The NEO‐CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight‐cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above‐mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met.Background.This multicenter, open‐label study (NEO‐CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer.Methods.Patients aged 18–75 years with histologically‐confirmed gastric adenocarcinoma (stage T2–4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3‐week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2–4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited.Results.Fifty‐five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent‐to‐treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow‐up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression‐free survival was 20.10 (95% confidence interval: 4.31—35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty‐four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3–4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles).Conclusion.These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late‐stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.
AbstractBackground.RAS testing is used to select patients with anti‐epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p‐IGF‐1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti‐EGFR resistance.Materials and Methods.We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12‐months progression‐free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild‐type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first‐line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12‐month PFS based on the analysis of clinical and selected biomarkers (α = .05, β = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves.Results.We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left‐sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60–0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61–0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61–0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58–0.73, p = .09).Conclusion.The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12‐month PFS.Implications for Practice.This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.
AbstractBackground.The effectiveness and cost‐effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost‐effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM).Materials and Methods.We performed a decision‐analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease‐free survival, quality‐adjusted life‐years (QALYs), cost in U.S. dollars, and cost‐effectiveness expressed as an incremental cost‐effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions.Results.Model results found median overall survival (34.5/28.0/22.0 months) and disease‐free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life‐years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost‐effective 92.4% of the time at a willingness‐to‐pay threshold of $100,000/QALY.Conclusion.Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost‐effectiveness standpoint. Additional clinical data that further define the long‐term effectiveness of nFOLFIRINOX are needed to confirm our results.Implications for Practice.Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision‐analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality‐adjusted life years, overall survival, and incremental cost‐effectiveness ratio.
AbstractBackground.The Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale is commonly used by physicians and nurses in oncology, as it correlates with cancer morbidity, mortality, and complications from chemotherapy and can help direct clinical decisions and prognostication. This retrospective cohort study aimed to identify whether ECOG‐PS scores rated by oncologist versus nurses differ in their ability to predict clinical outcomes.Materials and Methods.Over 19 months, 32 oncologists and 41 chemotherapy nurses from a single academic comprehensive cancer center independently scored ECOG‐PS (range: 0–5) for a random sample of 311 patients with cancer receiving chemotherapy. Logistic regression models were fit to evaluate the ability of nurse and physician ECOG‐PS scores, as well as the nurse‐physician ECOG‐PS score difference (nurse minus physician), to predict the occurrence of chemotherapy toxicity (CTCAE v4, grade ≥3) and hospitalizations within 1 month from ECOG‐PS ratings, as well as 6‐month mortality or hospice referrals.Results.Physician/nurse ECOG‐PS agreement was 71% (Cohen's κ = 0.486, p < .0001). Nurse ECOG‐PS scores had stronger odds ratio for 6‐month mortality or hospice (odds ratio [OR], 3.29, p < .0001) than physician ECOG‐PS scores (OR, 2.71, p = .001). Furthermore, ECOG‐PS ratings by nurses, but not physicians, correlated with 1‐month chemotherapy toxicity (OR, 1.44, p = .021) and 1‐month hospitalizations (OR, 1.57, p = .041). Nurse‐physician disagreement, but only when physicians gave “healthier” (lower) ratings, was also associated with worse outcomes (chemotherapy toxicity OR = 1.51, p = .045; 1‐month hospitalization OR, 1.86, p = .037; 6‐month mortality or hospice OR, 2.99, p < .0001).Conclusion.Nurse ECOG‐PS ratings seem more predictive of important outcomes than those of physicians, and physician‐nurse disagreement in ECOG‐PS ratings predicts worse outcomes; scoring by nurses may result in additional clinical benefit.Implications for Practice.Nurse‐rated Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scores, compared with those rated by oncologists, better predicted hospitalizations and severe chemotherapy toxicity within 1 month from ECOG‐PS assessment, as well as mortality or hospice referrals within 6 months. Physician‐nurse disagreement in ECOG‐PS scoring was associated with worse hospitalization, chemotherapy toxicity, and mortality and hospice referral rates. Rating performance statuses of patients with cancer by nurses instead or in addition to oncologists can result in additional clinical benefits, such as improved prognostication, as well as better informed clinical decision making regarding whether or not to administer chemotherapy, the need for additional supportive care, and goals of care discussions.
AbstractBackground.A standard approach to treating resectable esophageal adenocarcinoma is chemoradiotherapy (CRT) followed by surgery; however, recurrence is common. To improve this, we designed a single‐arm, phase II trial that added an epidermal growth factor receptor (EGFR) inhibitor, cetuximab (C), to CRT, with the hypothesis that EGFR inhibition would improve pathologic complete response (pCR) rate.Materials and Methods.We aimed to increase the pCR rate from 25% to 45%. A Simon two‐stage design (α and β of 0.10) required pCR/enrolled 5/18 for stage 1 and 14/40 total. CRT: oxaliplatin 85 mg/m2 days 1, 15, and 29; infusional 5‐fluorouracil 180 mg/m2/24 hours × 35 days; C 400 mg/m2 day 1 then 250 mg/m2 days 8, 15, 22, and 29 and radiation (intensity modulated radiotherapy [IMRT] allowed) 180 cGy/day × 25 fractions (Monday through Friday). Following esophagectomy, adjuvant chemotherapy (CT): weekly docetaxel 35 mg/m2 and C 250 mg/m2 5 out of 6 weeks for two cycles.Results.Of 21 eligible patients enrolled, 17 had surgery; 4 died before operation (due to pulmonary embolism 4 days after CRT, G3 diarrhea, progressive disease during CRT, sepsis/hypoxia during CRT, and acute respiratory distress syndrome [ARDS]). pCR = 7/17. Three postoperative deaths due to ARDS resulted in seven total study‐related deaths. Of the 14 remaining patients, 12 started and completed adjuvant CT. Two of seven patients with pCR died, both of ARDS. Out of the 21 eligible subjects in this study, 13 have died and 8 remain alive. The use of IMRT did not correlate with ARDS.Conclusion.This regimen demonstrated promising activity. Toxicity was significant, with seven study‐related deaths leading to closure after stage 1. All postoperative deaths were due to ARDS. This regimen is not recommended.Implications for Practice.Esophageal cancer is a disease with a high death rate. The current treatment involves giving chemotherapy plus radiation followed by surgery, but this cures only a quarter of patients. In order to improve survival, better treatments are needed. This trial evaluated the addition of a novel drug, cetuximab, to chemotherapy plus radiation. Unfortunately, the side effects were too great and the study was stopped early.
AbstractBackground.PALOMA‐2 confirmed that first‐line palbociclib + letrozole improved progression‐free survival (hazard ratio, 0.58; 95% confidence interval, 0.46–0.72) in postmenopausal women with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC). This analysis evaluated palbociclib‐associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and Methods.Postmenopausal women with ER+/HER2− ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).Results.PALOMA‐2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression‐free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12–700) days (grade ≥ 3, 28.0 [12–854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001).Conclusion.Palbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2− ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427)Implications for Practice.Palbociclib demonstrated an acceptable safety profile in PALOMA‐2 in women with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) receiving first‐line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib‐related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first‐line treatment for ER+/HER2− ABC.
AbstractBackground.A dexamethasone‐sparing regimen consisting of palonosetron plus 1‐day dexamethasone for the prevention of chemotherapy‐induced nausea and vomiting (CINV) has been studied previously. Here, we evaluate the noninferiority of the dexamethasone‐sparing regimen in overall antiemetic control using a meta‐analysis based on individual patient data (IPD).Materials and Methods.We conducted a systematic review for randomized trials reporting CINV outcomes for the comparison of palonosetron plus 1‐day dexamethasone (d1 arm) versus the same regimen followed by dexamethasone on days 2–3 after chemotherapy (d3 arm) in chemotherapy‐naïve adult patients undergoing either moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)‐containing chemotherapy. PubMed and MEDLINE were searched electronically. A manual search was also conducted. The primary endpoint was complete response (CR; no emesis and no rescue medication) in the overall 5‐day study period. The noninferiority margin was set at −8.0% (d1 arm−d3 arm).Results.Five studies (n = 1,194) were eligible for analysis and all IPD was collected. In the overall study period, the d1 arm showed noninferiority to the d3 arm for CR as well as complete control (pooled risk difference in CR rate − 1.5%, 95% confidence interval [CI] −7.1 to 4.0%, I2 = 0%; in complete control rate − 2.4%, 95% CI −7.7 to 2.9%, I2 = 0%). There was no significant interaction between dexamethasone regimen and risk factors (type of chemotherapy, sex, age, and alcohol consumption).Conclusion.This IPD meta‐analysis indicates that the dexamethasone‐sparing regimen is not associated with a significant loss in overall antiemetic control in patients undergoing MEC or AC‐containing chemotherapy, irrespective of known risk factors for CINV.Implications for Practice.Although dexamethasone in combination with other antiemetic agents has been used to prevent chemotherapy‐induced nausea and vomiting (CINV), it is of clinical importance to minimize total dose of dexamethasone in patients undergoing multiple cycles of emetogenic chemotherapy. This individual‐patient‐data meta‐analysis from five randomized controlled trials (1,194 patients) demonstrated a noninferiority of the dexamethasone‐sparing regimen for complete response and complete control of CINV. The outcomes were comparable across patients with different characteristics. These findings thus help physicians minimize use of the steroid and further reduce the burden of dexamethasone‐related side effects in patients undergoing multiple consecutive courses of emetogenic chemotherapy.
AbstractThis article provides an overview of radiofrequency ablation (RFA) and microwave ablation (MWA) for treatment of primary liver tumors and hepatic metastasis. Only studies reporting RFA and MWA safety and efficacy on liver were retained. We found 40 clinical studies that satisfied the inclusion criteria. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive to treat hepatic tumors. According to the literature, the overall survival, local recurrence, complication rates, disease‐free survival, and mortality in patients with hepatocellular carcinoma (HCC) treated with RFA vary between 53.2 ± 3.0 months and 66 months, between 59.8% and 63.1%, between 2% and 10.5%, between 22.0 ± 2.6 months and 39 months, and between 0% and 1.2%, respectively. According to the literature, overall survival, local recurrence, complication rates, disease‐free survival, and mortality in patients with HCC treated with MWA (compared with RFA) vary between 22 months for focal lesion >3 cm (vs. 21 months) and 50 months for focal lesion ≤3 cm (vs. 27 months), between 5% (vs. 46.6%) and 17.8% (vs. 18.2%), between 2.2% (vs. 0%) and 61.5% (vs. 45.4%), between 14 months (vs. 10.5 months) and 22 months (vs. no data reported), and between 0% (vs. 0%) and 15% (vs. 36%), respectively. According to the literature, the overall survival, local recurrence, complication rates, and mortality in liver metastases patients treated with RFA (vs. MWA) are not statistically different for both the survival times from primary tumor diagnosis and survival times from ablation, between 10% (vs. 6%) and 35.7% (vs. 39.6), between 1.1% (vs. 3.1%) and 24% (vs. 27%), and between 0% (vs. 0%) and 2% (vs. 0.3%). MWA should be considered the technique of choice in selected patients, when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size.Implications for Practice.Although technical features of the radiofrequency ablation (RFA) and microwave ablation (MWA) are similar, the differences arise from the physical phenomenon used to generate heat. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive than RFA to treat hepatic tumors. The benefits of MWA are an improved convection profile, higher constant intratumoral temperatures, faster ablation times, and the ability to use multiple probes to treat multiple lesions simultaneously. MWA should be considered the technique of choice when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size.
The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment‐naïve and TKI‐refractory patients with advanced GIST.Background.Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models.Methods.This was an investigator‐initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned.Results.Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose‐limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment‐emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression‐free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1‐mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment.Conclusion.Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib‐refractory patients.
AbstractBRAF and MEK inhibitors are highly active in the setting of BRAFV600 mutant melanoma. Rarely, patients without previous testing present with fulminant progression necessitating emergent treatment prior to BRAF testing results. The safety and efficacy of empiric treatment in this setting is unclear. Herein, we present two patients treated with empiric BRAF and MEK inhibitors, resulting in dramatic clinical improvement in one patient later found to have a BRAF mutation, and lack of improvement (but no accelerated progression) in a patient lacking this mutation. Empiric BRAF and MEK inhibitor treatment should not be routinely pursued but may be given safely in rare, emergent situations.
AbstractBackground.When carcinoid syndrome (CS) diarrhea (CSD) is inadequately controlled with long‐acting somatostatin analogs (SSAs), clinical practice guidelines recommend addition of the tryptophan hydroxylase inhibitor telotristat ethyl (TE). In a 12‐week multinational, randomized controlled trial, TE added to SSA reduced peripheral serotonin and the frequency of CSD. We evaluated real‐world effectiveness of TE using patient‐reported data from a nurse support program over 3 months.Materials and Methods.This study used a deidentified data set of patients initiating TE who opted into a nurse support program between March and November 2017 and reported CS symptom burden at baseline and at least one follow‐up time point at months 1, 2, and 3. Patients reported demographic and medical history information as well as frequency of bowel movements (BMs) and flushing episodes, severity of nausea, urgency and abdominal pain (0 “no/not at all” to 100 “worst imaginable/very urgent”), and stool form (1 “very hard” to 10 “watery”). Mean changes from baseline in CS symptom burden were reported using paired‐sample t tests and Wilcoxon signed‐rank tests.Results.Most patients initiating TE enrolled in the nurse program (791/898, 88%), of whom 369 (47%) were included in the analysis. Patients treated with TE reported significant reductions in CSD and other CS symptoms (all p < .001). At least half of patients treated with TE experienced ≥30% improvement from baseline in BM frequency and an average reduction of at least two BMs per day within 3 months.Conclusion.Patients taking SSA therapy showed substantial burden of disease before initiating TE and significant improvements with the addition of TE treatment in this real‐world effectiveness study.Implications for Practice.Patients with carcinoid syndrome diarrhea uncontrolled by high doses of long‐acting somatostatin analogs may be candidates for additional therapy with the tryptophan hydroxylase inhibitor telotristat ethyl. Understanding the real‐world prevalence of uncontrolled symptoms and the effectiveness of telotristat ethyl in clinical practice may further support clinical and policy decisions for these patients. This study investigated self‐reported carcinoid syndrome symptom burden and improvements among patients initiating telotristat ethyl and participating in a voluntary nurse support program. Disease burden and off‐label somatostatin analog treatment before initiating telotristat ethyl were high, and symptoms improved markedly over 1, 2, and 3 months of treatment.
AbstractBackground.The aim of this study was to explore outcomes of planned pregnancy in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKIs).Materials and Methods.Data of female patients proceeding with a planned pregnancy were retrospectively reviewed.Results.A total of 17 patients with CML who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, six were in MMR, two in molecular response 4 (MR4), and nine in molecular response 4.5 (MR4.5). TKI therapy was discontinued 6 weeks (range, 2–15 weeks) before conception in 4 patients and at gestational age of 4 weeks (range, 2–5 weeks) after determination of pregnancy in 13 patients. Apart from 1 patient who suffered a spontaneous abortion, 16 patients delivered uneventfully. A total of 10 patients lost MMR after stopping TKIs; 8 lost molecular response 2, and 3 lost complete hematological response. Log‐rank analyses showed achieving MR4 (p = .030) or MR4.5 (p = .031), complete cytogenetic response duration ≥3.5 years (p = .049), and MMR duration ≥3.5 years (p = .040) were significantly associated with longer MMR‐failure‐free survival during TKI interruption.Conclusion.Planned pregnancy might be pragmatic in female patients with CML on TKIs. Achieving deep molecular response and, importantly, MMR duration ≥3.5 years were significantly associated with maintaining MMR during pregnancy.Implications for Practice.Female patients with chronic myeloid leukemia on tyrosine kinase inhibitors (TKIs) wishing to conceive are currently advised to discontinue TKIs before conception. However, the ideal degree and duration of response before stopping TKI, in addition to whether there will be any adverse effect caused by a short exposure of TKI, is unknown. Data of 17 female patients, who achieved at least a major molecular response (MMR) before TKI interruption, was revised, and it was found that achieving deep molecular response and MMR duration ≥3.5 years was significantly associated with maintaining MMR during pregnancy. This provides direct evidence for a planned pregnancy strategy, and stopping TKI immediately after determination of pregnancy in female patients might be pragmatic.
AbstractBackground.Tumor mutational burden (TMB) measured via next‐generation sequencing (NGS)‐based gene panel is a promising biomarker for response to immune checkpoint inhibitors (ICIs) in solid tumors. However, little is known about the preanalytical factors that can affect the TMB score.Materials and Methods.Data of 199 patients with solid tumors who underwent multiplex NGS gene panel (OncoPrime), which was commercially provided by a Clinical Laboratory Improvement Amendments‐licensed laboratory and covered 0.78 megabase (Mb) of capture size relevant to the TMB calculation, were reviewed. Associations between the TMB score and preanalytical factors, including sample DNA quality, sample type, sampling site, and storage period, were analyzed. Clinical outcomes of patients with a high TMB score (≥10 mutations per megabase) who received anti‐programmed cell death protein 1 antibodies (n = 22) were also analyzed.Results.Low DNA library concentration (<5 nM), formalin‐fixed paraffin‐embedded tissue (FFPE), and the prolonged sample storage period (range, 0.9–58.1 months) correlated with a higher TMB score. After excluding low DNA library samples from the analysis, FFPE samples, but not the sample storage period, exhibited a marked correlation with a high TMB score. Of 22 patients with a high TMB score, we observed the partial response in 2 patients (9.1%).Conclusion.Our results indicate that the TMB score estimated via NGS‐based gene panel could be affected by the DNA library concentration and sample type. These factors could potentially increase the false‐positive and/or artifactual variant calls. As each gene panel has its own pipeline for variant calling, it is unknown whether these factors have a significant effect in other platforms.Implications for Practice.A high tumor mutational burden score, as estimated via next‐generation sequencing‐based gene panel testing, should be carefully interpreted as it could be affected by the DNA library concentration and sample type.
AbstractBackground.In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers.Aim.To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer.Methods.A systematic review was performed according to the Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca‐125], lymphadenopathy on magnetic resonance imaging, computed tomography, and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography [18FDG PET‐CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random‐effects meta‐analysis. Likelihood ratios were classified into small (0.5–1.0 or 1–2.0), moderate (0.2–0.5 or 2.0–5.0) or large (0.1–0.2 or ≥ 5.0) impact.Results.Eighty‐three studies, comprising 18,205 patients, were included. Elevated Ca‐125 and thrombocytosis were associated with a moderate increase in risk of LNM; lymphadenopathy on imaging with a large increase. Normal Ca‐125, cytology, and no lymphadenopathy on 18FDG PET‐CT were associated with a moderate decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only small impact.Conclusion.Ca‐125, thrombocytosis, and imaging had a large and moderate impact on risk of LNM and could improve preoperative risk stratification.Implications for Practice.Routine lymphadenectomy in clinical early‐stage endometrial carcinoma does not improve outcome and is associated with 15%–20% surgery‐related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.
AbstractBackground.Sub‐Saharan Africa is simultaneously facing a rising incidence of cancer and a dearth of medical professionals because of insufficient training numbers and emigration, creating a growing shortage of cancer care. To combat this, Massachusetts General Hospital and Beth Israel Deaconess Medical Center partnered with institutions in South Africa, Tanzania, and Rwanda to develop a fellowship exchange program to supplement the training of African oncologists practicing in their home countries.Methods.In its initial year, 2018, the Program for Enhanced Training in Cancer (POETIC) hosted a pilot cohort of seven fellows for 3‐week observerships in their areas of interest. Researchers distributed questionnaires for program evaluation to participants prior to arrival and upon departure; additionally, three participated in semistructured interviews.Results.Five themes emerged from the qualitative data: expectations of POETIC, differences between oncology in the U.S. and in sub‐Saharan Africa, positive elements of the program, areas for improvement, and potential impact. Fellows identified several elements of Western health care that will inform their practice: patient‐centered care; clinical trials; and collaboration among medical, radiation, and surgical oncologists. From the quantitative data, feedback was primarily around logistical areas for improvement.Discussion.POETIC was found to be feasible and valuable. The results from the pilot year justify the program's continuation in hopes of strengthening global health partnerships to support oncology training in Africa. One weakness is the small number of fellows, which will limit the impact of the study and the relevance of its conclusions. Future research will report on the expansion of the program and follow‐up with former participants.Implications for Practice.This work presents a novel model for fellowship exchange between lower‐ and higher‐resourced areas. The program is a short‐term observership with tumor boards and didactic teaching sessions incorporated. By attracting oncologists who aim to practice in their home countries, it facilitates international collaboration without contributing to the preexisting lack of medical professionals in low‐ and middle‐income countries.
AbstractBackground.As scientific techniques evolve, historical informed consent forms may inadequately address modern research proposals, leading to ethical questions regarding research with archived biospecimens.Subjects, Materials, and Methods.We conducted focus groups among patients with cancer recruited from Massachusetts General Hospital to explore views on medical research, biobanking, and scenarios based on real biospecimen research dilemmas. Our multidisciplinary team developed a structured focus group guide, and all groups were recorded and transcribed. Transcripts were coded for themes by two independent investigators using NVivo software.Results.Across five focus groups with 21 participants, we found that most participants were supportive of biobanks and use of their own tissue to advance scientific knowledge. Many favor allowing research beyond the scope of the original consent to proceed if recontact is impossible. However, participants were not comfortable speaking for other patients who may oppose research beyond the original consent. This was viewed as a potential violation of participants’ rights or interests. Participants were also concerned with a “slippery slope” and potential scientific abuse if research were permitted without adherence to original consent. There was strong support for recontact and reconsent when possible and for the concept of broad consent at the time of tissue collection.Conclusion.Our participants support use of their tissue to advance research and generally support any productive scientific approach. However, in the absence of broad initial consent, when recontact is impossible, a case‐by‐case decision must be made regarding a proposal's potential benefits and harms. Many participants support broad use of their tissue, but a substantial minority object to use beyond the original consent.Implications for Practice.For prospective studies collecting tissue for future research, investigators should consider seeking broad consent, to allow for evolution of research questions and methods. For studies using previously collected tissues, researchers should attempt recontact and reconsent for research aims or methods beyond the scope of the original consent. When reconsent is not possible, a case‐by‐case decision must be made, weighing the scientific value of the biobank, potential benefits of the proposed research, and the likelihood and nature of risks to participants and their welfare interests. This study's data suggest that many participants support broad use of their tissue and prefer science to move forward.
AbstractBackground.Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy‐naïve chemotherapy‐refractory advanced colorectal cancer.Patients and Methods.This single‐center, single‐arm, phase 2b study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy‐naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4‐week cycle. The primary endpoint was progression‐free survival (PFS) rate at week 8.Results.Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1–64.3); median PFS was 3.5 months (95% CI, 1.8–3.6). Median OS was 7.4 months (95% CI, 5.3–8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib‐related grade ≥3 adverse events were hypertension (36%), hand–foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib‐related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0–1 (5.4 months).Conclusion.These findings support the antitumor activity of regorafenib in antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC.Implications for Practice.The multikinase inhibitor regorafenib improved overall survival in the phase 3 CORRECT and CONCUR trials in heavily pretreated patients with treatment‐refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single‐center, single‐arm phase 2b study, regorafenib demonstrated antitumor activity in 59 antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand–foot skin reaction.
The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.Background.Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.Methods.This phase Ib study included a dose‐escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose‐expansion phase to examine preliminary efficacy in treatment‐naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.Results.No patients in the dose‐escalation phase (n = 22) experienced dose‐limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose‐expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression‐free survival was 5.6 months (95% CI, 3.5–not reached).Conclusion.The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
AbstractBackground.The ROXANE Italian prospective study evaluated the impact of the 21‐gene Recurrence Score (RS) results on adjuvant treatment decision for patients with early breast cancer.Materials and Methods.Nine centers participated. Physicians used the RS test whenever unsure about adjuvant treatment recommendation for patients with estrogen receptor‐positive/human epidermal growth receptor 2‐negative, T1–T3, N0–N1 early breast cancer. Pre‐RS and post‐RS treatment recommendations were collected.Results.A total of 251 patients were included. N0 patients (61%) showed higher grade (p < .001) and higher Ki67 (p = .001) and were more frequently progesterone receptor negative (p = .012) as compared with N1 patients. RS results were as follows: <11, n = 63 (25.1%); 11–25, n = 143 (57%); and ≥26, n = 45 (17.9%). Higher RS was found in N0 vs. N1 patients (p = .001) and in cases of G3 (p < .001) and higher Ki67 (p < .001). The rate of change in treatment decision was 30% (n = 75), mostly from chemotherapy (CT) plus hormone therapy (CT + HT) to hormone therapy (HT; 76%, n = 57/75). The proportion of patients recommended to CT + HT was significantly reduced from pre‐RS to post‐RS (52% to 36%, p < .0001). CT use reduction was more evident for N1 patients (55% to 27%) than for N0 patients (50% to 42%) and was observed only in cases of RS ≤17.Conclusion.Physicians predominantly used the 21‐gene assay in N0 patients with a more aggressive biology or in N1 patients showing more indolent biology. In this selected patient population, the use of RS testing led to a 30% rate of change in treatment decision. In the N1 patient subgroup, the use of RS testing contributed to reduce CT use by more than half.Implications for Practice.This study shows that, even in a context in which physicians recommend a high proportion of patients to endocrine treatment alone before knowing the results of the Recurrence Score (RS) assay, the use of the RS test, whenever uncertainty regarding adjuvant treatment recommendation is present, significantly contributes in further reducing the use of chemotherapy, especially for N1 patients.
AbstractPurpose.Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non‐small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first‐line treatment for advanced NSCLC.Materials and Methods.Published and presented literature was searched using the key search terms “non‐small cell lung cancer” AND “checkpoint‐inhibitors” (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first‐line advanced NSCLC were identified.Results.Four first‐line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab‐chemotherapy, atezolizumab‐chemotherapy, and atezolizumab‐bevacizumab‐chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor‐negative (EGFR−)/ anaplastic lymphoma kinase gene (ALK)− NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab‐chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab‐ipilimumab in all‐comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab‐chemotherapy administered based on PD‐L1 status and histology is a preferred treatment option. Outcomes for atezolizumab‐bevacizumab‐chemotherapy in EGFR+/ALK+ patients are promising and require further exploration.Conclusion.First‐line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR−/ALK− and squamous advanced NSCLC.Implications for Practice.Single‐agent immune checkpoint inhibitors are now standard of care for advanced non‐small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE‐189 and IMPower‐130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE‐407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first‐line NSCLC. Programmed death ligand‐1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.
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