Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

BACKGROUND: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. METHODS: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. RESULTS: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. CONCLUSION: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

Eosinophilic Fasciitis Following Checkpoint Inhibitor Therapy: Four Cases and a Review of Literature.

BACKGROUND: Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature. CASE PRESENTATION: We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy. CONCLUSION: Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator. IMPLICATIONS FOR PRACTICE: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.

BACKGROUND: Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). PATIENTS AND METHODS: This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. RESULTS: Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. CONCLUSIONS: Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.

Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. RESULTS: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). CONCLUSION: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

BACKGROUND: Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. OBJECTIVE: To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. DESIGN SETTING AND PARTICIPANTS: Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. INTERVENTION: Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. RESULTS AND LIMITATIONS: For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1-17%], arm 2: 17.1% [95% CI: 7-32%], arm 3: 11.9% [95% CI: 4-26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9-36.1]) relative to degarelix (52.9 wk [95% CI: 49.0-56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. CONCLUSIONS: Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. PATIENT SUMMARY: We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients.

INTRODUCTION: Aromatase inhibitors (AIs) have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. However, patients receiving AIs may experience joint symptoms, which may lead to early discontinuation of this effective therapy. We hypothesize that acupuncture is a safe and effective treatment for AI-induced arthralgias. METHODS: Postmenopausal women with early-stage breast cancer who had self-reported musculoskeletal pain related to adjuvant AI therapy were randomized in a crossover study to receive acupuncture twice weekly for 6 weeks followed by observation or vice-versa. The intervention included full body and auricular acupuncture, and a joint-specific point prescription. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life measure, and serum levels of inflammatory markers, IL-1 beta and TNF-alpha. RESULTS: Twenty-one women were enrolled and two discontinued early. From baseline to the end of treatment, patients reported improvement in the mean BPI-SF worst pain scores (5.3 to 3.3, p = 0.01), pain severity (3.7 to 2.5, p = 0.02), and pain-related functional interference (3.1 to 1.7, p = 0.02), as well as the WOMAC function subscale and FACT-G physical well-being (p = 0.02 and 0.04, respectively). No adverse events were reported. DISCUSSION/CONCLUSIONS: In this pilot study, acupuncture reduced AI-related joint symptoms and improved functional ability and was well-tolerated. IMPLICATIONS FOR CANCER SURVIVORS: Musculoskeletal side effects are common among breast cancer survivors on adjuvant AI therapy, therefore, effective treatments are needed for symptom relief and to improve adherence to these life-saving medications.

Patient-provider relationships, HIV, and adherence: requisites for a partnership.

This paper analyzes data collected through focus groups of patients at an outpatient AIDS clinic at a New York medical center. Seven focus groups were conducted with 42 HIV+ patients, and verbatim transcripts of focus group sessions were analyzed through a combination of ethnographic and content analysis. We examined patients' reports of interactions with and attitudes toward their providers and attempted to define what elements in the provider-patient relationship are necessary to enable patients to become more integrally involved in the management of their illness. Participants' statements emerged as consistent with three themes: (a) dynamics of provider-to-patient communication; (b) dynamics of patient-to-provider communication; and (c) dynamics of collaboration. Each of these themes is discussed in terms of its implications for creating patient-provider relationships based on mutual-participation, and requisites for effecting meaningful patient-provider partnerships are outlined.