Perioperative Outcomes of Melanoma Patients Undergoing Surgery After Receiving Immunotherapy or Targeted Therapy

World Journal of Surgery - Traditional chemotherapy agents adversely affect wound healing and need to be held prior to or after surgery. Immune checkpoint inhibitors (ICIs) and targeted agents are...     

S-phase modulation by irinotecan: pilot studies in advanced solid tumors

Two studies of irinotecan (CPT-11) followed 24 h later by an antimetabolite were conducted. The objectives of the studies were: (1) to determine whether the increase in S-phase in tumor cells seen 24 h after CPT-11 administration in animal studies is seen in advanced solid tumors in patients, (2) to determine the dose of CPT-11 required to produce this effect, (3) to compare two methods (immunohistochemistry, IHC, for cyclin A, and DNA flow cytometry, FC) for evaluating S-phase in tumor biopsies from patients, and (4) to establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of CPT-11, given 24 h before gemcitabine (GEM, 1000 mg/m²). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m² per week for 4 weeks every 6 weeks. Tumor biopsies were obtained before and 24 h after CPT-11 administration before administration of 5-FU and assayed for S-phase by IHC for cyclin A and by FC. The starting dose of CPT-11 was 80 mg/m² per week with subsequent exploration of 40 and 60 mg/m² per week to establish the dose-effect relationship of the increase in tumor cells in S-phase. In the second study, CPT-11 was given 24 h before GEM 1000 mg/m² per week for 2 weeks every 3 weeks. Doses of 20–80 mg/m² were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m² produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m². CPT-11 followed 24 h later by 5-FU 400 mg/m² per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m², 60 mg/m² of CPT-11 was the MTD.This work was presented in part at the 14th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Frankfurt, Germany, November 2002.     

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

BackgroundIn patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.MethodsPatients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).ResultsSymptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.ConclusionsNivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02320058","term_id":"NCT02320058"}}NCT02320058.     

Phase I and II clinical trials for gastric cancer

Gastric cancer remains a global public health problem with considerable heterogeneity in pathogenesis and clinical presentation across geographic regions. Improved understanding of the molecular biology of this disease has opened avenues for targeted intervention. An individualized treatment approach is required for optimal management of this cancer. Overcoming resistance to therapy requires combining targeted agents with the traditional options of chemotherapy/radiation therapy, and also targeting more than 1 pathway of carcinogenesis at a time. Encouraging molecular hypothesis and biomarker-driven trials will lead to improved patient outcomes and may eventually enable the therapeutic nihilism associated with gastric cancer to be overcome.     

Association of Technetium99m MAG-3 renal scintigraphy with change in creatinine clearance following chemoradiation to the abdomen in patients with gastrointestinal malignancies

Background

Information on differential renal function following abdominal chemoradiation is limited. This study evaluated the association between renal function as measured by biochemical endpoints and scintigraphy and dose volume parameters in patients with gastrointestinal malignancies.

Materials and methods

Patients who received abdominal chemoradiation between 2002 and 2009 were identified for this study. Technetium^99m MAG-3 scintigraphy and laboratory data were obtained prior to and after chemoradiation in 6 month intervals. Factors assessed included age, gender, hypertension, diabetes, and dose volume parameters. Renal function was assessed by biochemical endpoints and renal scintigraphy.

Results

Significant reductions in relative renal function of the primarily irradiated kidney and creatinine clearance were seen. Split renal function decreased from 49.75% pre-radiation to 47.74% and 41.28% at 6-12 months and >12 months post-radiation (P=0.0184). Creatinine clearance declined from 90.67ml/min pre-radiation to 82.23ml/min and 74.54ml/min at 6-12 months and >12 months post-radiation (P<0.0001). Univariate analysis of patients who had at least one post-radiation renogram showed the percent volumes of the primarily irradiated kidney receiving ≥ 25 Gy (V₂₅) and 40 Gy (V₄₀) were significantly associated with ≥5% decrease in relative renal function (P=0.0387 and P=0.0438 respectively).

Conclusion

Decline in split renal function using Technetium^99m MAG-3 scintigraphy correlates with decrease in creatinine clearance and radiation dose-volume parameters following abdominal chemoradiation. Change in split perfusion can be detected as early as 6 months post-radiation. Scintigraphy may provide early determination and quantification of subclinical renal injury prior to clinical evidence of nephropathy.     

Assessing the Value of Cemiplimab for Adults With Advanced Cutaneous Squamous Cell Carcinoma: A Cost-Effectiveness Analysis

ObjectivesTo evaluate the cost-effectiveness of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) from a payer perspective in the United States.MethodsA partitioned survival model was developed to assess the cost-effectiveness of cemiplimab versus historical standard of care (SOC). All inputs were identified based on a systematic literature review, supplemented by expert opinion where necessary. Clinical inputs for cemiplimab were based on individual patient data from a cemiplimab phase 2 single-arm trial (NCT27060498). For SOC, analysis was based on a pooled analysis of single-arm clinical trials and retrospective studies evaluating chemotherapy and epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and gefitinib) identified via a systematic literature review (6 of the 27 included studies). Overall survival and progression-free survival were extrapolated over a lifetime horizon. Costs were included for drug acquisition, drug administration, management of adverse events, subsequent therapy, disease management, and terminal care. Unit costs were based on published 2019 US list prices.ResultsIn the base case, cemiplimab versus SOC resulted in an incremental cost-effectiveness ratio of $99 447 per quality adjusted-life year (QALY), where incremental costs and QALYs were $372 108 and 3.74, respectively. At a willingness-to-pay threshold of $150 000/QALY, the probabilistic sensitivity analysis suggests a 90% probability that cemiplimab is cost-effective compared to SOC. Scenario analyses resulted in incremental cost-effectiveness ratios ranging from $90 590 to $148 738.ConclusionsCompared with historical SOC, cemiplimab is a cost-effective use of US payer resources for the treatment of advanced CSCC and is expected to provide value for money.