AbstractIn addition to its primary regulatory role, the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration (FDA) is engaged in many forms of scientific authorship. During the period of 2010 to 2018, FDA oncology staff contributed to 356 publications in the scientific literature. Here, we collaborated with analysts in the Office of Program Planning, Analysis, and Evaluation at the National Institute of General Medical Sciences, National Institutes of Health (NIH), to present a series of analyses aimed at quantifying the characteristics and potential impact of these contributions, as well as characterizing the areas of work addressed. We found that FDA oncology papers are enriched for high‐impact publications and have about two times the number of citations as an average NIH‐funded paper. Further impact of the publications was measured based on the presence of 65 publications that were cited by guidelines and 12 publications cited by publicly listed clinical trials. The results seen here are promising in determining the impact of FDA oncology publication work but prompt further investigation into longer‐term impacts, such as the influence of this work on other regulatory activities at FDA.Implications for Practice.This article describes the first comprehensive study of scientific publications produced by U.S. Food and Drug Administration (FDA) oncology staff. The analysis illustrates that staff are highly engaged in publishing in the scientific literature in addition to completing regulatory review work. Publications are generally in clinical medicine, consistent with the large number of medical oncologists working at the Office of Hematology and Oncology Products (OHOP). OHOP publications generally focus either on communicating important regulatory work (approval summaries) or highlighting regulatory science issues to encourage dialogue with the scientific community (commentaries, reviews, and expert working papers). The analysis also suggests that several FDA oncology publications may influence clinical guidelines, but further work is needed to evaluate impact.
AbstractLung cancer remains the leading cause of cancer‐related death worldwide. Affected patients frequently experience debilitating disease‐related symptoms, including dyspnea, cough, fatigue, anxiety, depression, insomnia, and pain, despite the progresses achieved in term of treatment efficacy.Physical activity and exercise are nonpharmacological interventions that have been shown to improve fatigue, quality of life, cardiorespiratory fitness, pulmonary function, muscle mass and strength, and psychological status in patients with lung cancer. Moreover, physical fitness levels, especially cardiorespiratory endurance and muscular strength, are demonstrated to be independent predictors of survival. Nevertheless, patients with lung cancer frequently present insufficient levels of physical activity and exercise, and these may contribute to quality of life impairment, reduction in functional capacity with skeletal muscle atrophy or weakness, and worsening of symptoms, particularly dyspnea.The molecular bases underlying the potential impact of exercise on the fitness and treatment outcome of patients with lung cancer are still elusive. Counteracting specific cancer cells’ acquired capabilities (hallmarks of cancer), together with preventing treatment‐induced adverse events, represent main candidate mechanisms.To date, the potential impact of physical activity and exercise in lung cancer remains to be fully appreciated, and no specific exercise guidelines for patients with lung cancer are available. In this article, we perform an in‐depth review of the evidence supporting physical activity and exercise in lung cancer and suggest that integrating this kind of intervention within the framework of a global, multidimensional approach, taking into account also nutritional and psychological aspects, might be the most effective strategy.Implications for Practice.Although growing evidence supports the safety and efficacy of exercise in lung cancer, both after surgery and during and after medical treatments, most patients are insufficiently active or sedentary. Engaging in exercise programs is particularly arduous for patients with lung cancer, mainly because of a series of physical and psychosocial disease‐related barriers (including the smoking stigma). A continuous collaboration among oncologists and cancer exercise specialists is urgently needed in order to develop tailored programs based on patients’ needs, preferences, and physical and psychological status. In this regard, benefit of exercise appears to be potentially enhanced when administered as a multidimensional, comprehensive approach to patients’ well‐being.
Effect of a Skills Training for Oncologists and a Patient Communication Aid on Shared Decision Making About Palliative Systemic Treatment: A Randomized Clinical Trial
AbstractBackground.Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM.Methods.In this multicenter randomized controlled trial with four parallel arms (2016–2018), oncologists (n = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients (n = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio‐recorded consultations. Secondary outcomes included patient‐reported SDM, patient and oncologist satisfaction, patients’ decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made.Results.The oncologist training had a large positive effect on observed SDM (Cohen's d = 1.12) and on patient‐reported SDM (d = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients’ decisional conflict, quality of life, consultation duration, or the decision made.Conclusion.Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient‐reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice. Trial registration. Netherlands Trial Registry NTR 5489.Implications for Practice.Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient‐reported SDM in clinical encounters (n = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists’ practice and should be implemented in (continuing) educational programs.
Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD‐L1 in Gastric Cancer Patients Treated with Either Adjuvant 5‐FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the…
AbstractBackground.Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown.Materials and Methods.In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA‐S, a randomized adjuvant trial of 5‐FU/LV versus sequential FOLFIRI and cisplatin‐docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD‐L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD‐L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5‐FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12).Conclusion.Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II–III GC and should be used as stratification factor in future trials. Tumor PD‐L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy.Implications for Practice.In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5‐FU/LV monotherapy as adjuvant treatment in the ITACA‐S trial, MSI‐high status was independently associated with better disease‐free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD‐L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5‐fluorouracil plus leucovorin (5‐FU/LV), whereas PD‐L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta‐analysis of individual patients’ data from available studies could yield data on the role of MSI status that could inform clinical decisions.
AbstractBackground.This work examined the association between pregnancy after breast cancer (BC) diagnosis and total mortality in Taiwanese patients with BC.Materials and Methods.The Taiwan Cancer Registry, National Health Insurance database, and Taiwan National Death Certificate database were reviewed. Patients who became pregnant after being diagnosed with BC were selected (n = 249). Four nonpregnant patients with BC were selected and matched to every pregnant patient with BC by age at diagnosis, year at diagnosis, and propensity score based on disease stage, tumor size, node involvement, and histological grade. The disease‐free time interval for the selected control needed to have been longer than the time interval between the cancer diagnosis and pregnancy for the index case. Follow‐up was calculated from the pregnancy date of the index case to the date of death or December 31, 2014, whichever came first. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).Results.After adjusting for age, year at BC diagnosis, stage, positive nodes, and hormone therapy, patients with BC who became pregnant after their cancer diagnosis had lower total mortality than did the comparison group (HR = 0.44, 95% CI = 0.23–0.84), including that of estrogen receptor‐positive patients (HR = 0.23, 95% CI = 0.07–0.77). The inverse association was more pronounced for those who became pregnant more than 3 years after diagnosis (HR = 0.19, 95% CI = 0.05–0.78).Conclusion.Our nationwide retrospective analysis revealed that pregnancy after BC diagnosis was associated with lower mortality than that of nonpregnant patients with BC at a similar age, year at diagnosis, and clinical characteristics.Implications for Practice.This article provides high‐level evidence based on an Asian population for pregnancy counseling after a breast cancer diagnosis, including for patients with estrogen receptor‐positive cancers. The study also revealed the optimal time for patients who would like to become pregnant after breast cancer.
Talazoparib in Patients with a Germline BRCA‐Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial
AbstractBackground.In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression‐free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2‐mutated HER2‐negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail.Materials and Methods.Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time‐varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient‐reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms.Results.The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3–4 months of receiving talazoparib. Grade 3‐4 anemia lasted approximately 7 days for both arms. Overlapping grade 3‐4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (<2%). A total of 150 (52.4%) patients receiving talazoparib had AEs associated with dose reduction. Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Among patients with anemia or nausea and/or vomiting AEs, PROs favored talazoparib. After accounting for the treatment‐emergent period, talazoparib was generally associated with a lower rate of hospitalization and supportive care medication use compared with chemotherapy.Conclusion.Talazoparib was associated with superior efficacy, favorable PROs, and lower HRU rate versus chemotherapy in gBRCA‐mutated ABC. Toxicities were manageable with talazoparib dose modification and supportive care.Implications for Practice.Talazoparib was generally well tolerated in patients with germline BRCA‐mutated HER2‐negative advanced breast cancer in the EMBRACA trial. Common toxicities with talazoparib were primarily hematologic and infrequently resulted in permanent drug discontinuation (<2% of patients discontinued talazoparib due to hematologic toxicity). Hematologic toxicities typically occurred during the first 3–4 months of treatment and were managed by dose modifications and supportive care measures. A significant efficacy benefit, improved patient‐reported outcomes, lower rate of health resource utilization and a tolerable safety profile support incorporating talazoparib into routine management of germline BRCA‐mutated locally advanced/metastatic breast cancer.
Lenvatinib Versus Sorafenib as First‐Line Treatment of Unresectable Hepatocellular Carcinoma: A Cost–Utility Analysis
AbstractBackground.In a global, phase III, open‐label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression‐free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10 years to receive approval as first‐line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost‐effectiveness of lenvatinib and sorafenib as a first‐line therapy of unresectable HCC.Materials and Methods.A state‐transition model of unresectable HCC was developed in the form of a cost–utility analysis. The model time horizon was 5 years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model.Results.Lenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost‐saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy.Conclusion.Lenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost‐saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost‐saving if a significantly cheaper generic sorafenib becomes available.Implications for Practice.This analysis suggests an actionable clinical policy that will achieve cost saving. This cost–utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost‐saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10 years in Canada provides an important opportunity for clinicians, researchers, and health care decision‐makers to explore potential modifications in recommendations and practice guidelines.
Computed Tomography‐Based Body Composition Is Not Consistently Associated with Outcome in Older Patients with Colorectal Cancer
AbstractBackground.Current literature is inconsistent in the associations between computed tomography (CT)‐based body composition measures and adverse outcomes in older patients with colorectal cancer (CRC). Moreover, the associations with consecutive treatment modalities have not been studied. This study compared the associations of CT‐based body composition measures with surgery‐ and chemotherapy‐related complications and survival in older patients with CRC.Materials and Methods.A retrospective single‐center cohort study was conducted in patients with CRC aged ≥65 years who underwent elective surgery between 2010 and 2014. Gender‐specific standardized scores of preoperative CT‐based skeletal muscle (SM), muscle density, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue, IMAT percentage, SM/VAT, and body mass index (BMI) were tested for their associations with severe postoperative complications, prolonged length of stay (LOS), readmission, and dose‐limiting toxicity using logistic regression and 1‐year and long‐term survival (range 3.7–6.6 years) using Cox regression. Bonferroni correction was applied to account for multiple testing.Results.The study population consisted of 378 patients with CRC with a median age of 73.4 (interquartile range 69.5–78.4) years. Severe postoperative complications occurred in 13.0%, and 39.4% of patients died during follow‐up. Dose‐limiting toxicity occurred in 77.4% of patients receiving chemotherapy (n = 53). SM, muscle density, VAT, SM/VAT, and BMI were associated with surgery‐related complications, and muscle density, IMAT, IMAT percentage, and SM/VAT were associated with long‐term survival. After Bonferroni correction, no CT‐based body composition measure was significantly associated with adverse outcomes. Higher BMI was associated with prolonged LOS.Conclusion.The associations between CT‐based body composition measures and adverse outcomes of consecutive treatment modalities in older patients with CRC were not consistent or statistically significant.Implications for Practice.Computed tomography (CT)‐based body composition, including muscle mass, muscle density, and intermuscular, visceral, and subcutaneous adipose tissue, showed inconsistent and nonsignificant associations with surgery‐related complications, dose‐limiting toxicity, and overall survival in older adults with colorectal cancer. This study underscores the need to verify whether CT‐based body composition measures are worth implementing in clinical practice.
Impact of Baseline Nutrition and Exercise Status on Toxicity and Outcomes in Phase I and II Oncology Clinical Trial Participants
AbstractBackground.Malnutrition and physical inactivity are common in patients with advanced cancer and are associated with poor outcomes. There are increasing data that altered body composition is related to the pharmacokinetic properties of cancer therapies. These adverse conditions may impact outcomes in early‐phase oncology clinical trials.Materials and Methods.We aimed to understand the relationships between baseline nutrition and exercise status with important trial endpoints including treatment‐related toxicity and survival. Baseline assessments of nutrition and exercise status were conducted in patients prior to initiation of phase I and II oncology clinical trials. Patients were followed prospectively for the onset of adverse events. Tumor response and survival data were also obtained. Fisher's exact test and chi‐square analysis were used to determine statistical significance. Kaplan‐Meier curves were used to compare patient duration on study and survival.Results.One hundred patients were recruited, of whom 87 were initiating a phase I trial. Sixty percent were initiating trials studying immunotherapeutic agents. Critical malnutrition was found in 39% of patients, and 52% were sedentary. Patients who were malnourished had significantly increased rates of grade ≥ 3 toxicity (p = .001), hospitalizations (p = .001), and inferior disease control rate (p = .019). Six‐month overall survival was significantly reduced in malnourished patients versus nonmalnourished patients (47% vs. 84%; p = .0003), as was median duration on study (48 days vs. 105 days; p = .047). Being sedentary at baseline was associated with decreased duration on study (57 days vs. 105 days; p = .019).Conclusion.Malnutrition and sedentary lifestyle are highly prevalent in patients enrolling on early‐phase oncology clinical trials and are associated with poor outcomes. The quality of data from these studies may be compromised as a result of these pre‐existing conditions.Implications for Practice.Phase I and II trials are critical steps in the development of effective cancer therapeutics, yet only a small percentage of agents are ultimately approved for human cancer care. Despite increasing awareness of the interactions between malnutrition, sarcopenia, and treatment‐related outcomes such as toxicity and response, these factors are not commonly incorporated into therapeutic decision making at the time of clinical trial consideration. Nutritional status and physical performance may be key biomarkers of mechanisms mediating treatment‐related toxicity, dose modifications, risk of hospitalizations, and success of novel agents. This study advocates that a baseline nutritional assessment and early nutritional support may improve tolerability and response to experimental therapies.
AbstractThere are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors—hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers. There are not yet consensus standardized criteria for defining hyperprogressive disease, but most commonly time to treatment failure less than 2 months and an increase in pace of progression of at least twofold between pre‐immunotherapy and on‐treatment imaging has been used. In some patients, the change in rate of progression can be especially dramatic—up to 35‐ to 40‐fold. MDM2 amplification and EGFR mutations have been suggested as genomic correlates of increased risk of hyperprogression, but these correlates require validation. The underlying mechanism for hyperprogression is not known but warrants urgent investigation.
Bevacizumab in Combination with TAS‐102 Improves Clinical Outcomes in Patients with Refractory Metastatic Colorectal Cancer: A Retrospective Study
AbstractObjective.TAS‐102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS‐102 improves clinical outcomes in refractory mCRC.Patients and Methods.We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS‐102 (35 mg/m2, twice a day) with (T‐B group) or without Bmab (TAS‐102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis.Results.Data from 57 patients were analyzed (T‐B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T‐B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T‐B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T‐B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups.Conclusion.Treatment with Bmab in combination with TAS‐102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies.Implications for Practice.Combining bevacizumab (Bmab) with TAS‐102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS‐102 is significantly associated with improved clinical outcomes in patients with mCRC.
Mutation Variants and Co‐Mutations as Genomic Modifiers of Response to Afatinib in HER2‐Mutant Lung Adenocarcinoma
AbstractBackground.Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti‐HER2 therapies in these patients prompt us to examine impact of HER2 variants and co‐mutations on responses to anti‐HER2 treatments in lung cancer.Patients and Methods.Patients with stage IV/recurrent HER2‐mutant lung cancers identified through next‐generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co‐mutations in lung cancer and a cohort B to assess associations between HER2 variants, co‐mutations, and clinical outcomes.Results.The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty‐one HER2 variants and 35 co‐mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co‐mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%–26.8%), 40% (4/10, 14.7%–72.6%), and 13% (1/8, 0.7%–53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression‐free survival in group 1 (1.2 months; 95% CI, 0–2.4) was shorter than those in group 2 (7.6 months, 4.9–10.4; hazard ratio [HR], 0.009; 95% CI, 0.001–0.079; p < .001) and group 3 (3.6 months, 2.6–4.5; HR, 0.184; 95% CI, 0.062–0.552; p = .003). TP53 co‐mutations (6.317; 95% CI, 2.180–18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098–92.039; p < .001) conferred additional resistance to afatinib.Conclusion.G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co‐mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co‐mutations may help improve the efficacy of anti‐HER2 treatment in lung cancer.Implications for Practice.Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti‐HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti‐HER2 treatments. TP53 is the most common co‐mutation in HER2‐mutant lung cancers. Co‐mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti‐HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.
AbstractBackground.The role of horizontal growth index of tumor size in survival prediction is still underappreciated in colon cancer because of the identification of vertical infiltration index reflected by T stage. We sought to reveal the impact of T stage on the prognostic and predictive value of tumor size in colon cancer.Materials and Methods.Data of patients with stage I–III colon cancer were extracted from Surveillance, Epidemiology, and End Results Program (SEER) and Fudan University Shanghai Cancer Center (FUSCC) databases. Harrell's concordance index (c‐index) and time‐dependent receiver operating characteristic curve (ROC) were used to analyze the discriminative ability of prognostic factors.Results.Stratified analyses based on T stage found that the increase of T stage significantly and negatively repressed the effect of tumor size on death and recurrence risk. In addition, tumor size showed the greatest hazard ratio of cancer‐specific death and relapse in T1 colon cancer. Even more importantly, the discriminatory ability of tumor size outperformed any other widely accepted prognostic clinical features in predicting cancer‐specific survival (SEER: c‐index 0.637, area under the ROC [AUC] 0.649; FUSCC: c‐index 0.673, AUC 0.686) and disease‐free survival (FUSCC: c‐index 0.645, AUC 0.656) in T1 stage colon cancer.Conclusion.Tumor size is a critical clinical factor with considerable prognostic and predictive value for T1 colon cancer, and it should be selectively incorporated into the current staging system to facilitate prediction of death and recurrence risk.Implications for Practice.To date, no consensus has been reached about the prognostic and predictive value of tumor size in colon cancer. Although tumor size is an independent prognostic factor for patients with colon cancer, the impact of tumor size on death or recurrence risk decreased notably with the increase of T stage. More importantly, the discriminative ability of tumor size outperformed any other clinical factors including N stage in patients with T1 colon cancer. Therefore, tumor size should be recommended to be incorporated into current staging systems to facilitate prognosis prediction for patients with T1 colon cancer.
Immune‐Related Adverse Events by Immune Checkpoint Inhibitors Significantly Predict Durable Efficacy Even in Responders with Advanced Non‐Small Cell Lung Cancer
AbstractBackground.Although predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders.Materials and Methods.Between December 2015 and September 2018, 106 patients with advanced non‐small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty‐three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression‐free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment.Results.The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non‐irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10–0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor‐2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04).Conclusion.Although this is a small sample–sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.Implications for Practice.Although the predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.
A Multidisciplinary Head‐to‐Head Comparison of American College of Radiology Thyroid Imaging and Reporting Data System and American Thyroid Association Ultrasound Risk Stratification Systems
AbstractBackground.Ultrasound plays a critical role in evaluating thyroid nodules. We compared the performance of the two most popular ultrasound malignancy risk stratification systems, the 2015 American Thyroid Association (ATA) guidelines and the American College of Radiology Thyroid Imaging and Reporting Data System (ACR TI‐RADS).Materials and Methods.We retrospectively identified 250 thyroid nodules that were surgically removed from 137 patients. Their ultrasound images were independently rated using both ATA and ACR TI‐RADS by six raters with expertise in ultrasound interpretation. For each system, we generated a receiver operating characteristic curve and calculated the area under the curve (AUC).Results.Sixty‐five (26%) nodules were malignant. There was “fair agreement” among raters for both ATA and ACR TI‐RADS. Our observed malignancy risks for ATA and ACR TI‐RADS categories were similar to expected risk thresholds with a few notable exceptions including the intermediate ATA risk category and the three highest risk categories for ACR TI‐RADS. Biopsy of 226 of the 250 nodules would be indicated by ATA guidelines based on nodule size and mean ATA rating. One hundred forty‐six nodules would be biopsied based on ACR TI‐RADS. The sensitivity, specificity, and negative and positive predictive values were 92%, 10%, 79%, and 27%, respectively, for ATA and 74%, 47%, 84%, and 33%, respectively, for ACR TI‐RADS. The AUC for ATA was 0.734 and for ACR TI‐RADS was 0.718.Conclusion.Although both systems demonstrated good diagnostic performance, ATA guidelines resulted in a greater number of thyroid biopsies and exhibited more consistent malignancy risk prediction for higher risk categories.Implications for Practice.With the rising incidence of thyroid nodules, the need for accurate detection of malignancy is important to avoid the overtreatment of benign nodules. Ultrasonography is one of the key tools for the evaluation of thyroid nodules, although the use of many different ultrasound risk stratification systems is a hindrance to clinical collaboration in everyday practice and the comparison of data in research. The first step toward the development of a universal thyroid nodule ultrasound malignancy risk stratification system is to better understand the strengths and weaknesses of the current systems in use.
AbstractBackground.Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC.Materials and Methods.This was a single‐institution study with a 3 + 3 dose‐escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression‐free survival (PFS), and overall survival (OS).Results.Twenty‐one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2. The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61–4.83 months), and median OS was 6.90 months (95% CI, 2.63–9.57 months).Conclusion.Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study.Implications for Practice.Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.
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