Between-group Differences In Overall Survival Research Articles

Clinicopathological features of adult T-cell leukemia/lymphoma with T-follicular helper phenotype.

T-follicular helper (TFH) cells are effector T-cells that are crucial for B-cell selection and differentiation. T-cell lymphomas derived from TFH cells have distinct characteristics. Additionally, in the World Health Organization (WHO) classification 5th edition, three lymphomas were introduced as independent disease entities with TFH cell origin. We aimed to investigate the clinicopathological features of adult T-cell leukemia/lymphoma (ATLL) with a TFH phenotype (TFHP). We performed TFH immunohistochemistry analysis of five biomarkers for the biopsy specimen, with TFHP being indicated by a positive result for more than two markers. Among 75 cases of ATLL, 37.3% of them showed TFHP. Compared with cases of ATLL without TFHP, cases of ATLL with TFHP showed higher C-reactive protein levels (p = 0.0219) and increased high endothelial venule proliferation (p = 0.024). However, there were no significant between-group differences in overall survival as well as other clinical and morphological findings. Furthermore, there was no significant between-group difference in TFH markers and FOXP3 expression. Some patients with ATLL may present a TFHP, which should not preclude the diagnosis of ATLL. Although presenting a TFHP does not affect prognosis, it is important to identify cases of ATLL with a TFHP since it may inform future treatment strategies.

Does month of birth influence colorectal cancer prognosis?

PurposeThe main aim of this study was to identify a possible association between month of birth of colorectal cancer (CRC) patients and overall survival (OS) or disease-free survival (DFS).MethodsThis observational study included all consecutive adult patients diagnosed with CRC undergoing oncological surgery from January 2005 to December 2019 with a minimum follow-up of 10 years. The outcome variables were locoregional recurrence, death due to cancer progression, OS and DFS. Non-supervised learning techniques (K-means) were conducted to identify groups of months with similar oncologic outcomes. Finally, OS and DFS were analysed using Kaplan–Meier and Cox regression tests. The model was calibrated with resampling techniques and subsequently a cross-validation was performed.ResultsA total of 2520 patients were included. Three birth month groups with different oncologic outcomes were obtained. Survival analysis showed between-group differences in OS (p < 0.001) and DFS (p = 0.03). The multivariable Cox proportional hazards model identified the clusters obtained as independent prognostic factors for OS (p < 0.001) and DFS (p = 0.031).ConclusionThere is an association between month of birth and oncologic outcomes of CRC. Patients born in the months of January, February, June, July, October and December had better OS and DFS than those born in different months of the year.

Genomic therapy matching in rare and refractory cancers: Updated results from a retrospective cohort study in the Molecular Screening and Therapeutic (MoST) program.

1540 Background: Biomarker actionability and therapy matching are two central concepts in precision oncology. However, the best strategy to align therapy with genomic alterations remains unclear. Here we report the updated results from a cohort study conducted in an Australian precision oncology program (MoST, ACTRN12616000908437), examining a therapy matching strategy based on comprehensive genomic profiling (CGP) results. Methods: All patients (pts) with rare or advanced solid tumours undergoing CGP from 2016 to 2021 after exhausting standard treatments were included. The primary outcome was overall survival (OS) from the date of CGP result, estimated using the Kaplan-Meier method. Pts were grouped according to tiers of actionability determined by matching against the TOPOGRAPH knowledge base ( https://topograph.info ) and stratified into clinically active (Tier 1-3, therapies with evidence from prospective trials), investigational (Tier 3B and 4, therapies with evidence from another cancer type, preclinical, or retrospective studies), or unmatched tier groups. To assess between-group differences in OS, hazard ratios (HR) were estimated in a time-varying Cox regression model adjusting for time to initiation of subsequent therapy. Results: This updated analysis included 3,383 pts (79% rare and less common). The median follow-up was 22.6 months (mo). For 2,065 pts who did not receive treatment after CGP, the median OS (mOS) was 8.2 mo (95% CI 7.4 to 9.0). For 1,318 pts who received ≥1 line of therapy after CGP, the mOS was 14.1 mo (13.4 to 15.2). 1,270 pts (38%) carried a genomic alteration linked to clinically active therapies (Tier 1-3). Of these, 116 (3.4%) received matched treatment after CGP, experiencing longer survival compared with 410 (32.2%) that received only unmatched therapy (mOS 21.2 v 12.8 mo, HR 0.58, 0.45 to 0.76, P&lt;0.001). Whilst receiving a matched therapy in the investigational tier group (n=133, T3B/4) did not show significant differences in outcomes (mOS 14.5 v unmatched 12.8 mo, n=536, HR 0.88, 0.72 to 1.08, p=0.24), exploratory analyses identified differences in survival for a subset of 41 pts with Switch/Sucrose Non-Fermentable complex mutations receiving matched Tier 4 therapies (mOS 30.1 v 9.6 mo, HR 0.29, 0.17 to 0.51, P&lt;0.0001). Pts receiving repurposed drugs that matched solely on biomarkers in non-cognate cancer types (Tier 3B) showed no survival difference over unmatched therapy (n=35 v 469, mOS 13.6 v 12.5 mo, HR 0.96, 0.65 to 1.41, p=0.83). Conclusions: This study provides insight into how biomarker-linked therapies can be rationally prioritised in rare and advanced cancer populations. Addressing the barriers of access to Tier 1-3 therapies may broaden the utility of genomic biomarker testing. Off-label drug repurposing without direct supporting evidence should only be undertaken in a clinical trial setting.

Prognostic impact of lymphovascular and perineural invasion in squamous cell carcinoma of the tongue

This study aimed to investigate the prognostic impact of lymphovascular and perineural invasions in patients with squamous cell carcinoma of the tongue who received surgery-based treatment at our institution between January 2013 and December 2020. Patients were divided into four groups based on the presence of perineural (P−/P +) and lymphovascular invasions (V−/V +): P–V−, P–V + , P + V−, and P + V + . Log-rank and Cox proportional hazard models were used to evaluate the association between perineural /lymphovascular invasion and overall survival (OS). Altogether, 127 patients were included, and 95 (74.8%), 8 (6.3%), 18 (14.2%), and 6 (4.7%) cases were classified as P–V−, P–V + , P + V−, and P + V + , respectively. Pathologic N stage (pN stage), tumor stage, histological grade, lymphovascular invasion, perineural invasion, and postoperative radiotherapy were significantly associated with OS (p < 0.05). OS was significantly different among the four groups (p < 0.05). Significant between-group differences in OS were detected for node-positive (p < 0.05) and stage III–IV (p < 0.05) cases. OS was the worst in the P + V + group. Lymphovascular and perineural invasions are independent negative prognostic factors for squamous cell carcinoma of the tongue. Patients with lymphovascular and/or perineural invasion may have significantly poorer overall survival than those without neurovascular involvement.

Real-World Efficacy of Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer.

BackgroundBevacizumab in combination with chemotherapy prolonged the progression-free survival (PFS) of patients with recurrent epithelial ovarian cancer (EOC) in large-scale randomized controlled trials. However, real-world data for the use of bevacizumab in Asian patients with EOC is lacking. This study investigated the efficacy of adding bevacizumab to chemotherapy and compared it with that of chemotherapy alone in patients with recurrent EOC using real-world data from an Asian population.MethodWe conducted a retrospective cohort study using data from a tertiary medical center in central Taiwan. Patients who had EOC with first relapse between 2011 and 2019 were enrolled. Patients’ medical histories, medication treatment, and relevant information were collected. The outcomes were PFS and overall survival (OS). The Kaplan-Meier plot was used to generate a survival curve for OS and PFS. Cox proportional hazard analysis was used to determine the associations of Bevacizumab treatment with OS and PFS with adjustment of relevant variables. Subgroup analyses were conducted to determine if there was a significant variation in the aforementioned associations.ResultsAfter a median follow-up of 23 months, 67% of patients in the Bevacizumab group and 81% of patients in the non-Bevacizumab group had disease progression or death. There was no significant between-group difference in OS (p = 0.475). The median duration of PFS was 18.9 and 9.6 months, respectively, favoring those who were treated with Bevacizumab. After multivariate adjustment, treatment with Bevacizumab was associated with a lower risk of disease progression (hazard ratio 0.33, 95% CI 0.13-0.85, p = 0.021). The improvement in PFS was consistent in the subgroups of different histological types, different disease stages at diagnosis, different treatment-free intervals, those undergoing or not undergoing secondary cytoreductive surgery, diverse chemotherapy regimens.ConclusionOur findings provided crucial insights into the efficacy of bevacizumab for the treatment of recurrent EOC in the real-world setting.

Comparisons of Modified Post-Transplantation Cyclophosphamide and Granulocyte Colony-Stimulating Factor/Antithymocyte Globulin Regimens for Haploidentical Stem Cell Transplantation in Patients with Aplastic Anemia

Haploidentical stem cell transplantation (HSCT) has become an alternative treatment option for patients with aplastic anemia (AA) without matched sibling donors or matched unrelated donors. Recently, post-transplantation cyclophosphamide (PTCy) and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimens have become the most common protocols used worldwide. In this retrospective study, we retrospectively reviewed and analyzed the clinical data of 130 AA patients who underwent haploidentical HSCT and received the modified PTCy (mPTCy) regimen (n=55) or G-CSF/ATG regimen (n=75) between January 2013 and June 2021 across 7 transplantation centers. Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCy group was 96.36% (95% confidence interval [CI], 94.57 to 97.57; P=.010). The median time to neutrophil engraftment in the G-CSF/ATG group was 10 days (range, 7 to 28 days), which was more rapid than that observed in the mPTCy group (P < .001). There was no significant difference in the incidence of graft-versus-host disease (GVHD) between the 2 groups. The cumulative incidence of grade II-IV acute GVHD was 18.40% (95% CI, 4.27% to 40.31%) in the mPTCy group and 19.32% (95% CI, 5.86% to 38.58%) in the G-CSF/ATG group, whereas the cumulative incidence of grade III-IV acute GVHD was 7.31% (95% CI, .09% to 37.48%) in the mPTCy group and 7.57% (95% CI, .20 to 34.19) in the G-CSF/ATG group. Similarly, there were no significant between-group differences in overall survival (OS), failure-free survival (FFS), and GVHD-free relapse-free survival (GRFS). The 2-year OS, FFS, and GRFS rates were 95.91% (95% CI, 84.59% to 98.96%), 92.25% (95% CI, 80.59% to 97.03%), and 86.68% (95% CI, 73.98% to 93.44%), respectively, in the mPTCy group and 86.67% (95% CI, 76.64% to 92.59%), 81.28% (95% CI, 70.45% to 88.46%), and 77.20% (95% CI, 65.89% to 85.16%), respectively, in the G-CSF/ATG group. Transplantation-related mortality (TRM) was significantly higher in the G-CSG/ATG group than in the mPTCy group (13.33% versus 1.96%; P=.022). In multivariate analysis, the use of a female donor, a higher Hematopoietic Cell Transplantation Comorbidity Index, and grade III-IV acute GVHD were associated with worse survival outcomes. The mPTCy and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCy regimen.

Safety and Feasibility of Minimally Invasive (Laparoscopic/Robotic-Assisted) Nipple-Sparing Mastectomy Combined with Prosthesis Breast Reconstruction in Breast Cancer: A Single-Center Retrospective Study.

Minimally invasive (robotic or laparoscopic-assisted) nipple-sparing mastectomy combined with prosthesis breast reconstruction (NSM-PBR) is associated with smaller scars and greater patient satisfaction. However, the oncological safety of minimally invasive NSM-PBR remains controversial. This was a retrospective study of patients with breast cancer who underwent breast reconstruction between 1 January 2006 and 20 February 2021. Demographic and clinicopathological characteristics, operation information, postoperative complications, and survival outcomes were analyzed. In all, 292 patients underwent minimally invasive NSM-PBR and 205 underwent open NSM-PBR for breast cancer. In the minimally invasive NSM-PBR group, 268 (91.8%) patients underwent laparoscopy and 24 (8.2%) patients underwent robot-assisted NSM-PBR. Mean operation time in the minimally invasive NSM-PBR group was significantly longer than that in the open NSM-PBR group (P = 0.023). Mean intraoperative blood loss was significantly less in the minimally invasive NSM-PBR group (P < 0.05). There was no significant between-group difference in total complications. Similarly, there were no significant between-group differences in overall survival, recurrence-free survival, and local recurrence rate (P = 0.450, P = 0.613, and P = 0.679, respectively). The complication, recurrence, and mortality rates in minimally invasive NSM-PBR group were comparable to those in open NSM-PBR group. Our preliminary results are encouraging and suggest that minimally invasive NSM-PBR affords good cosmetic results and its oncological safety is comparable to that of open surgery.

Development and validation of a nomogram for predicting survival in patients with surgically resected lung invasive mucinous adenocarcinoma.

BackgroundLung invasive mucinous adenocarcinoma (LIMA) is a unique and rare subtype of lung adenocarcinoma. We identified prognostic factors and developed a nomogram for predicting overall survival (OS) in LIMA patients after surgery.MethodsPatients diagnosed with LIMA between 2008 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database were randomized into training (n=1,254) and test (n=538) cohorts. A nomogram was established using the prognostic signature from the training cohort after multivariable Cox regression analysis. We externally validated the nomogram in a group of 369 patients from China. We separately tested for accuracy and clinical practicability using Harrell’s concordance-index (C-index), calibration plots, and decision curve analysis (DCA).ResultsWe included 2,161 patients in the analysis. Seven factors, all of which significantly affected OS, were incorporated into the final model, including age, sex, differentiation grade, the extent of surgery, lymphadenectomy, and T, N, and M stage. C-indexes for the training, test, and external validation cohorts were 0.735, 0.736, and 0.773, respectively. The areas under the time-dependent receiver operating characteristic curves at five years were 0.747, 0.798, and 0.777, respectively. The nomogram was discriminative and well-calibrated when applied to the test and external validation cohorts. Significant between-group differences in OS were observed when classifying groups by nomogram score (log-rank P<0.001). An online web server for clinical use was developed using the nomogram.ConclusionsThe nomogram facilitates accurate prediction of survival for patients with LIMA and can be used to stratify clinical risk groups for individualized treatment.

Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan-Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4-6 cycles of taxane plus platinum adjuvant chemotherapy. Eighty-nine and 138 patients received ≤ 3 and 4-6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4-6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518-2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619-2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

The role of pre-treatment and mid-treatment 18F-FDG PET/CT imaging in evaluating prognosis of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)

BackgroundIt has been reported the prognostic value of MTV in predicting the disease prognosis of peripheral T-cell lymphoma (PTCL) through pre-treatment PET/CT imaging. However, these are limited data on pretreatment evaluation and prognosis assessments of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). This study aimed to determine the prognostic values of pre-treatment and mid-treatment total metabolic tumor volume (MTV), total lesion glycolysis (TLG), and Deauville 5-Point Scale (D-5PS) in accessing the prognosis of PTCL-NOS.MethodsA retrospective analysis was conducted in 31 patients with pathologically diagnosed PTCL-NOS. These patients have undergone positron emission PET/CT scanning before and during chemotherapy. Follow-ups were also done to investigate the 2-year progression-free survival (PFS) and Overall Survival (OS) of these patients. During {}^{18}F-fluorodeoxyglucose ({}^{18}F-FDG) PET/CT scans, the MTV and TLG were recorded. Meanwhile, bigtriangleupMTV and bigtriangleupTLG were calculated. Furthermore, the receiver operating characteristic (ROC) curve was employed to classify and to define the threshold values. On the other hand, the mid-chemotherapy assessment and staging of these 31 patients were done by utilizing D-5PS. Subsequently, based on the D-5PS scores obtained, these patients were grouped into two categories: a group of patients with a score of <4 and another group with ge4 points. For these two groups of patients, the survival analysis was done by Kaplan–Meier analysis and a multivariate COX regression model. Moreover, Pearson’s chi-square test (chi ^{2} test) and Spearman rank correlation coefficient were used to comparing the collected data, respectively.ResultsDuring the 2-year follow-up period, 15 out of the 31 patients experienced disease progression. The optimal threshold values for both baseline MTV and TLG were 158.16 cm^{3} and 677.40.Additionally, the difference in 2-year PFS between the progressive and non-progressive groups was statistically significant (chi ^{2}=8.193, P=0.004<0.05; chi ^{2}=8.872, P=0.003<0.05), significant between-group difference was detected for MTV and for TLG (chi ^{2}=6.494, P=0.011<0.05; chi ^{2}=4.687, P=0.03<0.05). On the other hand, when these patients were classified into two groups according to the mid-chemotherapy Deauville score of <4 and ge4, the statistical difference of 2-year PFS between these two groups was significant, too (chi ^{2}=14.966, P=0.001<0.05),but there is no significant between-group difference in OS (chi ^{2}=3.337, P=0.068<0.05). COX analysis revealed that D-5PS are the independent factors influencing PFS, while MTV is the independent influencing factor of OS.ConclusionThe baseline total MTV obtained by PET/CT scanning, and D-5PS are crucial prognostic factors in evaluating the prognosis of PTCL-NOS.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

IntroductionThe number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer.MethodsData from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity.ResultsThe mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7).ConclusionsThis retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Hematopoietic Cell Transplantation Outcomes among Medicaid and Privately Insured Patients with Sickle Cell Disease

Compared with privately insured patients, recipients of Medicaid have been reported to have worse outcomes in several clinical conditions and following various surgical and medical procedures. However, the relationship between health insurance status and allogeneic hematopoietic cell transplantation (alloHCT) outcomes among patients with sickle cell disease (SCD) is not well described. We sought to compare alloHCT outcomes between patients with SCD who underwent alloHCT while enrolled on Medicaid versus those who underwent alloHCT while covered by private health insurance. We conducted a retrospective multicenter study using data reported to the Center for International Blood and Marrow Transplant Research. US patients enrolled on Medicaid or private insurance who underwent a first alloHCT for SCD between 2008 and 2018 were eligible for this study. The primary outcome was event-free survival (EFS), defined as time to death or graft failure. Secondary outcomes included overall survival (OS), graft failure, acute graft-versus-host disease (GVHD), and chronic GVHD. Univariate analysis was performed using the Kaplan-Meier method for EFS and OS. The proportion of patients with graft failure, acute GVHD, and/or chronic GVHD was calculated using the cumulative incidence estimator to accommodate competing risks (ie, death). Cox regression was used to identify factors associated with EFS, OS, graft failure, and acute and chronic GVHD. A total of 399 patients (Medicaid, n=225; private insurance, n=174) were included in this study. The median duration of follow-up was 34 months (range, 1.0 to 134.7 months) for the Medicaid group and 38.7 months (range, 0.3 to 139.3 months) for the private insurance group. Compared with the patients with private insurance, those on Medicaid had a significantly lower 3-year EFS (75.4% [95% confidence interval (CI), 69.4% to 81%] versus 82.2% [95% CI, 76.9% to 87.8%]; P=.0279) and a significantly higher 3-year cumulative incidence of graft failure (17.2% [95% CI, 12.5% to 22.5%] versus 10.5% [95% CI, 6.4% to 15.4%]; P=.0372). There were no significant between-group differences in 3-year OS (P=.6337) or in the cumulative incidence of acute GVHD (P=.4556) or chronic GVHD (P=.6878). Cox regression analysis after adjusting for other significant variables showed that the patients enrolled on Medicaid had a lower EFS (hazard ratio [HR], 2.36; 95% CI, 1.44 to 3.85; P=.0006) and a higher cumulative incidence of graft failure (HR, 2.57; 95% CI, 1.43 to 4.60; P=.0015), with no significant between-group differences in OS (HR, 0.99; 95% CI, 0.47 to 2.07; P=.9765), acute GVHD (HR, 0.94; 95% CI, 0.59 to 1.49; P=.7905), or cGVHD (HR, 0.98; 95% CI, 0.65 to 1.48; P=.9331). That EFS is worse in patients on Medicaid compared with privately insured individuals following alloHCT for SCD provides the rationale for research to better understand the mechanisms by which insurance status impacts alloHCT outcomes among patients with SCD.

Randomized trial of oral cyclophosphamide versus oral cyclophosphamide with celecoxib for recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer

BackgroundOral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. MethodsWe conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. ResultsIn Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84–13.18] vs. 12.55 months [6.67–17.61]) or in median time to treatment failure (1.84 months [1.68–2.76] vs. 1.92 months [1.64–5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. ConclusionsOral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

BackgroundThe oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. Patients and methodsIn this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). ResultsBetween March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. ConclusionsFinal results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

Systematic review of bladder cancer outcomes in patients with spina bifida

In patients with congenital bladder anomalies, bladder augmentation is used as a last resort to reduce intravesical pressure, but concerns about malignant transformation in augmented patients were first raised in the 1980s. The best evidence to date indicates that augmentation does not appear to increase the risk of bladder cancer in spina bifida patients. To date, oncologic outcomes from patients with spina bifida with and without augmentation have only been available in small case reports. To systematically evaluate factors in myelomeningocele patients with bladder cancer, including bladder augmentation, that contribute to overall survival (OS). A systematic review using PubMed was conducted by cross referencing terms 'myelomeningocele,' 'cystoplasty,' 'bladder cancer' and respective synonyms according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Inclusion criteria were studies with patients with an underlying diagnosis of myelomeningocele and bladder cancer with data on age, stage, and mortality status. Studies were excluded for spinal cord injury, history of tuberculosis or schistosomiasis, or prior ureterosigmoidostomy. Fifty-two patients were identified from 28 studies with a median age at bladder cancer diagnosis of 41 years (range 13-73); 37 (71%) presented with stage III or IV bladder cancer. Overall survival at 1 year and 2 years was 48.5% and 31.5%, respectively. Overall survival was different between those with and without augmentation (P=0.009) by log-rank analysis. No between-group differences in OS were seen based on age, management with indwelling catheter, diversion with ileal conduit or being on a surveillance program. Only stage remained a significant predictor of OS on multivariate analysis (HR 2.011, 95% CI 1.063-3.804, P=0.032). Secondary analysis was performed after removing patients with gastric augmentation (n=8), and no difference in OS was seen between patients with (n=8) and without augmentation (n=36, P=0.112). Of augmented patients, latency to development of bladder cancer was variable (SummaryFigure). Bladder cancer is a deadly diagnosis in patients with congenital bladder anomalies like spina bifida, and while overall prevalence of the two conditions occurring together is low, bladder cancer will go on to affect 2-4% of spina bifida patients. The present study examined overall survival, and further characterized outcomes in these patients. Presence of a bladder augment did not appear to worsen overall survival. Patients with myelomeningocele who developed bladder cancer had aggressive disease. Augmentation did not worsen OS, based on cases reported in the literature. Risk of bladder cancer should be discussed with all myelomeningocele patients.

Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma

To compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) ≤5cm with Child-Pugh A cirrhosis. This retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias. There was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group. For patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive.

Acute Myeloid Leukemia Patients with Pre-Transplant Ablated Marrows Have Similar Rates of Survival and Relapse Compared to Patients in Complete Remission after Allogeneic Hematopoietic Cell Transplantation

Introduction:Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Patients not in remission prior to undergoing allo-HCT continue to have a very poor prognosis. Complete remission with incomplete cell count recovery (CRi) following chemotherapy for acute myeloid leukemia (AML) has also been associated with reduced overall survival and increased risk of relapse. However, there is currently a paucity of data on transplant outcomes in AML patients with ablated marrows after prior chemotherapy. In these patients, waiting for count recovery for an extended time period leads to increased infectious complications, often making them ineligible for allo-HCT. We hypothesized that outcomes of AML patients with pre-transplant ablated marrows who undergo allo-HCT would be similar to those of patients who are in complete remission (CR) prior to allo-HCT. To answer this question, we retrospectively analyzed the outcomes of AML patients from a single institution who underwent allo-HCT in CR, CRi, or with an ablated marrow.Patient and methods:For this retrospective study, we analyzed the outcomes of 270 AML patients (median age 54 years, range 17 to 74 years, 146 males and 124 females) who underwent 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at Washington University School of Medicine in St. Louis between 2006 and 2013. Patients with persistent disease based on bone marrow biopsy immediately prior to transplant were excluded. Data was collected on baseline characteristics including patient and donor sex, AML type, induction therapy, conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prophylaxis. Based on their cell count and marrow recovery prior to allo-HCT, patients were divided into 3 categories: CR, CRi, and ablated marrow, using response criteria from the International Working Group. The primary outcomes were overall survival (OS) and disease-free survival (DFS), and the secondary outcomes were cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse, acute graft vs. host disease (aGVHD), and chronic graft vs. host disease (cGVHD). Propensity-score matching was used to adjust for potential confounding effects of patient characteristics, and the between-group differences in OS or DFS were compared by Cox proportional hazards model.Results:Of the 270 patients, 206 were in CR, 45 in CRi, and 19 had ablated marrow prior to their allo-HCT. Median follow-up for the CR, CRi, and ablated groups were 524, 410, and 290 days, respectively. The patients with ablated marrows had a 3-year OS of 47% and DFS of 40%, as compared to patients in CR whose 3-year OS and DFS were 49% and 45%, respectively (Fig. 1). Using a 1:3 propensity-score matching (3 CR per 1 ablated), no significant differences were found in OS (HR=1.66, 95% CI 0.88-3.12; P = 0.12) or DFS (HR=1.39, 95% CI 0.75 - 2.58; P = 0.30). The cumulative incidence of NRM in our ablated marrow cohort was 58%, significantly higher than those in CR and CRi who had cumulative incidences of NRM of 22% (P = 0.0004) and 16% (P = 0.002), respectively (Fig. 2). The cumulative incidence of grade 2-4 aGVHD in patients with CR, CRi, and ablated marrow, were 38%, 38%, and 42%, respectively (P = 0.93). Likewise, the cumulative incidence of cGVHD in patients with CR, CRi, and ablated marrow, were 34%, 38%, and 16%, respectively (P = 0.22).Conclusions:Allo-HCT continues to be the curative therapy for patients with AML. Based on our results, overall survival and disease-free survival following transplant for patients with ablated marrows do not differ significantly from those in CR or CRi. Interestingly, there was a higher incidence of non-relapse mortality among patient with ablated marrows compared to those in Cr or CRi, which is most likely related to the use of myeloablative conditioning regimen in our ablated patients. These results could have an important bearing on patients with ablated marrows whom treating physicians might post-pone allo-HCT to wait for marrow recovery, thereby potentially putting them at increased risk for infectious and bleeding complications. Smaller cohort size is the major limitation of our study, and our results suggest investigating this important question in a large registry. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combination Chemotherapy in Advanced Adrenocortical Carcinoma

BackgroundAdrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.MethodsWe randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.ResultsFor first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP–mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.ConclusionsRates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.)

Spotlight on Histamine Dihydrochloride in Acute Myeloid Leukaemia†

Histamine dihydrochloride (Ceplene®) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer (NK) cells. When given in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and NK cells by IL-2, resulting in the killing of cancer cells, including those of acute myeloid leukaemia (AML). In a large, 3-year, randomized, open-label, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than patients receiving no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were of grade 1 or 2 severity. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients (who represent the majority of AML patients), histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission.

Histamine Dihydrochloride

Histamine dihydrochloride (Ceplene) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer cells. When administered in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and natural killer cells by IL-2, resulting in the killing of tumour cells of various cancers, including acute myeloid leukaemia (AML). In a 3-year, randomized, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than recipients of no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were grade 1 or 2 of the National Cancer Institute Common Toxicity Criteria. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients, histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission.