Medical education and training consists of a series of stepped transitions, each marked by increasing autonomy and responsibility. Perhaps the most formidable transition begins upon the completion of ...one’s training and stretches well into the first year of “attendinghood.” This period is often defined by colossal changes that can extend far beyond the workplace and that are largely inconceivable beforehand. These changes can have important implications for job satisfaction, well-being, and resilience, especially in oncology, where rates of work-related burnout are particularly high. Unfortunately there is no “standard of care” or evidence-based guideline on how best to approach this period. However, it must be highlighted and deliberately discussed among current fellows and recent graduates not only to stimulate further study but also to provide support and community for those approaching or going through this transition.
Summary
Background
Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been ...prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC.
Methods
Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed.
Results
Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months.
Conclusion
Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.
Despite their remarkable efficacy in metastatic non-small cell lung cancer (NSCLC), EGFR- and ALK-targeted therapies have not been shown to confer any survival benefit in stage III disease, even in ...subsets of patients with driver mutations.
Here, two patients with unresectable stage III NSCLC carrying mutations in the ALK (case 1) and EGFR (case 2) genes are presented. Treatment of the patient carrying an ALK mutation with an ALK inhibitor and the patient carrying an EGFR mutation with an EGFR inhibitor resulted in dramatic and durable responses.
These cases demonstrated that ALK or EGFR mutation-positive stage III NSCLC patients can be treated with the corresponding inhibitors. They also highlight the urgent need for prospective data to assess their potential efficacy in order to improve patient outcomes.
Background
Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor ...Xa inhibitors (low‐molecular‐weight heparin LMWH or direct oral anticoagulants DOACs). However, to the authors' knowledge, the safety of such combinations has not been well characterized.
Methods
Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups.
Results
Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow‐up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28‐4.69 P = .007) and first‐onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13‐4.42 P = .02). Analysis of 6‐month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone.
Conclusions
Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.
The results of the current study suggest that there is an increased risk of bleeding with the concurrent use of vascular endothelial growth factor receptor tyrosine kinase inhibitors and factor Xa inhibitors in patients with metastatic cancer. Careful monitoring is required and future studies are warranted to further understand and assess how to safely administer concurrent treatment in this at‐risk population.
Background
Immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combinations are a new standard of care for the initial treatment of metastatic renal cell carcinoma (mRCC). Their efficacy ...and toxicity beyond the first‐line setting remain poorly defined.
Methods
We retrospectively reviewed charts for 85 adults with mRCC of any histology receiving combination of ICI/TKI in any line of treatment at two academic centers as of 05/01/2020. We collected clinical, pathological, and treatment‐related variables. Outcomes including objective response rate (ORR), progression‐free survival (PFS), and toxicity were analyzed via descriptive statistics and the Kaplan–Meier method.
Results
Patients received pembrolizumab, nivolumab, avelumab, or nivolumab–ipilimumab, with concurrent use of sunitinib, axitinib, pazopanib, lenvatinib, or cabozantinib. Thirty‐three patients received first‐line ICI/TKI therapy, while 52 received ≥ second‐line ICI/TKI. The efficacy of ICI/TKI therapy decreased with increasing lines of treatment (ORR: 56.7%, 37.5%, 21.4%, and 21%; median PFS mPFS: 15.2, 14.2, 10.1, and 6.8 months, for first, second, third, and ≥ fourth line therapy, respectively). In the ≥ second‐line setting, ICI/TKI was most useful in patients who received ICI only, with an ORR of 50% and a mPFS of 9.1 months. Efficacy was limited in patients who received both TKI and ICI previously, with an ORR of 20% and a mPFS of 5.5 months. Overall, ≥ second‐line ICI/TKI was tolerable with 25 of 52 (52%) patients developing grade ≥3 adverse events.
Conclusions
ICI/TKI combination therapy is feasible and safe beyond the first‐line setting. Prior treatment history appears to impact efficacy but has a lesser effect on safety/tolerability.
ICI/TKI combination therapy is effective and safe beyond the first‐line setting. Prior treatment history appears to impact efficacy but has a lesser effect on safety/tolerability.
Background
Salvage nivolumab and ipilimumab after prior anti‐PD‐1/PD‐L1 therapy is frequently used off‐label for clear cell metastatic renal cell carcinoma (mRCC). However, limited data are available ...to guide such therapy. We performed a meta‐analysis to characterize further the safety and efficacy of salvage nivolumab and ipilimumab.
Methods
We conducted a systematic review in accordance with PRISMA. Studies of salvage nivolumab and ipilimumab in patients with mRCC published in English before June 1, 2021 were included. We also included patients treated at the Ohio State University from 2012 to 2020 through a retrospective chart review. The included studies were further stratified into adaptive and standard groups based on their designs. We calculated objective response rate (ORR) and adverse events (AEs) via pooled data and quantitative synthesis using the Stata metaprop procedure. A conservative random effect model was used to combine values.
Results
A total of 7 studies and 310 patients were included. Salvage nivolumab and ipilimumab had an ORR of 14% (95% CI, 0.09–0.21) and median progression‐free survival ranged between 3.7 and 5.5 months. Four out of the seven studies were standard design, whereas the other three studies were adaptive. The ORR was numerically higher in the standard group compared with the adaptive group (21% and 9–10%, respectively). The responses to salvage nivolumab and ipilimumab did not correlate with the initial anti‐PD‐1/PD‐L1 responses (odds ratio = 1.45; p = 0.5). Grade ≥3 AEs occurred in 26% of the patients (95% CI, 0.19–0.33). There were no new safety signals observed in this study.
Conclusion
Salvage nivolumab and ipilimumab demonstrated moderate antitumor activity and a manageable safety profile in patients with mRCC who had prior anti‐PD‐1/PD‐L1 therapy.
Implication for Practice
Patients with metastatic renal cell carcinoma have limited treatment options after progressive disease on anti‐PD‐1/PD‐L1 therapy. The role of salvage nivolumab and ipilimumab in this patient population is poorly defined. The studies on this highly important and clinically relevant topic are limited by small sample sizes. The results from our meta‐analysis suggest that nivolumab and ipilimumab are feasible in the salvage setting with moderate efficacy and acceptable toxicity profile. The response rates differ with different treatment designs. This information will be beneficial to guide clinical decision‐making and accurately estimating toxicity.
The role of salvage nivolumab and ipilimumab after progressive disease on anti‐PD‐1/PD‐L1 therapy is poorly defined. The studies on this highly important and clinically relevant topic are limited by small sample sizes. The results from our meta‐analysis suggest that nivolumab and ipilimumab are feasible in the salvage setting with moderate efficacy and acceptable toxicity profile. The response rates differ with different treatment designs.
Docetaxel is widely used in metastatic castration-resistant prostate cancer (mCRPC), however its optimal use remains unclear in the current treatment landscape. Biomarkers to predict Docetaxel ...toxicity may help optimize treatment selection. We aimed to create a predictive model for toxicity-related Docetaxel discontinuation (TRDD).
Through Project Data Sphere, we accessed individual patient data from the control arms of three frontline mCRPC trials: ASCENT2, VENICE, and MAINSAIL. The inclusion criteria for these trials were all similar and included patients with chemotherapy-naïve mCRPC. The primary outcome was occurrence of TRDD. A competing risks regression (CRR) was used to predict TRDD, after accounting for the occurrence of competing events (death or progression). The output of the model was used as the dependent variable on a classification and regression tree (CART) to identify risk groups for TRDD.
Overall, 1568 patients were considered. Pooled CI of TRDD was 19% after accounting for competing events (death: 474; progression: 59) within 12 months of starting treatment. To build a risk calculator we relied on a CRR that ultimately included age, ECOG performance status, AST, bilirubin, use of analgesics, and presence of diabetes and chronic kidney disease. The CART analysis identified three risk groups that were named: low (model-derived TRDD risk ≤24%), intermediate (25-64%), and high (≥65%) risk group. In each risk group, probability of TRDD during treatment was 14%, 58%, and 79%, and median OS was 24 months, 20 months, and 13 months, respectively (p < 0.001).
Treatment selection in mCRPC remains a challenge. Our model can help clinicians balance Docetaxel toxicity and efficacy. The three risk categories that we identified correlated with OS and this is particularly useful for an optimal shared decision-making process.
Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors.
We report a ...case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia.
This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.
Objectives
Response to immune checkpoint inhibitor (ICI) remains limited to a subset of patients and predictive biomarkers of response remains an unmet need, limiting our ability to provide precision ...medicine. Using real-world data, we aimed to identify potential clinical prognosticators of ICI response in solid tumor patients.
Methods
We conducted a retrospective analysis of all solid tumor patients treated with ICIs at the Mount Sinai Hospital between January 2011 and April 2017. Predictors assessed included demographics, performance status, co-morbidities, family history of cancer, smoking status, cancer type, metastatic pattern, and type of ICI. Outcomes evaluated include progression free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Univariable and multivariable Cox proportional hazard models were constructed to test the association of predictors with outcomes.
Results
We identified 297 ICI-treated patients with diagnosis of non-small cell lung cancer (N = 81, 27.3%), melanoma (N = 73, 24.6%), hepatocellular carcinoma (N = 51, 17.2%), urothelial carcinoma (N = 51, 17.2%), head and neck squamous cell carcinoma (N = 23, 7.7%), and renal cell carcinoma (N = 18, 6.1%). In multivariable analysis, good performance status of ECOG ≤ 2 (PFS, ORR, DCR and OS) and family history of cancer (ORR and DCR) associated with improved ICI response. Bone metastasis was associated with worse outcomes (PFS, ORR, and DCR).
Conclusions
Mechanisms underlying the clinical predictors of response observed in this real-world analysis, such as genetic variants and bone metastasis-tumor microenvironment, warrant further exploration in larger studies incorporating translational endpoints. Consistently positive clinical correlates may help inform patient stratification when considering ICI therapy.
Antibiotic stewardship is an integral aspect of hospital care, limiting the potential for resistance while working to minimize waste. A similar system is needed in oncology, given the rapid ...proliferation of new therapies and the challenges of navigating a complicated reimbursement environment. A "cancer therapy stewardship program" has never been described in the literature. Here, we detail our efforts to design and implement such a program and share lessons learned to inform future projects.
For 1 year, a hematologist-oncologist (the "cancer therapy steward") at Mount Sinai Hospital was in charge of addressing all requests for nonformulary or off-label chemotherapeutic and supportive medications and regimens. Requests consisted of the rationale for use and supporting data from medical journal articles. This pilot initiative was focused mainly on inpatient malignant hematology.
Sixty-seven requests were made by 23 physicians, and all requests were ultimately approved. Requests tended to fall into 3 categories: 1) use of a single drug in a setting not approved by the FDA, 2) use of multiple drugs in novel combinations not approved by the FDA, and 3) adding novel drugs to existing FDA-approved regimens.
Our cancer therapy stewardship program yielded many useful insights into how our physicians face challenging clinical situations. It also helped to improve overall clinical quality and patient care by emphasizing the importance of value-based care and evidence-based medicine. Expanding this program will likely lead to many interesting experiments aimed at improving medical education and research, patient safety outcomes, and clinical quality.
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