Active Surveillance in Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with a variable clinical course. While therapies for treatment of this condition have progressed, they are not without toxicity. In some patients, active surveillance (AS) of this disease is increasingly considered to delay its toxicity. This article seeks to review the literature and discuss management of metastatic renal cell carcinoma, specifically regarding upfront AS, the role of radiation therapy in delaying systemic therapy, and surveillance after initial treatment with systemic therapy. Median time on AS prior to initiation of systemic therapy ranged from 14 to 60 months across studies. AS is appropriate to offer in favorable or intermediate risk, asymptomatic, and systemic treatment naïve patients with mRCC.

Incorporating Stereotactic Ablative Radiotherapy into the Multidisciplinary Management of Renal Cell Carcinoma.

Stereotactic ablative radiotherapy (SABR) has challenged the conventional wisdom surrounding the radioresistance of renal cell carcinoma (RCC). In the past decade, there has been a significant accumulation of clinical data to support the safety and efficacy of SABR in RCC. Herein, we review the use of SABR across the spectrum of RCC. We performed an online search of the Pubmed database from January 1990 through April 2023. Studies of SABR/stereotactic radiosurgery targeting primary, extracranial, and intracranial metastatic RCC were included. For SABR in non-metastatic RCC, this includes its use in small renal masses, larger renal masses, and inferior vena cava tumor thrombi. In the metastatic setting, SABR can be used at diagnosis, for oligometastatic and oligoprogressive disease, and for symptomatic reasons. Notably, SABR can be used for both the primary renal tumor and metastasis-directed therapy. Management of RCC is evolving rapidly, and the role that SABR will have in this landscape is being assessed in a number of ongoing prospective clinical trials. The objective of this narrative review is to summarize the evidence corroborating the use of SABR in RCC.

Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer.

BACKGROUND: Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. METHODS: To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. RESULTS: Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. CONCLUSIONS: Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.

Prostate brachytherapy utilization in the COVID-19 era: A cross-sectional study of radiation oncologists in the United States.

PURPOSE: Despite advantages such as abbreviated treatment course, brachytherapy (BT) utilization rates for prostate cancer (PC) in the United States (US) are declining. We surveyed practicing US radiation oncologists (ROs) to determine the proportion who offer BT for PC and whether the COVID-19 pandemic influenced practice patterns. MATERIALS AND METHODS: From July-October 2021, we surveyed practicing US ROs. Provider demographic and practice characteristics were collected. Questions assessing utilization of BT and external beam (EBRT) for patients of varying risk groups and the effect of the pandemic on practice patterns were administered. Descriptive statistics were reported. The bivariate relationships between provider characteristics and likelihood of offering BT were assessed using the Chi-square test (α < 0.05). RESULTS: Six percent of surveyed ROs responded, with 203 meeting inclusion criteria (72% male, 72% white, 53% non-academic, 69% >10 years in practice) and 156 (77%) treating PC. For low-risk, fewer providers offered BT (41% total; 25% low dose rate [LDR], 10% high dose rate [HDR], 6% both) than stereotactic body (SBRT) (54%) and moderately hypofractionated radiation therapy (MHFRT) (83%). For favorable intermediate risk, fewer offered BT (37% total; 21% LDR, 10% HDR, 6% both) than SBRT (48%), MHFRT (87%), and conventionally fractionated EBRT (38%). For high (44%) and very-high (37%) risk, fewer offered EBRT+BT than EBRT alone. For every risk group, academic ROs were significantly more likely to offer BT (all p-values<0.05). <1% of respondents reported increased pandemic-related BT usage. CONCLUSIONS: US ROs, particularly in non-academic settings, do not routinely offer BT monotherapy or boost (<50%). Practice patterns were unaffected by COVID-19. Retraining may be critical to increasing utilization.

Radiotherapy in Oligometastatic, Oligorecurrent and Oligoprogressive Prostate Cancer: A Mini-Review.

Globally, prostate cancer is one of the most common malignancies affecting men. With the advent of advanced molecular imaging, an increasing number of men are found to have oligometastatic disease (OD) either at primary diagnosis or at the time of biochemical failure. No strict definition exists for OD, with historical and ongoing studies utilizing diverse criteria. There is mounting evidence from many different malignancies that patients with OD have improved outcomes compared to their widely metastatic counterparts. As such, treatment intensification of those with OD or oligoprogressive disease has become an area of intense interest and study. This article will review the biology, evidence and controversy behind the treatment of de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer.

Bladder preservation in urothelial carcinoma: current trends and future directions.

PURPOSE OF REVIEW: To provide a contemporary rationale for bladder preservation as a treatment strategy for muscle-invasive urothelial carcinoma of the bladder. Although the standard of care for this important and serious clinical condition has been radical cystectomy augmented with neoadjuvant systemic chemotherapy, it is associated with substantial morbidity and quality of life (QoL) implications. This article explores the bladder sparing alternatives to radical cystectomy and urinary diversion to assist Urologists, Medical Oncologists, and Palliative Care providers in their informed decision making with patients. RECENT FINDINGS: Bladder sparing strategies such as partial cystectomy and trimodality therapy offer long-term cancer outcomes comparable to radical cystectomy in carefully selected patients. Moreover, the toxicity profile in patients, having improved over time, is acceptable, including a low risk of salvage cystectomy. SUMMARY: Bladder preservation therapy offers an alternative to radical cystectomy. In some patients, it can be done with curative intent and in others it can assist with symptom palliation. Bladder preservation can maintain QoL and provide similar oncologic outcomes to radical surgery, although randomized controlled trials have not been performed. Understanding patient selection is a critical step in balancing bladder preservation and cancer survival.

Overexpression of excision repair cross-complementing 1 gene associates with higher risk of therapeutic failure after definitive chemoradiation for unresectable non-small cell lung cancer.

BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) is typically treated with concurrent chemoradiation (CRT). Excision Repair Cross-Complementing 1 (ERCC1) is a protein involved in DNA damage repair. The objective of this study was to assess whether higher tumoral ERCC1 expression would associate with worse clinical outcomes in NSCLC treated with CRT. METHODS: Twenty-five patients were included. Relative expression levels of messenger RNA (mRNA) for ERCC1 were measured with a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and expressed as scaled ERCC1 mRNA gene expression value. Patients were followed every 3 months with history, physical exam, and imaging to assess clinical outcomes. We evaluated the associations between ERCC1, as well as other prognostic variables including stage, age, gender, race, histology, RT dose, performance status, and progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method and Cox regression. RESULTS: Recursive partitioning analysis identified a GeneExp cutoff of 1.54. Higher ERCC1 expression was associated with worse PFS [hazard ratio (HR) =1.70, P=0.04] and trended towards worse OS (HR =1.53, P=0.11). Increasing tumor volume (HR =1.001, P=0.055), squamous cell (HR =7.86, P=0.008) and poorly differentiated histology (HR =5.25, P=0.06) also associated with worse OS. The cumulative incidence of local recurrence at 1 year trended higher with ERCC1 GeneExp ≥1.54 (78.1%) compared to ERCC1 GeneExp <1.54 (14.9%, P=0.08). Distant relapse at 1 year was 72% with tumor ERCC1 expression ≥1.54 and 52% with ERCC1 expression <1.54 (P=0.28). CONCLUSIONS: Higher ERCC1 expression by qRT-PCR appears to correlate with worse PFS in locally advanced NSCLC treated with CRT. However, the overall sample size of the population was small; thus, larger studies are warranted to integrate molecular biomarkers to identify patients who might benefit from treatment intensification.

mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression.

Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of mdm2 was fully rescued in the background of p535KR/5KR , but not p534KR/4KR background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in p53-5KR cells. Notably, the early-onset tumor formation observed in p535KR/5KR and p53-null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.

Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC. METHODS: We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil-lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed. RESULTS: For patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. CONCLUSIONS: Our study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.

The Association of Radiation Dose-Fractionation and Immunotherapy Use With Overall Survival in Metastatic Melanoma Patients.

Objective Metastatic melanoma patients often receive palliative radiotherapy (RT) and immunotherapy (IT). However, the immunological interplay between RT dose-fractionation and IT is uncertain, and the optimal treatment strategy using RT and IT in metastatic melanoma remains unclear. Our main objective was to examine the effect of RT dose-fractionation on overall survival (OS). Methods Using the National Cancer Database (NCDB), we classified metastatic melanoma patients who received palliative RT into two dose-fractionation groups - conventionally fractionated RT (CFRT; <5 Gy/fraction) and hypofractionated RT (HFRT: ≥5 Gy/fraction) - with or without IT. Survival analysis was performed using the Cox regression model, Kaplan-Meier method, and propensity-score matching (PSM). Results A total of 5,281 metastatic melanoma patients were included, with a median follow-up of 5.9 months. The three-year OS was highest in patients who received HFRT+IT [37.3% (95% CI: 31.1-43.5)] compared to those who received HFRT alone [19.0% (95% CI: 16.2-21.9)], CFRT+IT [17.6 (95%CI: 13.9-21.6)], or CFRT alone [8.6% (95%CI: 7.6-9.7); p<0.0001]. The magnitude of OS benefit with the use of IT was greater in those who received HFRT (18.3%) compared with those who received CFRT (9.0%) (p<0.0001). The addition of IT to HFRT, compared to CFRT, was associated with greater OS benefit in patients treated with RT to the brain and soft tissue/visceral (STV) sites. On PSM analysis, HFRT+IT was associated with improved three-year OS compared to other treatments. Conclusion Metastatic melanoma patients who received HFRT+IT was associated with the greatest OS benefit. Our findings warrant further prospective evaluation as to whether higher RT dose-per-fraction improves clinical outcomes in metastatic melanoma patients receiving IT.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Evaluation of response to stereotactic radiosurgery in patients with radioresistant brain metastases.

PURPOSE: Renal cell carcinoma (RCC) and melanoma have been considered 'radioresistant' due to the fact that they do not respond to conventionally fractionated radiation therapy. Stereotactic radiosurgery (SRS) provides high-dose radiation to a defined target volume and a limited number of studies have suggested the potential effectiveness of SRS in radioresistant histologies. We sought to determine the effectiveness of SRS for the treatment of patients with radioresistant brain metastases. MATERIALS AND METHODS: We performed a retrospective review of our institutional database to identify patients with RCC or melanoma brain metastases treated with SRS. Treatment response were determined in accordance with the Response Evaluation Criteria in Solid Tumors. RESULTS: We identified 53 radioresistant brain metastases (28% RCC and 72% melanoma) treated in 18 patients. The mean target volume and coverage was 6.2 ± 9.5 mL and 95.5% ± 2.9%, respectively. The mean prescription dose was 20 ± 4.9 Gy. Forty lesions (75%) demonstrated a complete/partial response and 13 lesions (24%) with progressive/stable disease. Smaller target volume (p < 0.001), larger SRS dose (p < 0.001), and coverage (p = 0.008) were found to be positive predictors of complete response to SRS. CONCLUSION: SRS is an effective management option with up to 75% response rate for radioresistant brain metastases. Tumor volume and radiation dose are predictors of response and can be used to guide the decision-making for patients with radioresistant brain metastases.

Radiotherapy as a New Player in Immuno-Oncology.

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted.

Management of locally advanced rectal cancer in the elderly: a critical review and algorithm.

Colorectal cancer incidence and death rates have been declining over the past 10 years. However, it remains the second leading cause of death in men ages 60-79 and the third leading cause of death in men over 80 and in women over 60 years old. However, there is little data specific to the treatment of the elder patient, since few of these patients are included in trials. With the advent of improved therapies, there are many alternative options available. Still, no definitive consensus or guidelines have been defined for this particular patient population. The goal of this study is to review the literature on the management of rectal cancer in the elderly and to propose treatment algorithms to help the oncology team in treatment decision-making.

Decision-Making Strategy for Rectal Cancer Management Using Radiation Therapy for Elderly or Comorbid Patients.

Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients.

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses.

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.

Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression.

Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity.