Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease.

PURPOSE: Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP. PATIENTS AND METHODS: Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score. RESULTS: Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively. CONCLUSION: TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Testicular cancer in 2023: Current status and recent progress.

Testicular germ cell tumor (GCT) is the most common solid tumor in adolescent and young adult men. Progress in the management of GCT has been made in the last 50 years, with a substantial improvement in cure rates for advanced disease, from 25% in the 1970s to nearly 80%. However, relapsed or platinum-refractory disease occurs in a proportion, 20% of whom will die from disease progression. This article reviews the current evidence-based treatments for extracranial GCT, the acute and chronic toxic effects that may result, and highlights contemporary advances and progress in the field.

Resistance mechanism to fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma.

Precision medicine is a major achievement that has impacted on management of patients diagnosed with advanced cholangiocarcinoma (CCA) over the last decade. Molecular profiling of CCA has identified targetable alterations, such as fibroblast growth factor receptor-2 (FGFR-2) fusions, and has thus led to the development of a wide spectrum of compounds. Despite favourable response rates, especially with the latest generation FGFRi, there are still a proportion of patients who will not achieve a radiological response to treatment, or who will have disease progression as the best response. In addition, for patients who do respond to treatment, secondary resistance frequently develops and mechanisms of such resistance are not fully understood. This review will summarise the current state of development of FGFR inhibitors in CCA, their mechanism of action, activity, and the hypothesised mechanisms of resistance.

Prognosis Discussion and Referral to Community Palliative Care Services in Patients with Advanced Pancreatic Cancer Treated in a Tertiary Cancer Centre.

Advanced pancreatic cancer is associated with a poor prognosis, often less than 1 year. Honest prognosis discussions guide early community palliative care services input, facilitating timely advance care planning and improving quality of life. The aims were to assess if patients were offered prognosis discussions and community palliative care services referral. A retrospective analysis of consecutive case-notes of new advanced pancreatic cancer patients was conducted. Chi-squared test assessed the association with prognosis discussion and community palliative care services referral. In total, 365 cases (60%) had a documented prognosis discussion at any time-point in the treatment pathway; 54.4% during the first appointment. The frequency of prognosis discussion was greater with nurse clinician review at first appointment (p < 0.001). In total, 171 patients (28.1%) were known to community palliative care services at the first appointment. Of those not known, 171 (39.1%) and 143 (32.7%) were referred at this initial time-point or later, respectively. There was a significant association between the referral to community palliative care services at first appointment and the reviewing professional (this was greatest for nurse clinicians (frequency 65.2%)) (p < 0.001), and also if reviewed by clinical nurse specialist at first visit or not (47.8% vs. 35.6%) (p < 0.01). Prognosis discussions were documented in approximately two-thirds of cases, highlighting missed opportunities. Prognosis discussion was associated with clinician review and was most frequent for nurse clinician, as was referral to community palliative care services. Clinical nurse specialist review increased referral to community palliative care services if seen at the initial visit. Multi-disciplinary review, specifically nursing, therefore, during the first consultation is imperative and additive. It should be considered best practice to offer and negotiate the content and timing of prognosis discussions with cancer patients, and revisit this offer throughout their treatment pathway. Greater attention to prognosis discussion documentation is recommended.

Supportive care interventions for men with urological cancers: a scoping review.

PURPOSE: To identify supportive care interventions for men with urological cancers. METHODS: Experimental studies conducted among men with any urological cancer were eligible for inclusion. Academic Search Complete, CINAHL Plus with Full Text, MEDLINE, APA PsycArticles, APA PsycInfo, Social Sciences Full Text (H.W. Wilson), SocINDEX with Full Text, ERIC, Google Scholar and ClinicalTrials.gov were searched on 6 December 2022. No database limits were applied. The included studies were methodologically appraised. A narrative synthesis of the results was conducted. RESULTS: Thirty studies were included with 10 categories of interventions identified. Over 300 outcomes were measured, and more than 100 instruments were used. Multicomponent interventions generally led to positive changes in physiological outcomes like body mass index, as well as exercise tolerance and quality of life. This change, however, was not sustained in the long term. Cognitive-behavioural interventions significantly improved psychological symptoms but seldom physical symptoms. Telephone and web-based interventions showed great promise in improving outcomes like depression, positive affect, negative affect, perceived stress, spiritual wellbeing and fatigue. Findings from physical activity/exercise-based interventions were promising for both, physical and psychological outcomes. Rehabilitative interventions were associated with significant improvements in quality of life, urinary symptoms and psychological symptoms, albeit in the short term. Mixed results were reported for nurse-led interventions, family-based interventions and nutritional interventions. CONCLUSION: All but one study focused exclusively on prostate cancer. The included studies were significantly heterogeneous. Multicomponent, cognitive-behavioural, telephone and web-based, physical activity/exercise-based and rehabilitative interventions showed great promise in improving various outcomes. This improvement, however, was often short-lived.

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. EXPERIMENTAL DESIGN: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. RESULTS: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. CONCLUSIONS: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

The current role for adjuvant and neoadjuvant therapy in renal cell cancer.

PURPOSE OF REVIEW: Here we explore the recent and relevant trials for treatment of renal cell cancer (RCC) in the adjuvant and neoadjuvant settings as well as recent updates to the guidelines for RCC management. RECENT FINDINGS: Most phase III studies of tyrosine kinase inhibitors in the adjuvant setting have been negative. Notably, sunitinib received regulatory approval by the FDA after showing improved disease-free survival in high risk populations. Recent improvements in the genetic classification and understanding of RCC molecular and genetic disorder will hopefully improve patient selection. Meanwhile, recent advances in metastatic RCC treatment, particularly with the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors, have given rise to hope that advances can be made by moving these treatment strategies forward to the adjuvant or neoadjuvant settings. SUMMARY: In the absence of a clinical trial, observation remains the standard of care. Based on the S-TRAC data, sunitinib is approved for use in the adjuvant setting, and can be considered under select circumstances. Although there is optimism for checkpoint monotherapy and combination therapy in the adjuvant or neoadjuvant setting, ongoing studies will determine clinical benefit and tolerability in this setting. Therefore, for patients with high risk of recurrent disease clinical trials of checkpoint inhibitor therapy are viable options.

PI3K inhibition to overcome endocrine resistance in breast cancer.

INTRODUCTION: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. AREAS COVERED: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. EXPERT OPINION: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.