Safety of extended interval dosing immune checkpoint inhibitors: a multicenter cohort study.

BACKGROUND: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown. METHODS: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described. RESULTS: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront). CONCLUSIONS: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials.

Effects of abiraterone acetate plus prednisone on bone turnover markers in chemotherapy-naïve mCRPC patients after ADT failure: A prospective analysis of the italian real-world study ABITUDE.

BACKGROUND: Bone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. METHODS: Patients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). RESULTS: Of 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53-93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. CONCLUSIONS: AAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

The treatment of melanoma brain metastases before the advent of targeted therapies: associations between therapeutic choice, clinical symptoms and outcome with survival.

The management of melanoma brain metastases (MBM) includes different therapeutic modalities, such as surgery, radiotherapy and chemotherapy. Despite the choice of treatments, survival remains poor, exceeding 1 year only in patients with solitary metastases and absence of extracranial disease. A total of 115 consecutive MBM patients observed between 1994 and 2010 were included in an historical cohort study. Demographic, clinical data and tumour characteristics were collected and survival status was ascertained across the follow-up window. The statistical associations between individual and tumour data and overall survival were investigated using Kaplan-Meier survival function and Cox's multiple regression analysis. The median survival was 4.3 months (95% confidence interval 2.6-6.1). Patients who underwent surgery or stereotactic radiosurgery showed a significantly (P<0.001) better prognosis than those who received chemotherapy and/or radiotherapy or supportive therapies. Patients without clinical symptoms experienced a statistically significant better survival (P=0.02) than patients with clinical symptoms; analogue difference was observed to be in favour of patients whose symptoms improved after the first treatment of MBM (P<0.001). The presence of symptoms, clinical outcome and first treatment received were the only independent variables to predict survival. Patients who cannot receive surgery or stereotactic radiosurgery have the worst overall survival.

Primary melanoma of the esophagus with non-metastatic dark lymph nodes in a female breast cancer patient.

BACKGROUND: Primary melanoma of the esophagus is a very rare and aggressive neoplasm; only a small number of patients survive more than 1 year after initial diagnosis. CASE REPORT: We describe a case of primary melanoma of the esophagus in a woman with a history of invasive breast cancer. The patient suffered from dysphagic and dyspeptic disorders. The abdomen ultrasonography and the esophagogastroscopy showed a lesion located at the esophago-gastric junction extending to the gastric fundus. Histological and immunohistochemical studies revealed a primary esophageal infiltrating melanoma. A total gastrectomy and regional lymphadenectomy with a partial resection of the distal esophagus was performed. RESULTS: During laparotomic exploration, numerous dark lymp hnodes were found. On frozen sections, surprisingly neither malignant cells nor melanin were detected in the lymph nodes. Resection margins were not involved with the tumor. CONCLUSION: Patient is still alive with no evidence of recurrence at 24 months after surgical treatment, alone.

Targeted therapies in melanoma.

In the last decade the incidence of melanoma has been rising. Despite this, survival remains substantially constant because early diagnosis of thin lesions has increased. By contrast, metastatic melanoma continues to have a poor prognosis and it still represents a challenge for oncologists. Response rates with single agent dacarbazine range from 10% to 25% with median survival of 8 months. The advent of new drugs with specific mechanisms of action could help to improve the poor results of traditional therapies. In this review, we focused on the novel agents that entered clinical trials in melanoma patients. We show the results of some clinical trials with target-oriented drugs in melanoma patients. Moreover pre-clinical data and rationale for use in melanoma was explained. Trials with protein-kinase inhibitors, anti-CTLA-4 agents, pro-apoptotic oligonucleotides and anti-angiogenic agents were reviewed. Combinations with chemotherapeutic agents, immunotherapy and vaccine therapy were also analyzed.

Update: current management issues in malignant melanoma.

The incidence of melanoma has increased continuously during the last decade. Surgery is the mainstay of therapy but, for patients with thick lesions or regional metastatic lymph nodes, there is a high risk of relapse. For this group of patients, there is no standard therapy or general agreement amongst oncologists. In this article, we review the current management of melanoma with regard to past completed adjuvant trials and open trials. Moreover, we discuss the role of chemotherapy in metastatic melanoma, in particular with attention to the use of fotemustine.

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer.

BACKGROUND: Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC. PATIENTS AND METHODS: Forty-eight patients entered the trial and received irinotecan 350 mg/m2 d.1 and raltitrexed 3 mg/m2 d.2, every three weeks. After recruitment of the first 16 patients, grade III-IV toxicity was observed in 6 patients (38%). Therefore, an amendment reduced by 15% the dose of both drugs (irinotecan 300 mg/m2, raltitrexed 2.6 mg/m2). RESULTS: A total of 290 cycles were administered (range 1-18, median number 6). According to intention-to-treat analysis, the overall response rate was 27% (95% confidence interval 16%-42%), including 3 complete responses and 10 partial responses. The median duration of response was 10 months, while median progression-free survival and overall survival were 5 and 14 months, respectively. In the first 16 patients, the main toxicities were grade III-IV diarrhea in 25% and grade III-IV neutropenia in 13%. In the subsequent 32 patients, they were grade III-IV diarrhea in 34% and grade III neutropenia in 6%. Two toxic deaths occurred. CONCLUSION: The combination irinotecan-raltitrexed is an active regimen, but the significant incidence of side-effects requires accurate patient selection and, eventually, new schedules.