs between 2008 and 2016 in 21 rheumatologists in Germany were included in this study (index date). The main outcome was the rate of persistence with biological drugs as a function of the duration of the treatment-free interval used to define discontinuation. The secondary outcomes were the duration of the treatment-free interval, the probability of restarting therapy, and their respective association with age, gender, and diagnosis (i.e., rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis). Results: A total of 4925 patients were included in this study. After 5 years of follow-up, the rate of persistence was 32.6%, 51.1%, and 65.7% if discontinuation was defined as a gap of 90, 180, and 360 days respectively. The majority of patients restarted therapy between 91 and 180 days after the discontinuation date. Advanced age was associated with a decreased probability of restarting biological therapy after a treatment-free interval of at least 91 days, with odds ratios ranging from 0.34 in people aged 61–70 years to 0.66 in those aged 31–40 years (reference value: ≤ 30 years). Finally, patients over 70 and those suffering from ankylosing spondylitis had shorter treatment-free intervals compared to those 30 years or younger (adjusted difference of − 117 days) and those suffering from rheumatoid arthritis (− 48 days) respectively. Conclusion: Persistence varied widely depending on the definition of discontinuation, with the majority of nonpersistent patients restarting biological therapy shortly after discontinuation. [ABSTRACT FROM AUTHOR]

Aim: To identify patients with recurrent glioblastoma after temozolomide (TMZ) concurrent with and adjuvant to radiotherapy who could benefit from TMZ rechallenge at the time of disease progression. Methods:We retrospectively evaluated 106 glioblastoma patients who had nonprogressive disease at first magnetic resonance imaging after completion of TMZ concurrent with and adjuvant to radiotherapy, a treatment-free interval (TFI) of at least 8 weeks and received TMZ rechallenge or a nitrosourea at the time of progression. Results: In patients with TFI ≥5 months, median survival was 17.7 and 11.6 months and median progression-free survival was 8.1 and 5.8 months in the TMZ and nitrosourea group, respectively. Longer TFI was associated with reduced risk for death (p = 0.002) and for disease progression (p = 0.005). Conclusion: TFI ≥5 months represents a predictor of retained TMZ sensitivity. [ABSTRACT FROM AUTHOR]

The outcome of the 5th Ovarian Cancer Consensus Conference (OCCC) held in November 2015 in Tokyo, Japan, was the development of new and revised consensus statements to guide clinical investigations in ovarian cancer. The OCCC statements may also have direct application to daily clinical practice. This review examines the consensus statements for recurrent ovarian cancer and their impact on treatment paradigms. Importantly, patients are no longer to be categorized by the platinum-free interval (with its arbitrary 6-month cut-off points) but according to the question: 'is platinum still an option for the patient?' Another important change since the 4th OCCC in 2010 is the inclusion of BRCA mutation status when defining patient subgroups for entry into clinical trials. [ABSTRACT FROM AUTHOR]

Trabectedin + pegylated liposomal doxorubicin (PLD) offers a well tolerated and effective nonplatinum, nontaxane alternative for treatment of ovarian cancer patients with a treatment-free interval after platinum beyond 6 months, especially for those relapsing between 6 and 12 months and those who are not candidates to receive platinum-based therapy. Using the nonplatinum trabectedin + PLD combination gives patients time to recover from platinum-related toxicities and may restore platinum sensitivity in tumor cells. The sequence effect, by which intercalation of trabectedin + PLD between platinum regimens may enhance the activity of next platinum and improve survival, is currently under investigation in the Phase III prospective INternational OVArian cancer patients Trial with YONdelis. [ABSTRACT FROM AUTHOR]

Immunotherapies and targeted therapies for the treatment of metastatic or advanced melanoma produce unique patterns of antitumor response. Conventional outcome measures, such as median progression-free and overall survival, may not be ideally suited to identify all patients who derive a benefit from such therapies. Therefore, the introduction of additional endpoint measures, such as milestone comparisons, may be necessary to characterize the potential benefit of such treatment approaches. Immune checkpoint inhibitors induce durable responses in a portion of patients that may continue after treatment cessation. Measuring the associated treatment-free interval, treatment-free survival, and associated patient-reported outcomes could provide important information when implemented in prospective clinical trials. In this article, we discuss the limitations of current endpoint measures and the potential advantage of using novel endpoints and how these might be used in designing clinical trials to address critical unanswered questions for patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Objectives While primary treatment for high-grade serous ovarian cancer tends to be uniform – maximal debulking and platinum/taxane adjuvant chemotherapy – there is little standardization of treatment in the recurrent setting beyond the exhaustive use of platinum therapies. Using secondary data from multiple centers participating in the Cancer Genome Atlas study (TCGA), we seek to characterize clinical features, timing and serial response data to provide empirical evidence for treatment expectations in the recurrent setting. Methods We conducted a retrospective survival analysis of TCGA study primary and secondary patient chemotherapy regimens by characterizing the dynamics of 1119 lines of therapy comprising the treatment of 461 high-grade serous ovarian cancer patients. All patients with post-surgical drug therapy information from the TCGA database were included in this study. Results A complete response to adjuvant therapy led to longer overall survival, but did not affect treatment free intervals (TFIs) after relapse of disease. A strong predictor of the TFI on the next treatment regimen was the previous TFI with a decaying effect. The number of previous treatments, of platinum treatments, and the length of time from surgery all have an exponentially decreasing effect on TFI. Re-treatment times appear to cluster at predictable times following surgery. Conclusions While patients experience a consistent reduction in TFI with increasing re-treatment, the initial adjuvant interval is unrelated to later interval lengths. Platinum re-treatment remained an effective option in patients typically thought to be platinum resistant and the timing of monitoring visits may drive overall re-treatment patterns. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To identify prognostic factors of recurrent endometrial cancer, and clarify whether the treatment-free interval (TFI) predicts outcome in a wide spectrum of patients. Study design: The clinical data of 60 patients treated for recurrent stage I–IV endometrial cancer between 1997 and 2012 were reviewed retrospectively. The Kaplan–Meier method and Cox regression analysis were used to estimate overall survival (OS) following recurrence and determine the factors influencing outcomes. Results: The median age at initial treatment was 59 (range 38–80) years and the median post-recurrence overall survival time was 40.0 (range 1.8–156.7) months. Multivariate analysis showed lymph node metastasis (hazard ratio (HR) 2.80; 95% confidence interval (95%CI) 1.29–6.09; p =0.009), TFI (HR 0.33; 95% CI 0.15–0.76; p =0.008), and symptomatic recurrence (HR 2.31, 95% CI 1.11–4.83, p =0.0025) were independent prognostic factors. Patients whose tumors recurred after a TFI≥12 months had better response rates than did those with a TFI<12 months (p <0.001). Conclusion: TFI is a significant prognostic factor in recurrent endometrial cancer. Furthermore, the effect of chemotherapy on recurrent endometrial cancer is probably influenced by the duration of TFI. [Copyright &y& Elsevier]

The standard postoperative chemotherapy for epithelial ovarian cancer is a combination therapy including platinum and taxanes. The aim this study was to investigate the degree of platinum sensitivity in patients with relapsed epithelial ovarian cancer according to the treatment-free interval (TFI) and the histological tumor type. The medical records of 405 patients diagnosed with stage III/IV ovarian cancer, including 107 patients who relapsed after attaining a clinical complete response with first-line treatment, were retrospectively reviewed. The degree of platinum sensitivity was assessed by comparing the progression-free survival (PFS) following the second-line treatment. In patients with serous/endometrioid adenocarcinoma who were treated with platinum following relapse, there were significant differences in the PFS between the following groups of patients: those who relapsed within 6 months and those who relapsed between 6 and 12 months; those who relapsed between 6 and 12 months and those who relapsed between 12 and 18 months; and those who relapsed between 12 and 18 months and those who relapsed after 18 months. By contrast, in patients with clear cell/mucinous adenocarcinoma who were treated with platinum following a relapse, there were no significant differences in the PFS between patients who relapsed within 6 months and those who relapsed between 6 and 12 months, while there were significant differences in the PFS between those who relapsed between 6 and 12 months and those who relapsed after 12 months. With regard to the patients who relapsed after 12 months, the PFS of those with clear cell/mucinous adenocarcinoma was significantly shorter compared with the PFS of those with serous/endometrioid adenocarcinoma. Therefore, we considered it justified to classify patients with clear cell/mucinous adenocarcinoma who relapsed within 12 months as platinum-resistant and those who relapsed after 12 months as platinum-sensitive. [ABSTRACT FROM AUTHOR]

Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to investigate, in ovarian carcinoma cases, the predictive association between the treatment-free interval (TFI) after an initial paclitaxel plus carboplatin (TC) therapy and the subsequent effectiveness of a second-line taxane-containing chemotherapy. Methods: Patients with a TFI < 6 months from the first-line TC therapy were treated with a combination chemotherapy using docetaxel and irinotecan; patients with a TFI ≥ 6 months were retreated with the same regimen as the initial TC therapy. The clinical data of these patients were retrospectively analyzed for this study. Results: The response rate of those with a TFI equal to 6-12 months was greater than that of those with a TFI < 6 months ( p = 0.014) and less than that of those with a TFI > 12 months ( p = 0.012). The progression-free survival of the cases with TFI equal to 6-12 months was longer than that of those with TFI < 6 months ( p = 0.012) and shorter than that of those with TFI > 12 months ( p = 0.0011). Overall survival of cases with a TFI equal to 6-12 months was longer than that of those with TFI < 6 months ( p = 0.012) and shorter than that of those with TFI > 12 months ( p = 0.0005). Conclusions: The effectiveness of using a second-line taxane-containing chemotherapy was shown to be predictable by the TFI after the first-line taxane-containing chemotherapy, implying that the theory of 'taxane-sensitivity' may be applied for second-line chemotherapy in the same way as that of 'platinum-sensitivity'. [ABSTRACT FROM AUTHOR]

Background: While the impact of various treatments on myeloma patients' health-related quality of life (HRQL) has been reported, the impact of a treatment-free interval (TFI) is currently unclear. The aims of this study were to assess if (1) a TFI is associated with a better HRQL vs. other treatment phases and (2) the length of the TFI influences HRQL. Methods: A cross-sectional postal survey was conducted in the UK. The survey was sent to 605 multiple myeloma patients via the charity Myeloma UK and asked patients to rate their HRQL using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ-MY20 and the EQ-5D. The results were analysed using ordinary least squares regression. Results: Surveys of 402 (67 %) were returned; 370 (61 %) were considered eligible for analysis. Results demonstrated that being in a first TFI relative to other treatment phases and experiencing a longer TFI were significantly associated with better HRQL as assessed by various domains of the QLQ-C30, MY20 and EQ-5D. Conclusion: Patients enjoy better HRQL when in their first TFI, and the length of the TFI also positively impacts on HRQL This information may be important for patients and their physicians making treatment decisions and has implications for treatment protocols incorporating extended therapy. [ABSTRACT FROM AUTHOR]

Background Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer. Patients and methods Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms. Results A total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone. Conclusions The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer. [ABSTRACT FROM PUBLISHER]

Purpose: A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline. Methods: During the 2000-2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed. Results: Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ≥ or <6 months was demonstrated to be significantly associated with the response to second-line chemotherapy ( P = 0.0026), progression-free survival ( P = 0.0003) and overall survival ( P = 0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6 months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641-7.388, P = 0.0012, and 2.341, 95% CI, 1.034-5.301, P = 0.042, respectively). Conclusions: Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6 months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy. [ABSTRACT FROM AUTHOR]

ZAP-70, CD38 and IGHV mutations have all been reported to have prognostic impact in chronic lymphocytic leukemia (CLL), both individually and in paired combinations. We aimed to determine whether the combination of all three factors provided more refined prognostic information concerning the treatment-free interval (TFI) from diagnosis. ZAP-70, CD38 and IGHV mutations were evaluated in 142 patients. Combining all three factors, the ZAP-70-/CD38-/Mutated group showed the longest median TFI (62 months, n = 37), ZAP-70+/CD38+/Unmutated cases the shortest (11 months, n = 37) and cases discordant for ≥1 factor, an intermediate TFI (27 months, n = 68) (p = 0.006). Analysis of discordant cases revealed values that were otherwise masked when measuring single prognostic factors. The presence or absence of cytogenetic abnormalities did not explain the variability among discordant cases. Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Weekly paclitaxel (WP) has been reported to have significant activity in patients with ovarian and primary peritoneal cancer patients while retaining a favorable toxicity profile. This study assessed the current usage of WP in routine clinical practice in a tertiary cancer center. Methods: We conducted a retrospective audit in 53 patients with recurrent ovarian or primary peritoneal cancer treated with WP (80–100 mg/m2) over a 2-year period (Nov 2003–Nov 2005). Toxicity was assessed using Common Toxicity Criteria, and response was evaluated using radiological and CA-125 criteria. Results: Patients had a median age of 69 (36–86) and previously received a median of 3 treatments (range 1–7). A median of 13 weekly doses of paclitaxel (range 1–39) were given. The response rate was 48% by radiological criteria and 69% by CA-125 assessment. Grade 3 toxicities were fatigue (13% of patients), peripheral neuropathy (11%) and neutropenia (8%) and there were no grade 4 toxicities. The median progression-free survival was 4. 8 months and median survival was 13. 5 months. There was no significant difference in efficacy between those 24 patients previously treated with taxanes (radiol. response 43%/CA-125 response 63%) and those 29 patients who had not received prior taxanes (radiol. response 52%/CA-125 response 76%). There was also no difference in efficacy for patients with platinum-free or treatment-free intervals of less than 6 months compared to 6 months or longer. Conclusions: WP is a well tolerated and active regimen in patients with pre-treated ovarian cancer and its use in recurrent disease is likely to increase. Further studies should aim to assess the importance of the “paclitaxel-free interval” in predicting response in relapsed disease, along similar lines as are now established for platinums. [Copyright &y& Elsevier]

Background/aim: The aim of the study was to compare platinum resistance and treatment-free interval (TFI) following treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS) in women with advanced epithelial ovarian cancer (EOC)., Patients and Methods: The study included patients diagnosed with primary EOC, stage IIIC or IV, between 2005 and 2013. Patients were grouped according to first-line treatment (PDS vs. NACT-IDS). Date of second-line treatment initiation was used to evaluate platinum sensitivity., Results: The study population included 521 patients, of which 371 (71%) and 150 (29%) underwent PDS and NACT-IDS, respectively. We found no difference in platinum resistance between groups. Platinum-sensitive patients treated with NACT-IDS had a shorter median TFI (372 vs. 497 days, p=0.042). Similarly, patients with no residual tumor after IDS had a shorter median TFI (280 vs. 302 days, p=0.005)., Conclusion: NACT-IDS may shorten the TFI after first-line platinum-based chemotherapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To assess the cost-effectiveness of treatment sequences for patients with intermediate- to poor-risk advanced renal cell carcinoma. Patients & methods: A discrete event simulation model was developed to estimate patients' lifetime costs and survival. Efficacy inputs were derived from the CheckMate 214 and CheckMate 025 studies and network meta-analyses. Safety and cost data were obtained from the published literature. Results: The estimated average quality-adjusted life-years (QALYs) gained was the highest on nivolumab + ipilimumab-initiated sequences (3.6-5.3 QALYs) versus tyrosine kinase inhibitor (TKI)-initiated sequences (2.1-3.7 QALYs). Incremental cost per QALY gained for nivolumab + ipilimumab-initiated sequences was below the willingness-to-pay threshold of $150,000 versus other sequences. Conclusion: Immuno-oncology combination therapy followed by TKIs is cost-effective versus TKI sequences followed by immuno-oncology or sequencing TKIs.

The standard definition of platinum-resistant ovarian cancer or primary peritoneal carcinoma commonly includes patients whose disease initially responded to a platinum-based combination regimen, but recurred less than 6 months after the completion of primary therapy. Recent experience with several patients with these malignancies treated in the Gynecologic Cancer Program of the Cleveland Clinic Foundation, whose disease recurred within this period but who subsequently responded to platinum therapy, calls into question the validity and clinical relevance of this commonly employed definition, both for the conduct of phase 2 trials of new agents in ovarian cancer and primary peritoneal carcinoma, and for the standard management of women in this clinical setting. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions., Methods: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population., Results: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline., Conclusions: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

In this article the author examines the effectiveness of combination therapy that incorporates nonplatinum agents in the treatment of women with recurrent ovarian cancer. The author is critical that J. Sehouli and colleagues failed to report the superiority of a nonplatinum doublet based from topotecan compared with single agent. The author also suggests that treatment using a platinum-based combination should remain the established standard of care.

Objective: Treatment-free interval has been confirmed as a significant prognostic factor in recurrent gynecological cancers. However, treatment-free interval has not been evaluated in previous studies investigating brain metastasis from gynecological malignancies. The aim of the study was to establish a predictive model of survival period after brain metastasis from gynecological cancer., Methods: Of a total of 2848 patients with gynecological cancer, patients with brain metastasis were included in the study. Data at the time of brain metastasis diagnosis, which included primary origin, presence of extracranial metastasis, the Eastern Cooperative Oncology Group (ECOG) performance status, the number of brain metastases, brain-metastasis free-interval, treatment-free interval and treatment for brain metastasis were collected. Survival data were analyzed using Kaplan-Meier methods and Cox proportional hazards models., Results: Incidences of brain metastasis were 1.7% (47/2848). Median survival period after diagnosis of brain metastasis was 20 weeks (4-5 months). The 6-, 12- and 24-month survival rates after brain metastasis were 44.0%, 22.0% and 16.5%, respectively. Cox regression analysis showed that extracranial metastasis (hazard ratio [HR], 5.2; 95% confidence interval [CI]: 1.04-26.3), ECOG performance status of 3-4 (HR, 3.1; 95% CI: 1.20-7.91), treatment-free interval of <6 months (HR, 3.8; 95% CI: 1.09-13.1), and no anti-cancer treatment for brain metastasis (HR, 3.6; 95% CI: 1.34-9.41) were significantly and independently related to poor survival., Conclusion: Treatment-free interval should be assessed in a future study to verify prognostic predictors of brain metastasis from gynecological cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs). Study Design: We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC). Results: Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months). Conclusion: Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy. [Copyright &y& Elsevier]

Improvements in ovarian cancer management mean that it may now be a long-term disease for which treatment must be carefully considered. Optimal sequencing of chemotherapy may help to enhance patients'' benefit of therapy and minimize toxicity. The response to retreatment with platinum or a platinum/taxane combination is strongly influenced by the treatment-free interval after initial therapy with a platinum combination. Response rates to platinum retreatment in platinum-resistant patients (relapse within 6 months) are lower than those in platinum-sensitive patients (relapse after 6 months). Increasing the platinum-free interval by using non-platinum-based chemotherapy for treatment after relapse appears to increase the likelihood of response to later rechallenge with platinum. Many alternative agents have been investigated for the treatment of patients with relapsed ovarian cancer, including single-agent topotecan, which has been shown to achieve favorable responses. Topotecan may cause myelosuppression, which is noncumulative but tends to increase in direct correlation with the number of prior chemotherapy courses. Therefore, the best use of topotecan may be early in the course of salvage therapy. The hematologic toxicities associated with topotecan can also be reduced by adjusting the dose and schedule. Prolonged use of topotecan may be feasible and potentially beneficial in some patients. [Copyright &y& Elsevier]

The standard postoperative chemotherapy for epithelial ovarian cancer is a combination therapy including platinum and taxanes. The aim this study was to investigate the degree of platinum sensitivity in patients with relapsed epithelial ovarian cancer according to the treatment-free interval (TFI) and the histological tumor type. The medical records of 405 patients diagnosed with stage III/IV ovarian cancer, including 107 patients who relapsed after attaining a clinical complete response with first-line treatment, were retrospectively reviewed. The degree of platinum sensitivity was assessed by comparing the progression-free survival (PFS) following the second-line treatment. In patients with serous/endometrioid adenocarcinoma who were treated with platinum following relapse, there were significant differences in the PFS between the following groups of patients: those who relapsed within 6 months and those who relapsed between 6 and 12 months; those who relapsed between 6 and 12 months and those who relapsed between 12 and 18 months; and those who relapsed between 12 and 18 months and those who relapsed after 18 months. By contrast, in patients with clear cell/mucinous adenocarcinoma who were treated with platinum following a relapse, there were no significant differences in the PFS between patients who relapsed within 6 months and those who relapsed between 6 and 12 months, while there were significant differences in the PFS between those who relapsed between 6 and 12 months and those who relapsed after 12 months. With regard to the patients who relapsed after 12 months, the PFS of those with clear cell/mucinous adenocarcinoma was significantly shorter compared with the PFS of those with serous/endometrioid adenocarcinoma. Therefore, we considered it justified to classify patients with clear cell/mucinous adenocarcinoma who relapsed within 12 months as platinum-resistant and those who relapsed after 12 months as platinum-sensitive.

Objective: To analyze the efficacy and safety of combination chemotherapy of docetaxel and irinotecan for paclitaxel and carboplatin (TC) -refractory or -resistant ovarian carcinomas and for first treatment of primary clear cell and mucinous ovarian carcinomas., Study Design: Between 2002 and 2009, we conducted a prospective Phase II study of the efficacy and safety of combination chemotherapy using docetaxel and irinotecan in 62 patients with TC-refractory or -resistant ovarian carcinoma cases (GOGO-OV2) and 15 patients with primary clear cell and mucinous ovarian carcinoma cases (GOGO-OV3). The dose of docetaxel and irinotecan was determined during our previous Phase I study., Results: A docetaxel plus irinotecan regimen provided a 53% response rate, 6 months progression-free survival (PFS), and 12 months overall survival (OS) for primary clear cell and mucinous ovarian carcinomas (similar to TC therapy). The differences of anti-tumor and survival effects between refractory and resistant cases were not statistically significant. The regimen also provided a 15% response rate, 5 months PFS, and 15 months OS for TC-refractory or TC-resistant cases, when used as a second-line chemotherapy. These data are similar to previous reports, however, our study provides the first data exclusively for the cases refractory or resistant to a gold standard TC therapy as a second-line chemotherapy. The regimen was demonstrated to be well tolerable., Conclusion: Combination chemotherapy of docetaxel and irinotecan may be a useful option to treat TC-refractory/resistant cases and primary clear cell and mucinous adenocarcinoma cases of ovarian carcinoma., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)