Front-Line Therapeutic Strategy in Metastatic Hormone Sensitive Prostate Cancer: An Updated Therapeutic Algorithm.

Prostate carcinoma (PC), the second most diagnosed cancer globally, saw approximately 1,414,000 new cases in 2020, with 17% being de novo metastatic. In these cases, the 5-year relative survival rate is 32%. Metastatic hormone-sensitive prostate cancer (mHSPC) includes those with metastatic disease at initial diagnosis or after initial therapy without long-term androgen deprivation therapy (ADT), eventually progressing to castration-resistant prostate cancer (CRPC). The established therapeutic principle of ADT has persisted for 80 years, with luteinizing hormone-releasing hormone (LHRH) agonists like leuprorelin being commonly used. LHRH antagonists, such as degarelix, have also emerged. Recent advances in mHSPC treatment involve combination strategies with drugs proven effective in CRPC, considering prognostic factors like disease volume and presentation. This review outlines pivotal trials leading to drug approvals in mHSPC and proposes a treatment decision algorithm for the same, based on statement from the Tuscan Interdisciplinary Uro-Oncological Group. A multidisciplinary approach is crucial to tailor treatment intensity and weigh risks and benefits effectively.

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. In addition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients.

BACKGROUND/OBJECTIVES: Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. METHODS: Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). CONCLUSIONS: We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system.

Impact of Metastatic Site in Favorable-Risk Renal Cell Carcinoma Receiving Sunitinib or Pazopanib.

BACKGROUND: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. MATERIAL AND METHODS: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. RESULTS: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. CONCLUSION: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites.

A case report of a lung cancer patient with two uncommon EGFR mutations and a review of the literature: two sides of the same coin.

Lung cancer is the malignancy with the highest morbidity and mortality worldwide. Approximately 60% of non-small cell lung cancer (NSCLC) presents driver alterations most of which are targetable. Nowadays, limited clinical data are available regarding the efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with NSCLC harboring uncommon EGFR mutations, considering their heterogeneity. Herein, we report a rare case of EGFR-mutated lung adenocarcinoma which has developed into squamous cell carcinoma with uncommon EGFR (Ex18) compound mutations and phosphatidylinositol 3-kinase mutation receiving afatinib at the forefront.

Platinum-based chemotherapy in metastatic prostate cancer: what possibilities?

Metastatic prostate cancer is a major health burden worldwide, necessitating the continuous development of effective treatment strategies. Androgen deprivation therapy remains the cornerstone of prostate cancer treatment, but novel approaches are needed for metastatic castration-resistant prostate cancer (mCRPC). Recent studies have highlighted the prevalence of mutations in DNA repair genes, including BRCA1 and BRCA2, in mCRPC patients, rendering them more susceptible to platinum-based chemotherapy and Poly (ADP-ribose) polymerase (PARP) inhibitors. Platinum-based chemotherapy, particularly in combination with taxanes, has demonstrated encouraging activity in mCRPC, as well as homologous recombination gene alterations have shown increased sensitivity to platinum compounds in these patients. The combination of platinum-based chemotherapy with PARP inhibitors represents a novel and potentially effective therapeutic strategy for this subgroup of patients. However, the optimal sequence of administering these agents and the potential for cross-resistance and cross-toxicities remain areas requiring further investigation. Prospective randomized studies are essential to elucidate the most effective treatment approach for this challenging patient population. This review aims to explore the potential of platinum-based chemotherapy in the context of prostate cancer, and more in detail in homologous recombination repair (HRR) mutated patients. We discuss the synergistic effects of combining platinum compounds with PARP inhibitors and the potential benefits of adopting specific therapeutic sequences.

Prognostic role of sodium levels in colorectal cancer patients receiving aflibercept plus FOLFIRI.

Aim: To investigate the impact of natremia in metastatic colorectal cancer (mCRC) patients treated with aflibercept plus folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRI). Patients & methods: A total of 84 mCRC patients receiving aflibercept plus FOLFIRI as second-line treatment were enrolled and divided into two groups based on their median sodium value. Progression-free survival and overall survival were analyzed. Results: Patients with sodium levels ≥140 mEq/l had significantly longer median progression-free survival (4.1 vs 2 months; p < 0.01) and median overall survival (12 vs 7.3 months; p < 0.01) compared with those with lower levels. Conclusion: This study suggests that higher pretreatment serum sodium levels are associated with improved outcomes in mCRC patients receiving aflibercept and FOLFIRI, potentially serving as a prognostic marker to aid treatment management.

What is this article about? Colorectal cancer (CRC) is a common and deadly disease. Despite advances in treatment options, the prognosis remains poor for patients who progress beyond the first-line therapy. Antiangiogenic therapy, which targets blood vessel growth in tumors, has become an important treatment approach for metastatic CRC (mCRC). Aflibercept is a drug used in combination with chemotherapy to treat mCRC patients who have progressed after initial treatment. However, there is limited knowledge about factors that can predict the effectiveness of this treatment. This study aimed to investigate the relationship between sodium levels and treatment outcomes in 84 mCRC patients receiving aflibercept and chemotherapy as second-line therapy. What were the results? The results showed that patients with baseline sodium levels of ≥140 mEq/l had significantly longer progression-free survival and overall survival compared with patients with lower sodium levels. This finding suggests that baseline serum sodium levels could serve as a prognostic factor for survival outcomes in mCRC patients treated with aflibercept and chemotherapy. Other factors associated with better survival outcomes included longer survival without disease progression after first-line chemotherapy, receiving maintenance treatment with aflibercept and completing more treatment cycles. What do the results of the study mean? This study highlights the potential significance of serum sodium levels as a predictor of treatment effectiveness in mCRC patients. Further research is needed to confirm these findings and better understand the underlying mechanisms. Evaluating serum sodium levels could be a useful tool in predicting outcomes and improving treatment strategies for mCRC patients.

Sodium Levels and Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving Nivolumab.

Importance: Low sodium levels have been associated with negative outcomes among patients with metastatic renal cell carcinoma (mRCC) receiving therapies other than immune checkpoint inhibitors (ICIs). Objective: To investigate the role of natremia in patients with mRCC receiving nivolumab as a second-line or subsequent therapy. Design, Setting, and Participants: In this retrospective cohort study, the clinical and biochemical data of patients with mRCC receiving nivolumab were collected from October 2015 to November 2019 as part of a multicenter Italian study. Data analysis was performed from February to March 2023. Exposure: Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks and, since May 2018, at a fixed dose of 240 mg every 2 weeks or 480 mg every 4 weeks. Patients were divided into 2 groups according to their median serum sodium value (<140 or ≥140 mEq/L). Main Outcomes and Measures: The primary outcomes were the associations of pre-ICI and post-ICI sodium levels with overall survival (OS), progression-free survival (PFS), objective response rate, and disease control rate (DCR). The Kaplan-Meier method was used to estimate PFS and OS, and differences between groups were compared using the log-rank test. Results: A total of 401 patients with mRCC receiving nivolumab as second-line therapy were evaluated, and 355 eligible patients (median [range] age, 76 [44-84] years; 258 male patients [72.7%]) were included in the final cohort. Among patients with pre-ICI sodium greater than or equal to 140 mEq/L compared with those with sodium less than 140 mEq/L, the median PFS was 9.3 months (95% CI, 6.5-11.5 months) vs 7.4 months (95% CI, 4.6-10.1 months; P = .90), and the median OS was 29.2 months (95% CI, 21.8-35.9 months) vs 20.0 months (95% CI, 14.1-26.8 months; P = .03). Patients with post-ICI sodium values greater than or equal to 140 mEq/L had longer PFS (11.1 months [95% CI, 8.5-1.5 months] vs 5.1 months [95% CI, 4.1-7.5 months]; P = .01) and OS (32.9 months [95% CI, 25.1-42.6 months] vs 17.1 months [95% CI, 12.6-24.5 months]; P = .006) compared with patients with sodium values less than 140 mEq/L. Patients with both pre-ICI and post-ICI sodium values greater than or equal to 140 mEq/L exhibited a significant improvement in clinical outcomes compared with those with a value less than 140 mEq/L (PFS, 11.5 months [95% CI, 8.8-16.4 months] vs 5.8 months [95% CI, 4.4-8.3 months]; P = .008); OS, 37.6 months [95% CI, 29.0-49.9 months] vs 19.4 months [95% CI, 14.1-24.5 months]; P = .01). Moreover, sodium levels greater than or equal to 140 mEq/L were associated with significantly better DCR than lower sodium levels. Conclusions and Relevance: In this retrospective cohort study of patients with mRCC receiving nivolumab, sodium values greater than or equal to 140 mEq/L, both before and/or after ICI, were associated with better OS and PFS, as well as a higher DCR, compared with levels less than 140 mEq/L. These findings suggest that sodium levels may be associated with survival outcomes in patients with mRCC and may have potential use as variables to consider in patients' risk scores.

Enfortumab vedotin in metastatic urothelial carcinoma: the solution EVentually?

Metastatic urothelial carcinoma (mUC) is an aggressive malignancy with a dismal prognosis. Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of an antibody targeting Nectin-4. This protein is highly expressed in UC cells. After binding, monomethyl auristatin E is released into cells, causing UC cell death. EV has been approved as a single agent for pre-treated mUC, with interesting improvements in response rate and survival in a setting with limited treatment options. More recently, EV approval occurred in cisplatin-ineligible naïve mUC patients in combination with pembrolizumab. Our review aims to summarize the pharmacological properties, clinical studies, and future developments of EV in mUC.

Personalized medicine for metastatic prostate cancer: The paradigm of PARP inhibitors.

Despite remarkable progress in the last decade, metastatic prostate cancer (mPCa) remains incurable. The approval of PARP inhibitors (PARPis) represents a milestone in this field, which definitively enters the era of precision medicine, as mPCa is often enriched for defects of homologous recombination repair genes. PARPis are now used as single agents for patients with metastatic castration-resistant PCa. Moreover, combinations of PARPis plus androgen-receptor targeted agents and immune checkpoint inhibitors, and earlier applications of PARPis in the metastatic hormone-sensitive PCa are under evaluation, representing the possible upcoming applications of these agents. Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents.

Immunotherapy-related biomarkers: Confirmations and uncertainties.

Immunotherapy profoundly changed oncology treatment, becoming one of the main therapeutical strategies. Remarkable improvement has been achieved in survival outcomes, but the percentage of patients who benefit from immunotherapy is still limited. Only one-third of patients receiving immune checkpoint inhibitors (ICIs) achieve long-term response. Several patients are not responsive to treatment or relapse after an initial response. To date, programmed death-ligand 1, microsatellite instability, and tumor mutational burden are the three biomarkers validated to predict the ICIs response, but a single variable seems still insufficient in the patient's selection. Considering the substantial and increasing use of these drugs, the identification of new predictive biomarkers of ICI response is of paramount importance. We summarize the state of the art and the clinical use of immune biomarkers in oncology, highlighting the strength and weaknesses of currently approved biomarkers, describing the emerging tissues and circulating biomarkers, and outlining future perspectives.

Cancer management during the COVID-19 world pandemic.

Since 2019, the world has been experiencing an outbreak of a novel beta-coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV)-2. The worldwide spread of this virus has been a severe challenge for public health, and the World Health Organization declared the outbreak a public health emergency of international concern. As of June 8, 2023, the virus' rapid spread had caused over 767 million infections and more than 6.94 million deaths worldwide. Unlike previous SARS-CoV-1 and Middle East respiratory syndrome coronavirus outbreaks, the COVID-19 outbreak has led to a high death rate in infected patients; this has been caused by multiorgan failure, which might be due to the widespread presence of angiotensin-converting enzyme 2 (ACE2) receptors-functional receptors of SARS-CoV-2-in multiple organs. Patients with cancer may be particularly susceptible to COVID-19 because cancer treatments (e.g., chemotherapy, immunotherapy) suppress the immune system. Thus, patients with cancer and COVID-19 may have a poor prognosis. Knowing how to manage the treatment of patients with cancer who may be infected with SARS-CoV-2 is essential. Treatment decisions must be made on a case-by-case basis, and patient stratification is necessary during COVID-19 outbreaks. Here, we review the management of COVID-19 in patients with cancer and focus on the measures that should be adopted for these patients on the basis of the organs or tissues affected by cancer and by the tumor stage.

Tumor microenvironment in renal cell carcinoma: what is the current impact?

Tweetable abstract Tumor microenvironment plays a critical role in tumor progression and response to therapy. Recent studies show the potential of gene expression signatures and T cells to predict response to immunotherapy in renal cell carcinoma.

Tyrosine kinase and immune checkpoints inhibitors in favorable risk metastatic renal cell carcinoma: Trick or treat?

Over the past decade, the management of metastatic renal cell carcinoma (RCC) has undergone rapid evolution, culminating in a significant improvement in prognosis with frontline immunotherapy. RCC is a highly immunogenic and pro-angiogenic cancer, and mounting evidence has established the immunosuppressive effects of pro-angiogenic factors on the host's immune system. Anti-angiogenic agents such as tyrosine kinase inhibitors (TKIs) and bevacizumab, which obstruct the vascular endothelial growth factor pathway, have demonstrated the potential to enhance antitumor activity and improve the efficacy of immune checkpoint inhibitors (ICIs). Consequently, various combinations of TKIs and ICIs have been assessed and are currently considered the preferred regimens for all metastatic RCC patients, regardless of their prognostic risk score. Nevertheless, some inquiries have arisen within the medical community, as metastatic RCC patients with favorable risk scores who received ICIs and TKIs in combination showed no statistically significant advantage in overall survival compared to those treated with sunitinib alone. Considering these concerns, this review aims to elucidate the rationale behind TKI and ICI combination therapies, provide a summary of current first-line metastatic RCC combinations approved for use, with a focus on favorable-risk patients, and outline present challenges and future perspectives in this context.

Clinical outcome and safety profile of metastatic pancreatic cancer patients treated with more than six cycles of nab-paclitaxel plus gemcitabine.

The phase III MPACT trial demonstrated the superiority of gemcitabine plus nab-paclitaxel (NABGEM) versus gemcitabine alone in previously untreated patients with metastatic pancreatic cancer (mPC). The aim of this study was to evaluate the responses in terms of efficacy and safety in patients treated with more than 6 cycles of chemotherapy. From January 2015 to December 2018, patients with mPC receiving first-line treatment with NABGEM were included in a multicentre retrospective observational study. Exploratory analyses of efficacy and safety were performed. The cohort included 153 patients with performance status of 1. The median overall survival and progression-free survival were 20 months (hazard ratio [HR] 0.28, 95% confidence interval [CI]: 0.17-0.44) and 10 months (HR 0.24 95% CI: 0.16-0.38) respectively, in patients who received >6 cycles compared to 9 and 5 months in those treated with ≤6 cycles (p < 0.001). The disease control rate was 100% versus 56% in patients receiving >6 and ≤6 cycles, respectively. No progression of disease was recorded in patients who received >6 cycles. Grade 1 neuropathy and grade 3 neutropenia were more frequent in patients treated with >6 cycles compared to patients receiving ≤6 cycles (p = 0.01; p = 0.03, respectively). Dose reduction was necessary for 70.1% and 53.4% of patients treated with >6 or ≤6 cycles, whereas treatment interruption occurred in 37.1% and 21.6%, respectively. Our results confirmed the efficacy and safety of NABGEM in untreated mPC. In particular, we highlighted significant clinical efficacy in patients who received >6 cycles of chemotherapy compared to those who received ≤6 cycles, with manageable toxicity profile.

Prognostic value of alkaline phosphatase and gamma-glutamyl transferase in patients with metastatic pancreatic cancer.

Background: Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. This study evaluated the prognostic role of serum alanine phosphatase (ALP) and gamma-glutamyl-transferase (GGT) in metastatic PC patients. Materials & methods: 153 patients with metastatic PC receiving first-line treatment with nab-paclitaxel/gemcitabine were retrospectively enrolled in a multicenter study and stratified according to ALP (≤ or >260 U/l) and GGT (≤ or >45.5 U/l) levels. Results: Improved overall survival was recorded in patients with GGT levels ≤45.5 U/l (p < 0.05). In patients with liver metastasis, overall survival was significantly lower in patients with high ALP (p = 0.01) and GGT (p = 0.02). Conclusion: High levels of ALP and GGT were related to a poor prognosis in PC patients with liver metastasis receiving nab-paclitaxel/gemcitabine.

Pancreatic cancer is a deadly form of cancer. This study looked at whether levels of two enzymes, alanine phosphatase (ALP) and gamma-glutamyl-transferase (GGT), in the blood of patients with metastatic pancreatic cancer could predict how long they would live. The study included 153 patients who were receiving their first treatment for metastatic pancreatic cancer. The patients were divided into groups based on whether their ALP and GGT levels were high or low. The researchers found that patients with low GGT levels tended to live longer. Patients with liver metastasis (spread of cancer to the liver) who had high levels of ALP and GGT tended to have a worse prognosis than patients with low levels of these enzymes. Therefore, higher levels of ALP and GGT in the blood may be associated with a poor prognosis in pancreatic cancer patients with liver metastasis who are receiving nab-paclitaxel/gemcitabine treatment.

Immune checkpoint inhibitors in non-conventional histologies of renal-cell carcinoma.

For years, prospective randomized clinical trials excluded patients with non-conventional histologies of renal cell carcinoma (RCC). The paucity of data has led to adopting the same treatment strategies used for clear-cell RCC (ccRCC). In the present narrative review, we explored state of the art about use of immune checkpoint inhibitors (ICIs) in variant histologies of RCC. According to the results collected, ICIs as monotherapy showed promising antitumor activity in advanced non-clear cell (ncc)RCC. The objective response rate (ORR) was similar to that observed with single-agent anti-PD-1 in the ccRCC population, either in the first-line or the second-line setting, and responder patients experienced an early and durable benefit. Combined ICI-based strategies have shown increasing evidence in nccRCC and robust results in the sarcomatoid variants of RCC. A definitive recommendation about treating non-conventional histologies, either in adjuvant or metastatic settings, should be supported by more extensive dedicated trials.

DNA repair deficiency as circulating biomarker in prostate cancer.

Deleterious aberrations in DNA repair genes are actionable in approximately 25% of metastatic castration-resistant prostate cancers (mCRPC) patients. Homology recombination repair (HRR) is the DNA damage repair (DDR) mechanism most frequently altered in prostate cancer; of note BRCA2 is the most frequently altered DDR gene in this tumor. Poly ADP-ribose polymerase inhibitors showed antitumor activity with a improvement in overall survival in mCRPC carrying somatic and/or germline alterations of HHR. Germline mutations are tested on peripheral blood samples using DNA extracted from peripheral blood leukocytes, while the somatic alterations are assessed by extracting DNA from a tumor tissue sample. However, each of these genetic tests have some limitations: the somatic tests are related to the sample availability and tumor heterogeneity, while the germline testing are mainly related to the inability to detect somatic HRR mutations. Therefore, the liquid biopsy, a non-invasive and easily repeatable test compared to tissue test, could identified somatic mutation detected on the circulating tumor DNA (ctDNA) extracted from a plasma. This approach should better represent the heterogeneity of the tumor compared to the primary biopsy and maybe helpful in monitoring the onset of potential mutations involved in treatment resistance. Furthermore, ctDNA may inform about timing and potential cooperation of multiple driver genes aberration guiding the treatment options in patients with mCRPC. However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.