AbstractBackground.This study aimed to assess the characteristics of breakthrough cancer pain (BTcP) in patients receiving low doses of opioids for background pain in comparison with patients receiving at least 60 mg of oral morphine equivalents (OME).Materials and Methods.Patients with advanced cancer receiving less than 60 mg/day of OME with episodes of BTcP were included in the analysis (group L). Data were compared with patients receiving doses of opioids ≥60 mg of OME (group H). Pain intensity, current analgesic therapy, number of BTcP episodes, intensity of BTcP, its predictability and triggers, onset duration, interference with daily activities, BTcP medications, and time to meaningful pain relief were collected. Adverse effects imputable to a BTcP medication were recorded.Results.A total of 1,418 and 2,474 patients were included in groups L and H, respectively. A lower number of BTcP episodes (p = .005), a lower BTcP intensity (p = .0001), a faster BTcP onset (p = .024), and a longer time to meaningful pain relief after taking a BTcP medication (p = .009) were found in group L as compared with group H. In group L, BTcP interference on daily activity was less than in group H (p = .009). Patients in group L were less likely to be prescribed an opioid as BTcP medication in comparison with patients in group H (p = .0001). Opioid doses used for BTcP were significantly higher in group H. Patients in group L were more likely to be less satisfied (p = .003) than patients in group H. No adverse effects of severe intensity were reported in both groups.Conclusion.Patients receiving lower doses of opioids exhibit some differences in BTcP presentation: fewer episodes with lower intensity and a faster onset, a longer time to meaningful pain relief, and less satisfaction with BTcP medication. A relevant percentage of patients was receiving fentanyl preparations normally reserved for patients receiving higher doses of opioids.Implications for Practice.Breakthrough pain is present in patients receiving low doses of opioids. It has its own peculiarities: less frequent, lower intensity, faster onset, longer time to meaningful pain relief, and less satisfaction with medication. Many patients were prescribed fentanyl preparations, which are normally reserved for patients receiving higher doses of opioids.
Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5‐Fluorouracil, and Leucovorin Versus Oxaliplatin, 5‐Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A…
AbstractBackground.The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum.Subjects, Materials, and Methods.Patients with stage II/III rectal cancer who had completed neoadjuvant 5‐fluorouracil‐based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles.Results.E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow‐up of 72 months, there was no difference in 5‐year overall survival (88.3% vs. 83.7%) or 5‐year disease‐free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment‐related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3–4 treatment‐related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue.Conclusion.At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer.Implications for Practice.At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow‐up of 72 months, there was no significant difference in 5‐year overall survival (88.3% vs. 83.7%) or in 5‐year disease‐free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.
A Pilot Feasibility Study of Yttrium‐90 Liver Radioembolization Followed by Durvalumab and Tremelimumab in Patients with Microsatellite Stable Colorectal Cancer Liver Metastases
AbstractLessons Learned.Radioembolization with yttrium‐90 resin microspheres can be combined safely with full doses of durvalumab and tremelimumab in patients with metastatic colorectal cancer.Regional radioembolization with yttrium‐90 resin microspheres did not result in any hepatic or extrahepatic responses to a combination of durvalumab and tremelimumab. The lack of immunomodulatory responses to yttrium‐90 on biopsies before and after treatment rules out a potential role for this strategy in converting a “cold tumor” into an “inflamed,” immune responsive tumor.Background.PD‐1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (CRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD‐1 blockade.Methods.Patients with MSS metastatic CRC with liver‐predominant disease who progressed following at least one prior line of treatment were treated with yttrium‐90 (Y90) radioembolization to the liver (SIR‐Spheres; Sirtex, Woburn, MA) followed 2–3 weeks later by the combination of durvalumab and tremelimumab. A Simon two‐stage design was implemented, with a planned expansion to 18 patients if at least one response was noted in the first nine patients.Results.Nine patients enrolled in the first stage of the study, all with progressive disease (PD) during or after their first two cycles of treatment. Per preplanned design, the study was closed because of futility. No treatment‐related grade 3 or greater toxicities were recorded. Correlative studies with tumor biopsies showed low levels of tumor‐infiltrating lymphocyte (TIL) infiltration in tumor cancer islands before and after Y90 radioembolization.Conclusion.Y90 radioembolization can be added safely to durvalumab and tremelimumab but did not promote tumor‐directed immune responses against liver‐metastasized MSS CRC.
Single‐Center Experience with Ifosfamide Monotherapy as Second‐Line Treatment of Recurrent/Metastatic Osteosarcoma
AbstractBackground.The effectiveness of second‐line palliative chemotherapy in patients with recurrent/metastatic osteosarcoma is not well defined. Several small studies (6–19 patients) have reported on ifosfamide as second‐line treatment. In this study we report our single‐center experience with second‐line ifosfamide monotherapy in patients treated for recurrent/metastatic osteosarcoma.Methods.A chart review was conducted of all patients with osteosarcoma treated with ifosfamide from 1978 until 2017. Until 1997 a 5 g/m2 regimen was used, and from 1997 onwards a 9 g/m2 regimen was used. Overall survival (OS) from start of ifosfamide was the primary endpoint. Progression‐free survival (PFS) from start of treatment was also studied. To assess difference in survival between groups the log rank test was applied. To investigate the effect of ifosfamide dose and World Health Organization performance status (PS) a Cox proportional hazard regression model was estimated.Results.Sixty‐two patients were selected with recurrent/metastatic osteosarcoma treated with second‐line ifosfamide monotherapy (dose of 5 g/m2, n = 26; 9 g/m2, n = 36). OS was significantly better in univariate analysis for 9 g/m2 compared with 5 g/m2 (10.9 months [95% confidence interval (CI), 9.3–12.6] vs. 6.7 months [95% CI, 5.9–7.6], respectively) and for PS (median OS PS 0, 13.0 months [95% CI, 2.3–23.8]; PS 1, 8.2 months [95% CI, 5.4–11.1]; PS ≥2, 6.2 months [95% CI, 2.2–10.3]; and unknown PS, 5.4 months [95% CI, 2.2–8.5]). In multivariate analysis only PS showed a significant difference. No difference in PFS was found between 5 and 9 g/m2 ifosfamide treatment or PS.Conclusion.This study suggests that ifosfamide is an effective second‐line treatment for patients with recurrent/metastatic osteosarcoma.Implications for Practice.Ifosfamide monotherapy is commonly used as second‐line treatment in osteosarcoma, although large series to support this are lacking. This retrospective study reports overall and progression‐free survival for regimens with 5 g/m2 and with 9 g/m2. This study was unable to show a significant difference in survival between 5 and 9 g/m2 but showed an important impact of World Health Organization performance status on overall survival. This study sets a standard and reference for comparison with the multiple phase II studies under development.
An Open‐Label, Single‐Arm, Two‐Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas
AbstractBackground.The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC.Methods.This single‐arm, two‐stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m2 of TLC388 intravenously on days 1, 8, and 15 of a 28‐day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next‐generation sequencing.Results.Twenty‐three patients with a median age of 61 (range, 44–73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0–6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression‐free survival was 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival was 4.3 (95% CI, 1.7–15) months. The most common treatment‐related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH.Conclusion.TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273.Implications for Practice.Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum‐based chemotherapy remain elusive. In this single‐arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression‐free survival of 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival of 4.3 (95% CI, 1.7–15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.
AbstractBackground.We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here.Methods.We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety‐related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns.Results.Fifty‐five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety‐related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions—new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety‐related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety‐related changes in the first 2 years after approval.Conclusion.Based on our analysis we conclude that although there was a greater incidence of substantial safety‐related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit‐risk profile of the drug.Implications for Practice.The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.
AbstractPatients with cancer can go though many stages in their disease, including diagnosis, recurrence, metastasis, and treatment failure. Cancer stem cells (CSCs) are a subgroup of cells within tumors that may explain the mechanism by which tumors recur and progress. CSCs can both self‐renew and produce progenitor cells of more differentiated cancer cells as well as heterogeneously demonstrate resistance and the abilities to migrate and metastasize. These “stemness” characteristics are often the result of dysregulation of one or more pathways, which can be detected by various biomarkers. Although there has been considerable laboratory research conducted on CSCs, its relevance to the practicing oncologist may seem questionable. We sought to determine the clinical impact of CSCs on patients. A systematic literature search was conducted to identify analyses containing survival information based on the expression of known CSC biomarkers in any cancer. Overall, 234 survival analyses were identified, of which 82% reported that high expression of CSC biomarker(s) resulted in poor overall survival and/or disease‐free survival compared with low or no expression of the biomarker. Elevated stemness biomarker levels were also associated with decreased tumor differentiation, altered TNM stage, and increased metastasis. This analysis would suggest that CSCs have a clinical impact on patients and that practicing oncologists need to start considering incorporating CSC‐targeting therapies into their patients’ treatment regimens.Implications for Practice.Cancer stem cells (CSCs) may occur at any stage of cancer and are implicated in the occurrence of resistance, recurrence, and metastasis. A systematic literature analysis has shown that the presence of CSCs, identified via the upregulation of stemness pathway biomarkers, results in reduced survival across all cancers studied. Several CSC‐targeting agents are currently approved, and several others are in clinical trials. Future treatment regimens will likely include CSC‐targeting agents to enable the elimination of these holdouts to current therapies.
Incorporating Patient‐Reported Outcome Measures into Breast Surgical Oncology: Advancing Toward Value‐Based Care
AbstractValue in health care is defined as the health outcome achieved per unit of cost. For health care systems, improving value means achieving better outcomes at lower costs. Improving outcomes, including patient‐reported outcomes (PROs), as well as more established metrics such as mortality and complication rates, ensures high‐quality care. This is particularly true in breast cancer surgery, where survival and recurrence rates are comparable across different surgical approaches. Outcomes reflecting survivorship quality may therefore better inform decision making regarding surgical approaches. PROs can be assessed using validated instruments known as patient‐reported outcome measures (PROMs). They are obtained directly from patients reflecting their health‐related quality of life (HRQOL). Ongoing initiatives strive to define PROMs that accurately reflect HRQOL and demonstrate value, with the goal of establishing benchmarks for quality of care. Clinicians caring for patients with breast cancer are well positioned to be involved in defining meaningful measures of value‐based breast cancer care. This article reviews value‐based breast cancer care in the context of locoregional therapy, with attention paid to the work done by the International Consortium of Health Outcome Measures in which a “standard set” of value‐based patient‐centered outcomes for breast cancer for international use is defined. In addition, an overview is provided of relevant PROMs and previously reported scores. Recommendations and future challenges for implementation of routine collection of PROs are also discussed.Implications for Practice.Opportunity exists to act as early adopters of the routine collection of longitudinal patient‐reported outcome data for breast cancer, allowing transition of current care to value‐based cancer care.
Molecular Analyses of Left‐ and Right‐Sided Tumors in Adolescents and Young Adults with Colorectal Cancer
AbstractBackground.The incidence of colorectal cancer (CRC), particularly left‐sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right‐sided tumors (RT) in AYA.Materials and Methods.A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next‐generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data.Results.RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer‐predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB‐high regardless of MSI status.Conclusion.Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA.Implications for Practice.Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right‐ and left‐sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right‐ and left‐sided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double‐strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.
Exceptional Response of Cryoablation Followed by Pembrolizumab in a Patient with Metastatic Cervical Carcinosarcoma with High Tumor Mutational Burden: A Case Report
AbstractCervical carcinosarcoma is an extremely rare type of neoplasm that lacks standard of care. Preclinical and clinical evidence has suggested that cryoablation in combination with immunotherapy may result in a synergistic effect, generating a more robust immune response to distant lesions. A few clinical trials have evaluated the efficacy of such combination treatment in a variety of solid tumors, but with conflicting results. This report describes the first clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden (TMB)‐high metastatic cervical carcinosarcoma that was negative for programmed cell death protein 1 expression, microsatellite instability stable, and had mutations in DNA polymerase epsilon (POLE). She had achieved complete response (CR) after 3 months of pembrolizumab treatment and had maintained CR as of the time of submission of this manuscript, with a progression‐free survival of 11 months and counting. The case exhibited an exceptional response to cryoablation followed by pembrolizumab, potentially attributed to mutations in POLE, which lead to an extremely high TMB. This report paves the avenue for establishing treatment regimens for patients with TMB‐high cervical carcinosarcoma.Key Points.Owing to its rarity, cervical carcinosarcoma has not been well characterized, and currently, there is no standard of care for this disease.This report describes the first case of clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden‐high metastatic cervical carcinosarcoma.The case exhibited an exceptional response (maintained CR as of the time of submission of this article: 11 months) to cryoablation followed by pembrolizumab.This is the first POLE‐mutated cervical carcinosarcoma case.
Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704
AbstractBackground.Several registry‐based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population‐based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial.Materials and Methods.This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97‐04. Survival analysis was performed using the Kaplan‐Meier method and compared using the log‐rank test. Multivariate analysis was performed using the Cox proportional hazards regression model.Results.Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease‐free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients.Conclusion.Ancillary analysis of data from NRG Oncology/RTOG 97‐04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216.Implications for Practice.Several population‐based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.
AbstractBackground.The fluoropyrimidines, 5‐fluorouracil (5‐FU) and capecitabine, are commonly used chemotherapeutic agents that have been associated with coronary vasospasm.Methods.In this retrospective case‐control study, we identified patients at our institution who received 5‐FU or capecitabine in 2018. We compared characteristics of patients who experienced cardiotoxicity with controls. We described phenotypes and outcomes of cardiotoxic cases.Results.We identified 177 patients who received fluoropyrimidines. After adjudication, 4.5% of the cohort met the criteria for cardiovascular toxicity. Coronary artery disease was more common among cases than controls (38% vs. 7%, p < .05). There was also a trend toward increased prevalence of cardiovascular risk factors in cases compared with controls. Most cardiotoxic cases had chest pain, although a minority of cases presented with nonischemic cardiomyopathy.Conclusion.Cardiotoxicity phenotypes associated with fluoropyrimidine use are not limited to coronary vasospasm. Cardiac risk factors and ischemic heart disease were highly prevalent among patients with cardiotoxicity.
Phase II Trial of Trifluridine/Tipiracil in Patients with Advanced, Refractory Biliary Tract Carcinoma
AbstractLessons Learned.Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5‐fluorouracil refractory tumors.FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first‐line therapy.Background.Patients with advanced biliary tract carcinoma (BTC) refractory to first‐line therapy lack an established second‐line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine‐sensitive and ‐resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.Methods.Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression‐free survival (PFS), and toxicity.Results.Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.Conclusion.FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.
Subtype‐Guided 18F‐FDG PET/CT in Tailoring Axillary Surgery Among Patients with Node‐Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: A Feasibility Study
AbstractBackground.The purpose of this study was to investigate the value of 18[F]‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) in tailoring axillary surgery by predicting nodal response among patients with node‐positive breast cancer after neoadjuvant chemotherapy (NAC).Methods.One hundred thirty‐three patients with breast cancer with biopsy‐confirmed nodal metastasis were prospectively enrolled. 18F‐FDG PET/CT scan was performed before NAC (a second one after two cycles with baseline maximum standardized uptake value [SUVmax] ≥2.5), and a subset of patients underwent targeted axillary dissection (TAD). All the patients underwent axillary lymph node dissection (ALND). The accuracy was calculated by a comparison with the final pathologic results.Results.With the cutoff value of 2.5 for baseline SUVmax and 78.4% for change in SUVmax, sequential 18F‐FDG PET/CT scans demonstrated a sensitivity of 79.0% and specificity of 71.4% in predicting axillary pathologic complete response with an area under curve (AUC) of 0.75 (95% confidence interval, 0.65–0.84). Explorative subgroup analyses indicated little value for estrogen receptor (ER)‐negative, human epidermal growth factor receptor 2 (HER2)‐positive patients (AUC, 0.55; sensitivity, 56.5%; specificity, 50.0%). Application of 18F‐FDG PET/CT could spare 19 patients from supplementary ALNDs and reduce one of three false‐negative cases in TAD among the remaining patients without ER‐negative/HER2‐positive subtype.Conclusion.Application of the subtype‐guided 18F‐FDG PET/CT could accurately predict nodal response and aid in tailoring axillary surgery among patients with node‐positive breast cancer after NAC, which includes identifying candidates appropriate for TAD or directly proceeding to ALND. This approach might help to avoid false‐negative events in TAD.Implications for Practice.This feasibility study showed that 18[F]‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) could accurately predict nodal response after neoadjuvant chemotherapy (NAC) among patients with breast cancer with initial nodal metastasis except in estrogen receptor‐negative, human epidermal growth factor receptor 2‐positive subtype. Furthermore, the incorporation of 18F‐FDG PET/CT can tailor subsequent axillary surgery by identifying patients with residual nodal disease, thus sparing those patients supplementary axillary lymph node dissection. Finally, we have proposed a possibly feasible flowchart involving 18F‐FDG PET/CT that might be applied in post‐NAC axillary evaluation.
Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy
AbstractBackground.Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy.Methods.We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR <242 and nonsarcopenic), intermediate‐risk (PLR <242 and sarcopenic), high‐risk (PLR ≥242 and nonsarcopenic), and very‐high‐risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival.Results.Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high‐risk, high‐risk, and intermediate‐risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65–27.01; p < .001; HR, 5.32; CI, 1.96–14.43; p = .001; and HR, 4.01; CI, 1.66–9.68; p = .002, respectively) and progression‐free survival (HR, 12.29; CI, 5.15–29.32; p < .001; HR, 3.51; CI, 1.37–9.02; p = .009; and HR, 2.14; CI, 1.12–4.10; p = .022, respectively) compared with low‐risk patients.Conclusion.Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy‐treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents.Implications for Practice.Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk‐stratification system that combined sarcopenia and platelet‐to‐lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression‐free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk‐stratify patients who are beginning treatment with immunotherapy.
Novel Risk Scoring System for Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors
AbstractBackground.The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the gold standard for risk‐stratifying patients with metastatic renal cell cancer (mRCC). We developed a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (ICIs).Methods.We performed a retrospective analysis of 100 ICI‐treated patients with mRCC at Winship Cancer Institute from 2015 to 2018. Several baseline variables were collected, including markers of inflammation, body mass index (BMI), and sites of metastatic disease, and all were considered for inclusion in our risk scoring system. Upon variable selection in multivariable model, monocyte‐to‐lymphocyte ratio (MLR), BMI, and number and sites of metastases at baseline were used for risk score calculation. Patients were categorized using four‐level risk groups as good (risk score = 0), intermediate (risk score = 1), poor (risk score = 2), or very poor (risk score = 3–4). Cox's proportional hazard model and the Kaplan‐Meier method were implemented for survival outcomes.Results.Most patients were male (66%) with clear cell renal cell carcinoma (72%). The majority (71%) received anti–programmed cell death protein‐1 monotherapy. Our risk scoring criteria had higher Uno's concordance statistics than IMDC in predicting overall survival (OS; 0.71 vs. 0.57) and progression‐free survival (0.61 vs. 0.58). Setting good risk (MLR <0.93, BMI ≥24, and D_Met = 0) as the reference, the OS hazard ratios were 29.5 (95% confidence interval [CI], 3.64–238.9), 6.58 (95% CI, 0.84–51.68), and 3.75 (95% CI, 0.49–28.57) for very poor, poor, and intermediate risk groups, respectively.Conclusion.Risk scoring using MLR, BMI, and number and sites of metastases may be an effective way to predict survival in patients with mRCC receiving ICI. These results should be validated in a larger, prospective study.Implications for Practice.A risk scoring system was created for patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. The results of this study have significant implications for practicing oncologists in the community and academic setting. Importantly, these results identify readily available risk factors that can be used clinically to risk‐stratify patients with metastatic renal cell carcinoma who are treated with immune checkpoint inhibitors.
PD‐L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study
AbstractBackground.PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab.Methods.Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1.Results.CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p = .018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p = .026).Conclusion.Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS.Implications for Practice.The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.
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