Radiosensitizing Chemotherapy Research Articles

Peptide receptor radionuclide therapy for ectopic Cushing's syndrome caused by metastatic neuroendocrine neoplasms.

Metastatic gastroenteropancreatic neuroendocrine neoplasms (GEPNEN) can cause ectopic Cushing's syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. To describe the characteristics and outcomes of patients with ECS treated with PRRT. Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006 to 2023. Patients were aged 17-75 (female n = 6). The primary site was the pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one had a previous BA). A median of 34.4 GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) were also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within 1 week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5-6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), and one had a partial metabolic response. PFS was 3-208 months. Two patients progressed at the first follow-up. The longest ECS remission and CMR continues at >17 years. PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.

To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG). Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety. This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia. Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use. The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS). 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone. Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Phase 3 KEYNOTE-992 study of pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer (MIBC).

TPS720 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for patients (pts) with MIBC who seek a bladder-preserving alternative to radical cystectomy and/or not candidates for radical cystectomy. The anti–PD-1 antibody pembrolizumab is approved for metastatic bladder cancer and non–muscle-invasive bladder cancer (NMIBC). The randomized, double-blind, phase 3 KEYNOTE-992 study (NCT04241185) is evaluating efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in pts with MIBC who chose bladder preservation. Methods: Eligibility criteria include adultswho have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted. Approximately 636 pts will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV or placebo IV every 6 weeks for up to 9 cycles, both with CRT. Investigator’s choice of chemotherapy will be specified before random assignment. Pts will be stratified by ECOG PS (0 and 1 vs 2), PD-L1 combined positive score (&lt;10 vs ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). Radiosensitizing chemotherapy will be cisplatin monotherapy (35 mg/m2 IV weekly on day 1), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly on days 1 and 4). Radiation therapy will be conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Imaging via CT and CT urography or magnetic resonance urography will be performed 10 weeks after completion of CRT, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). Primary end point is bladder-intact event-free survival (defined as time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause) as assessed by blinded independent central review and/or central pathology review. Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04241185 .

Patterns of concurrent chemotherapy selection in US patients undergoing trimodality therapy for muscle-invasive bladder cancer.

554 Background: Trimodality therapy (TMT) consists of concurrent chemoradiation following maximal transurethral resection of the bladder tumor for muscle-invasive bladder cancer (MIBC). Current TMT treatment guidelines allow for several different radiosensitizing chemotherapy regimens, however there is limited data on existing use patterns. Methods: Using data from CancerLinQ Discovery, 71,499 patients with a bladder tumor diagnosed between 2000-2022 were included. Patients with documented radiation to “bladder” or “pelvis” with no known metastatic disease and a documented chemotherapy regimen started within a 30-day window of radiation, were included in the final analyses (n=233). Chemotherapy regimens included cisplatin, gemcitabine, 5FU+ mitomycin, taxanes, and other. Through bivariate analyses, patient characteristics and TMT treatment patterns were characterized. Results: The most commonly utilized TMT chemotherapy regimen was cisplatin alone (42.5%) followed by gemcitabine (19.3%), 5FU+ mitomycin (15.8%), taxanes (12.5%) and other (9.9%). These data demonstrated a significant relationship between age at diagnosis and chosen TMT regimen (p=0.017). Patients &lt;65 were more likely to receive cisplatin (27.3%), 5FU mitomycin (29.7%) or other (30.4%) while patients 85+ were more likely to receive gemcitabine (28.9%). Patients more frequently received cisplatin alone prior to 2017 (before 2011: 28.3% vs. 2011-2016: 53.5% vs. 2017-2022:18.2%, p-value &lt;.001), with a trend towards more gemcitabine use in the most recent period between 2017-2022 (51.1% vs. before 2011: 20.0% vs 2011-2016: 28.9%, p-value &lt;.001). Additionally, there was less taxane use over time (before 2011: 37.9% vs. 2011-2016: 55.2% vs 2017-2022: 6.9%, p-value &lt;.001). Finally, the association between TMT regimen and Charlson Comorbidity Index (CCI) trended toward significance—those treated with cisplatin alone were most likely to have a CCI of 0 (62.6%, p-value = 0.081) while patients receiving gemcitabine alone or 5FU + mitomycin were more likely to have a CCI of 1+ (gemcitabine alone: 51.1%, 5FU + mitomycin 51.4%, p-value = 0.081). Conclusions: There remains wide variation in the use of chemotherapy regimens in TMT with cisplatin monotherapy as the most utilized radiosensitizing agent overall. Since 2000, there has been a shift away from taxane therapy and increased gemcitabine use. Patients with lower CCI had a trend to more frequently receive cisplatin and older patients more frequently received gemcitabine. Further investigations are needed to better characterize patient characteristics as well as toxicity and survival by drug regimen to better help inform treatment guidelines.

The role of obesity in treatment planning for early-stage cervical cancer

ObjectivesOptimal management of obese patients with early-stage cervical cancer is debated despite evidence of non-inferior survival in obese patients undergoing radical hysterectomy with pelvic lymphadenectomy (RH) compared to primary radiation with or without radiosensitizing chemotherapy (RT). Objectives included describing patient factors affecting disposition to RH versus RT; comparing RH outcomes for obese (BMI >30 mg/m2) and non-obese patients; and comparing differences in recurrence free survival (RFS) and overall survival (OS). MethodsThis was a single institution cohort study of all cervical cancer patients who underwent RH or were candidates for RH based on clinical stage. Demographic, clinicopathologic and treatment outcomes were collected and analyzed. ResultsRT patients (n = 39, 15%) had a higher BMI (p = 0.004), older age (p < 0.001), more life-limiting comorbidities (LLC) (p < 0.001), larger tumor size (p = 0.001), and higher clinical stage (p = 0.013) compared to RH patients (n = 221, 85%). On multivariable survival analysis there was no difference in OS based on treatment modality; significant predictors of worse OS were larger tumor size, higher number of LLC and recurrence. Among the RH group, obese patients had a longer operative time (p = 0.01) and more LLC (p = 0.02); there were no differences in demographic or clinicopathologic characteristics, operative outcomes, RFS or OS compared to non-obese patients. ConclusionIn this cohort of RH-eligible cervical cancer patients, BMI was independently associated with disposition to RT. Studies demonstrate that RH is feasible and safe in obese patients with no difference in RFS or OS when compared to non-obese patients. Thus, the decision for disposition to RT should not be based on obesity alone.

Trial in Progress: Adaptive RADiation Therapy with Concurrent Sacituzumab Govitecan (SG) for Bladder Preservation in Patients with MIBC (RAD-SG).

A substantial proportion of patients with muscle invasive bladder cancer do not receive curative intent therapy, especially if unfit for or refuse radical cystectomy. Concurrent chemoradiation is an effective alternative to radical cystectomy, however systemic radio-sensitizing chemotherapy may have off target side effects. A Phase I study is accruing which will investigate the concurrent administration of a bladder cancer targeted antibody drug conjugate (Sacituzumab Govitecan) with radiotherapy. This trial in progress is a Phase I study of Adaptive RADiation therapy with concurrent Sacituzumab Govitecan (SG) for bladder preservation in patients with muscle invasive bladder cancer (MIBC). Eligible patients will have localized muscle invasive bladder cancer (MIBC) confined to the bladder. The initial cohort is expected to accrue 20 patients. The primary endpoint is to establish the safety, tolerability, and feasibility of bladder preservation therapy treatment with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are to determine the bladder intact event-free survival (BI-EFS) with concurrent SG and radiation therapy for MIBC and compare to historical controls with other concurrent chemoradiation regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, radical cystectomy, or death from any cause. Sacituzumab Govitecan targets TROP-2, a surface protein expressed in urothelial cancers of the bladder. SG will be delivered IV, 10 mg/kg, 21-day cycles for 1 loading cycle prior to radiation and two subsequent cycles with concurrent adaptive radiotherapy over a period of 6 weeks (64 Gy). Correlative objectives (Supported by NCI/NIH U54) and will involve 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus radiation therapy and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus radiation. To be determined. To be determined.

Stereotactic Ablative Radiotherapy Boost to Bladder Tumor for Bladder Preservation in Patients with Muscle-Invasive Bladder Cancer

Previous studies showed that selective bladder-sparing approach using TMT is an established therapy of MIBC with outcomes that are comparable to those of radical cystectomy. However, it has been shown that the 5-year local recurrence in the bladder is greater than 40% after TMT. One of the possible reasons was that the RT dose to the bladder tumor or tumor bed was insufficient. Thus, we assessed the effectiveness and safety of Stereotactic Ablative Radiotherapy (SABR) boost to bladder tumor or tumor bed for patients with muscle invasive bladder cancer (MIBC). A total of 59 consecutive patients with cT2-4 bladder cancer underwent transurethral resection of bladder tumor (TURBT). TURBT was visibly complete in 25 cases. Patients received SABR to the tumor or tumor bed in the bladder followed by conventionally fractionated RT (CFRT) to pelvis and total bladder with concomitant weekly radio-sensitizing chemotherapy. During SABR intravesical installation of isovolumetric saline through urinary catheter ensured adequate bladder filling. Response rate was assessed by cystoscopic evaluation and pelvic MRI or CT. Toxicities were reported per the RTOG acute and late Radiation Morbidity Scoring Schema. The median age of all patients was 76 years (35-90 years). All patients completed SBRT boost and 61% patients received concurrent Gemcitabine chemotherapy. After a median follow-up time of 28 months, the rate of local control (LC) at 3 years was 90.0%. The overall survival (OS) and cancer-specific survival (CSS) rates at 3 years were 61.6% and 77.5%, respectively. Of the surviving patients, 84.4% have a disease-free and functioning bladder. Acute grade 3 gastrointestinal (GI) or genitourinary (GU) toxicities occurred in only 1.7% of the patients. Late grade 3 GU toxicity occurred in 5.1% of the patients. No patients experienced grade 4 GI or GU toxicities. SABR boost followed by chemoradiation to the pelvis was found to be a well-tolerated and effective treatment for MIBC patients who are either not candidates for cystectomy or who desire bladder preservation. Randomized study is required to further evaluate this novel tri-modality treatment paradigm.

IMRT followed by pembrolizumab in the adjuvant setting in anaplastic cancer of the thyroid (IMPAACT): Phase II trial adjuvant pembrolizumab after IMRT in ATC.

TPS6117 Background: Anaplastic thyroid carcinoma (ATC) has historically been an almost uniformly rapidly fatal disease. In patients with loco-regional disease with no distant metastasis (stage IVB), and without a targetable mutation, a combination of external beam radiation delivered via intensity modulated techniques (IMRT) +/- concurrent cytotoxic chemotherapy is the current standard of care. However, the relapse rate is very high within the first year of diagnosis. Our data show that 90% of ATCs express PD-L1, with 43% having expression levels greater than 50%. A clinical trial with an anti-PD1 drug in ATC patients with active disease showed that patients with ATC had a response rate of 19%. Additionally, as tumor PD-L1 expression has been linked to radioresistance and there is a need to target micrometastatic disease, using adjuvant checkpoint inhibitor is a rational strategy in these patients. Methods: This is an open label, single center, phase 2 trial of adjuvant pembrolizumab after external beam radiation to the primary tumor in patients with stage IVB ATC. The primary cohorts will include those with gross, locoregional disease who have completed treatment with IMRT +/- concurrent radiosensitizing chemotherapy. Patients will be treated with adjuvant pembrolizumab (400mg IV Q6 weeks for up to 9 cycles), 2-6 weeks after completion of radiation. Patients will be enrolled based on dose of radiation in cohort 1 (high dose group, &gt; 51 Gy), cohort 2 (palliative dose group, &lt; 50 Gy). Cohort 3, consisting of those who underwent surgery followed by IMRT plus concurrent chemotherapy will be an exploratory cohort. Restaging scans will be performed every 12 weeks after enrollment. MRI brain will be repeated every 6 months in the absence of evidence of progression. The primary endpoint is median PFS (from the start of adjuvant pembrolizumab) in cohorts 1 and 2. Secondary endpoint is median overall survival in cohorts 1 and 2. Cohort 3 (5 patients) will have an exploratory endpoint, to estimate the median disease-free survival (DFS). Statistics: Survival analyses will be performed using the Kaplan-Meier method. Based on historical data, the median PFS for unresected patients is 6.8 months. For an expected improvement of median PFS by 3.7 months, with a combined total of 30 evaluable patients in cohorts 1 and 2, we anticipate having 80.0% power using 1-sided 10% alpha for a one-sample log rank test. The trial began enrollment in July 2022. This trial is sponsored by philanthropic funds and Merck. ClinicalTrials.gov ID NCT05059470. Clinical trial information: NCT05059470 .

The relationship between tumour dosimetry, response, and overall survival in patients with unresectable Neuroendocrine Neoplasms (NEN) treated with 177Lu DOTATATE (LuTate)

Peptide Receptor Radionuclide Therapy (PRRT) delivers targeted radiation to Somatostatin Receptor (SSR) expressing Neuroendocrine Neoplasms (NEN). We sought to assess the predictive and prognostic implications of tumour dosimetry with respect to response by 68 Ga DOTATATE (GaTate) PET/CT molecular imaging tumour volume of SSR (MITVSSR) change and RECIST 1.1, and overall survival (OS).MethodsPatients with gastro-entero-pancreatic (GEP) NEN who received LuTate followed by quantitative SPECT/CT (Q-SPECT/CT) the next day (Jul 2010 to Jan 2019) were retrospectively reviewed. Single time-point (STP) lesional dosimetry was performed for each cycle using population-based pharmacokinetic modelling. MITVSSR and RECIST 1.1 were measured at 3-months post PRRT.ResultsMedian of 4 PRRT cycles were administered to 90 patients (range 2–5 cycles; mean 27.4 GBq cumulative activity; mean 7.6 GBq per cycle). 68% received at least one cycle with radiosensitising chemotherapy (RSC). RECIST 1.1 partial response was 24%, with 70% stable and 7% progressive disease. Cycle 1 radiation dose in measurable lesions was associated with local response (odds ratio 1.5 per 50 Gy [95% CI: 1.1–2.0], p = 0.002) when adjusted by tumour grade and RSC. Median change in MITVSSR was -63% (interquartile range -84 to -29), with no correlation with radiation dose to the most avid lesion on univariable or multivariant analyses (5.6 per 10 Gy [95% CI: -1.6, 12.8], p = 0.133). OS at 5-years was 68% (95% CI: 56–78%). Neither baseline MITVSSR (hazard ratio 1.1 [95% CI: 1.0, 1.2], p = 0.128) nor change in baseline MITVSSR (hazard ratio 1.0 [95% CI: 1.0, 1.1], p = 0.223) were associated with OS when adjusted by tumour grade and RSC but RSC was (95% CI: 0.2, 0.8, p = 0.012).ConclusionRadiation dose to tumour during PRRT was predictive of radiologic response but not survival. Survival outcomes may relate to other biological factors. There was no evidence that MITVSSR change was associated with OS, but a larger study is needed.

MP56-01 THE EFFECT OF DIFFERENT CONCURRENT CHEMOTHERAPY REGIMENS ON OUTCOMES IN PATIENTS TREATED WITH RADIATION FOR MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP56-01 THE EFFECT OF DIFFERENT CONCURRENT CHEMOTHERAPY REGIMENS ON OUTCOMES IN PATIENTS TREATED WITH RADIATION FOR MUSCLE INVASIVE BLADDER CANCER Francis Lemire, Ronald Kool, Marcq Gautier, Robert Siemens, Bobby Shayegan, Michael Kim, Ionut Busca, Hamidreza Abdi, Mark Dawidek, Michael Uy, Gagan Fervaha, Fabio Cury, Nimira Alimohamed, Jonathan Izawa, Claudio Jeldres, Ricardo Rendon, Peter Black, Girish Kulkarni, Wassim Kassouf, and Rodney Breau Francis LemireFrancis Lemire More articles by this author , Ronald KoolRonald Kool More articles by this author , Marcq GautierMarcq Gautier More articles by this author , Robert SiemensRobert Siemens More articles by this author , Bobby ShayeganBobby Shayegan More articles by this author , Michael KimMichael Kim More articles by this author , Ionut BuscaIonut Busca More articles by this author , Hamidreza AbdiHamidreza Abdi More articles by this author , Mark DawidekMark Dawidek More articles by this author , Michael UyMichael Uy More articles by this author , Gagan FervahaGagan Fervaha More articles by this author , Fabio CuryFabio Cury More articles by this author , Nimira AlimohamedNimira Alimohamed More articles by this author , Jonathan IzawaJonathan Izawa More articles by this author , Claudio JeldresClaudio Jeldres More articles by this author , Ricardo RendonRicardo Rendon More articles by this author , Peter BlackPeter Black More articles by this author , Girish KulkarniGirish Kulkarni More articles by this author , Wassim KassoufWassim Kassouf More articles by this author , and Rodney BreauRodney Breau More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003309.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radiotherapy is an accepted treatment approach for well-selected patients with bladder cancer. Randomized control trials have shown superior outcomes to patients who receive concurrent chemotherapy compared to radiation monotherapy. However, there are limited data to guide selection of the optimal radio-sensitizing regimen. METHODS: Canadian academic centres contributed to a retrospective cohort of muscle invasive (cT2-4N0-2) bladder cancer patients treated with curative-intent radiotherapy, with or without concurrent chemotherapy. Patients were stratified and analyzed by radio-sensitizing chemotherapy regimen. Outcomes were metastasis-free, cancer-specific, and overall survival (MFS, CSS, and OS). RESULTS: Of 656 patients, 268 (41%) were treated with radiation monotherapy, 174 (27%) with cisplatin, 108 (16%) with gemcitabine, 74 (11%) with 5FU-MMC, and 32 (5%) with carboplatin. The median follow-up was 24 months (95% CI: 21–27). In the entire cohort, the median MFS was 35 months (95% CI: 29–44), median CSS not reached (95% CI: 94–not reached) and median OS 52 months (95% CI 42–60). Disease characteristics were similar between groups, but patients who received radio-sensitizing chemotherapy were younger and had fewer comorbidities. Compared to no chemotherapy, concurrent cisplatin was associated with improved MFS (HR 0.46; 95% CI: 0.35-0.60), CSS (HR 0.44; 95% CI: 0.31-0.64) and OS (HR 0.33; 95% CI: 0.24-0.43). Concurrent 5FU-MMC was also associated with improved MFS (HR 0.60; 95% CI: 0.40-0.88), CSS (HR 0.32; 95% CI: 0.16-0.66), and OS (HR 0.45; 95% CI: 0.28-0.71). Concurrent gemcitabine was associated with improved MFS (HR 0.77; 95% CI 0.58-1.02), CCS (0.76; 95% CI 0.49-1.27), and OS (HR 0.76; 95% CI 0.57-1.02). Concurrent carboplatin was associated with improved MFS (HR 0.55; 95% CI: 0.33-0.92), CSS (HR 0.64; 0.43-1.27), and OS (HR 0.52; 95% CI: 0.30-0.89). CONCLUSIONS: Patients with MIBC treated with RT have better oncologic outcomes with all forms of radio-sensitizing chemotherapy. While the best outcomes are associated with cisplatin, other radiosensitizers seem to be effective for platinum-ineligible patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e773 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Francis Lemire More articles by this author Ronald Kool More articles by this author Marcq Gautier More articles by this author Robert Siemens More articles by this author Bobby Shayegan More articles by this author Michael Kim More articles by this author Ionut Busca More articles by this author Hamidreza Abdi More articles by this author Mark Dawidek More articles by this author Michael Uy More articles by this author Gagan Fervaha More articles by this author Fabio Cury More articles by this author Nimira Alimohamed More articles by this author Jonathan Izawa More articles by this author Claudio Jeldres More articles by this author Ricardo Rendon More articles by this author Peter Black More articles by this author Girish Kulkarni More articles by this author Wassim Kassouf More articles by this author Rodney Breau More articles by this author Expand All Advertisement PDF downloadLoading ...

Combined Modality Bladder-Sparing Therapy for Muscle-Invasive Bladder Cancer: How (Should) We Do It? A Narrative Review.

Organ-sparing combined-modality treatment for muscle-invasive bladder cancer remains underutilized despite high-quality evidence regarding its efficacy, safety, and preservation of quality of life. It may be offered to patients unwilling to undergo radical cystectomy, as well as those unfit for neoadjuvant chemotherapy and surgery. The treatment plan should be tailored to each patient's characteristics, with more intensive protocols offered to patients who are fit for surgery but opt for organ-sparing. After a thorough, debulking transurethral resection of the tumor and neoadjuvant chemotherapy, the response evaluation should trigger further management with either chemoradiation or early cystectomy in non-responders. A hypofractionated, continuous radiotherapy regimen of 55 Gy in 20 fractions with concurrent radiosensitizing chemotherapy with gemcitabine, cisplatin, or 5-fluorouracil and mitomycin C is currently preferred based on clinical trials. The response should be evaluated with repeated transurethral resections of the tumor bed and abdominopelvic-computed tomography after chemoradiation, with quarterly assessments during the first year. Salvage cystectomy should be offered to patients fit for surgery who failed to respond to treatment or developed a muscle-invasive recurrence. Non-muscle-invasive bladder recurrences and upper tract tumors should be treated in line with guidelines for respective primary tumors. Multiparametric magnetic resonance can be used for tumor staging and response monitoring, as it may distinguish disease recurrence from treatment-induced inflammation and fibrosis.

Stereotactic Radiotherapy Boost as Part of Tri-Modality Treatment for Bladder Preservation in Patients with Muscle-Invasive Bladder Cancer

<h3>Purpose/Objective(s)</h3> To review our experience with bladder preserving tri-modality treatment (TMT) using stereotactic body radiotherapy (SBRT) boost for treatment of patients with muscle invasive bladder cancer (MIBC). <h3>Materials/Methods</h3> A total of 68 consecutive patients with cT2-4a bladder cancer underwent transurethral resection of bladder tumor (TURBT). TURBT was visibly complete in 26 cases. Patients received SBRT to the tumor or tumor bed in the bladder followed by conventionally fractionated RT (CFRT) to pelvis and total bladder with concomitant weekly radio-sensitizing chemotherapy. During SBRT, intravesical installation of isovolumetric saline through urinary catheter ensured adequate bladder filling. Response rate was assessed by cystoscopic evaluation and pelvic MRI or CT. Toxicities were reported per the RTOG acute and late Radiation Morbidity Scoring Schema. <h3>Results</h3> The median age of all patients was 76 years (35-92 years). A complete response (CR) was confirmed in 98.5% of the patients. After a median follow-up time of 18 months, 3 patients had a muscle-invasive recurrence. The overall survival (OS) and cancer-specific survival (CSS) rates at 2 years were 84.5% and 90.6%, respectively. Of the surviving patients, 86.3% have a disease-free and functioning bladder. All patients completed SBRT boost and 63% patients received concurrent Gemcitabine chemotherapy. Acute grade 3 gastrointestinal (GI) or genitourinary (GU) toxicities occurred in only 1.5% of the patients. Late grade 3 GU toxicity occurred in 4.4% of the patients. No patients experienced grade 4 GI or GU toxicities. <h3>Conclusion</h3> SBRT boost followed by chemoradiation to the pelvis was found to be a well-tolerated and effective treatment for MIBC patients who are either not candidates for cystectomy or who desire bladder preservation. Additional study is required to further evaluate this novel tri-modality treatment paradigm.

Cervical cancer disparities in an urban setting: Is distance traveled or residential neighborhood associated with treatment delays? (280)

Cervical cancer disparities in an urban setting: Is distance traveled or residential neighborhood associated with treatment delays? (280)

Disparities in the management and outcomes of cervical carcinoma: A multi-institutional database analysis (518)

<b>Objectives:</b> To investigate the presence of disparities in the management of patients with cervical cancer and their impact on survival outcomes. <b>Methods:</b> The National Cancer Database was accessed, and Black or non-Hispanic White (NHW) patients with no history of another tumor diagnosed between 2004 and 2015 with cervical carcinoma were identified. Patients with early-stage (FIGO 2009 stage IB1), locally advanced (FIGO 2009 stage IB2-IVA), and metastatic (FIGO 2009 stage IVB) disease were selected for further analysis. Overall survival (OS) was evaluated for patients who had at least one month of follow-up and compared with the log-rank test. Cox models were constructed to control for a priori selected confounders. <b>Results:</b> A total of 47767 patients were identified; 78% were NHW and 22% were Black. Black patients were more likely to be managed at academic facilities (55.9% vs 41.9%, p<0.001) and reside within 12.5 miles of the treatment facility (67.5% vs 44%, p<0.001). For stage IVB disease, after controlling for confounders, Black patients were less likely to receive chemotherapy (OR: 0.75, 95% CI: 0.65-0.86). Among patients receiving chemotherapy, after controlling for confounders there was no difference in OS between NHW and Black patients (HR: 1.04, 95% CI: 0.95-1.14). For patients with locally advanced disease, after controlling for confounders, Black patients were less likely to receive external beam radiation therapy (EBRT) (OR: 0.90, 95% CI: 0.85-0.95); if EBRT was administered, they were less likely to receive vaginal brachytherapy (VBT) (OR: 0.87, 95% CI: 0.81-0.92) or radio-sensitizing chemotherapy (OR: 0.81, 95% CI: 0.74-0.87). Among patients with locally advanced disease who received EBRT, radio-sensitizing chemotherapy, and VBT, after controlling for confounders there was no difference in OS between NHW and Black patients (HR: 0.97, 95% CI: 0.89-1.05). Black patients with stage IB1 disease, after controlling for confounders, were less likely to undergo hysterectomy/trachelectomy (OR: 0.71, 95% CI: 0.62-0.81), or radical hysterectomy (if they underwent hysterectomy) (OR: 0.87, 95% CI: 0.74-1.00). Black patients undergoing surgery were more likely to have prolonged hospital stay (defined as >5 days) (OR: 1.73, 95% CI: 1.38-2.18) and have unplanned readmission within 30 days from surgery (OR: 1.38, 95% CI: 1.04-1.83). Among patients with stage IB1 disease undergoing radical hysterectomy with lymphadenec- tomy, after controlling for confounders there was no difference in OS between NHW and Black patients (HR: 1.08, 95% CI: 0.80-1.46). <b>Conclusions:</b> While Black patients with cervical cancer were more likely to reside closer to treatment facilities and receive care at academic institutions, they were less likely to receive guideline conformant care compared to NHW regardless of disease stage. For patients receiving guideline conformant care, overall survival was comparable to NHW patients.

Timing of radio-sensitizing chemotherapy initiation and impact on overall survival of patients with locally advanced cervical cancer undergoing definitive chemoradiation (358)

<b>Objectives:</b> To investigate the impact of delay in radio-sensitizing chemotherapy initiation on the survival of patients with locally advanced cervical cancer (LACC) receiving definitive chemoradiation. <b>Methods:</b> Patients diagnosed between 2004-2015 with LACC (FIGO 2009 stage IB2-IVA), who received external beam radiotherapy of at least 45 Gy, known radiation-chemotherapy interval and had at least one month of follow-up were identified in the National Cancer Database. Patients were categorized into same-day chemotherapy and radiotherapy initiation, same week (within one week from radiotherapy initiation), delayed (1-2 weeks from radiotherapy initiation), and significantly delayed (2-3 weeks from radiotherapy initiation). Overall survival was compared with the log-rank test while the Cox model was constructed to control for a priori selected confounders. <b>Results:</b> A total of 11600 patients who met the inclusion criteria were identified; 6079 (52.4%) initiated chemotherapy the same day as radiotherapy, 4513 (38.9%) initiated chemotherapy within one week, while 733 (6.3%) and 275 (2.4%) patients initiated chemotherapy 1-2 week (delayed) and 2-3 weeks (significantly delayed), respectively, after radiotherapy started. A higher percentage of patients with comorbid conditions was observed in the delayed (17.8%) and significantly delayed (15%) groups compared to the same day (12.4%) and same week (14.5%) groups, p<0.001. Similarly, a higher percentage of patients in the significantly delayed (62.9%) and delayed (54%) groups had stage III-IVA disease compared to those in the same day (45.2%) and same week (47%) groups (p<0.001). Lastly, a higher percentage of Black patients was observed in the significantly delayed (26.5%) and delayed (20.5%) groups compared to the same day (15.2%) and same week (18.3%) groups (p<0.001). Median overall survival was 103.3 and 91.93 months for same day and same week groups compared to 69.19 and 39.23 months for the delayed and significantly delayed groups (p<0.001 from log-rank). Following stratification by disease stage, there was no difference in OS between the four groups for stage IB2-II disease (p=0.17). For patients with stage III-IVA, median OS was better for patients in the same day (median: 53.68 months) group compared to those in the same week (median: 41.13 months), delayed (median: 38.28 months), and significantly delayed (median: 32.49 months) groups (p<0.001). After controlling for patient age, race, insurance status, presence of comorbid conditions, brachytherapy use, and disease stage, compared to same-day chemotherapy initiation, patients who received chemotherapy within one week (HR: 1.07, 95% CI: 1.01-1.14), 1-2 weeks (HR: 1.14, 95% CI: 1.01-1.28) or 2-3 weeks (HR: 1.32, 95% CI: 1.12-1.57) after radiotherapy initiation had worse overall survival. <b>Conclusions:</b> Any delay in administering radio-sensitizing chemotherapy relative to radiotherapy initiation may be associated with a detrimental effect on the survival of patients with LACC, especially for those with stage III-IVA disease. Same-day initiation of chemotherapy with radiation should be encouraged.

Disparities in the quality of definitive radiation therapy for patients with locally advanced cervical cancer (059)

<b>Objectives:</b> To examine disparities and patterns of definitive radiation therapy administration for patients with locally advanced cervical cancer (LACC) and their impact on overall survival. <b>Methods:</b> Black and non-Hispanic White (NHW) patients diagnosed between 2004 and 2015 with locally advanced cervical cancer (FIGO 2009 stage IB2-IVA), who had no history of another tumor, did not undergo hysterectomy, received external beam radiation therapy of at least 45 Gy, and had at least one month of follow-up, were identified in the National Cancer Database. We examined three quality metrics described in the National Comprehensive Cancer Network (NCCN) guidelines; utilization of radio-sensitizing chemotherapy (defined as chemotherapy administered within two weeks from radiotherapy initiation), receipt of brachytherapy, and completion of radiation treatment within eight weeks from initiation. Clinical-pathologic characteristics were compared with the Chi-square test. Overall survival was evaluated with Cox models after controlling for a priori selected confounders. <b>Results:</b> A total of 9940 patients with LACC were identified; 2242 (22.6%) were Black, and 7698 (77.4%) were NHW. Black patients were more likely to have squamous cell histology (91.3% vs 84.7%, p<0.001), medical comorbid conditions (17.1% vs 14.5%, p<0.001), government-issued insurance (55% vs 46.2%, p<0.001), and be managed at academic facilities (55.6% vs 42.3%, p<0.001). Stage distribution (49.5% vs 47.2% stage III-IVA, p=0.06) and patient age (median 52 years for both groups) were comparable between Black and NHW patients. However, Black patients were more likely to receive all treatment at the reporting facility (79.3% vs 71.7%, p<0.001) and reside within a short distance (<12.5 miles) from the treatment facility (69.3% vs 47.2%, p<0.001). In the present cohort, 5432 (54.6%) patients completed treatment within eight weeks, 8794 (88.5%) received radio-sensitizing chemotherapy, and 6453 (64.9%) received brachytherapy. All three-quality metrics were met for 2981 patients (30%). Black patients were less likely to have treatment that fulfilled all three-quality metrics (26% vs 31.2%, p<0.001) even after controlling for histology, age, insurance, comorbid conditions, and disease stage (OR: 0.82, 95% CI: 0.73-0.91). Patients who received guideline conformant radiation therapy had better OS after controlling for age, comorbid conditions, disease stage, histology, and insurance (HR: 0.67, 95% CI: 0.63-0.72). A survival advantage for patients receiving guideline conformant radiation therapy was present for both WNH (HR: 0.69; 95% CI: 0.64-0.75) and Black patients (HR: 0.60, 95% CI: 0.51-0.71). <b>Conclusions:</b> Approximately one in three patients with LACC received definitive radiotherapy that met all quality metrics and had superior outcomes even after controlling for confounders. Black patients were less likely to receive guideline conformant radiotherapy than WNH, even though they reside closer to treatment facilities and are more likely to present to academic institutions.

Quality of adjuvant radiation therapy and impact on overall survival of patients with lymph node positive squamous cell carcinoma of the vulva (420)

Quality of adjuvant radiation therapy and impact on overall survival of patients with lymph node positive squamous cell carcinoma of the vulva (420)

Role of adjuvant radiation therapy for squamous cell carcinoma (SCC) of the vulva and single lymph node metastasis (159)

<b>Objectives:</b> To evaluate the utilization and outcomes of adjuvant radiation therapy for early-stage squamous cell carcinoma of the vulva with single inguinal lymph node metastasis following comprehensive inguinal lymphadenectomy. <b>Methods:</b> The National Cancer Database and patients without a history of another tumor, diagnosed between 2004 and 2015 with T1b squamous cell carcinoma of the vulva who underwent surgical excision and inguinal lymphadenectomy with at least ten lymph nodes removed and had only one positive lymph node per pathology report were identified. Clinical-pathologic and demographic characteristics were compared based on the receipt of adjuvant radiotherapy (defined as receipt of external beam radiation at a dose of at least 50 Gy within six months from surgery). Overall survival (OS) was calculated and compared with the log-rank test following the generation of Kaplan-Meier curves. A Cox model was constructed to control for a priori selected confounders. <b>Results:</b> A total of 250 patients who met the inclusion criteria were identified; 77 (30.8%) received adjuvant radiation therapy at a median of 57 days from surgery (IQR: 22) with a median dose of 50.4 Gy and a median treatment duration of 44 days (IQR: 12), while 32 (41.6%) of them received radio-sensitizing chemotherapy. Patients who received adjuvant radiation were more likely to have tumors ≥4 cm (46.8% vs 29.5%, p=0.046). Patient age, race, insurance status, presence of comorbid conditions, type of treatment facility, tumor grade, and surgical margin status were comparable between the two groups. By univariate analysis, patients who received adjuvant chemoradiation or radiation therapy alone did not have better OS compared to patients who did not receive any treatment (p=0.45); 5-year OS rates were 61.1% compared to 53.4% and 56.5%, respectively. After controlling for patient age, presence of comorbid conditions, insurance status, and tumor size, administration of adjuvant chemoradiation (HR: 0.74, 95% CI: 0.45-1.23) or radiation therapy alone (HR: 0.87, 95% CI: 0.43-1.76) were not associated with a survival benefit. <b>Conclusions:</b> Administration of adjuvant radiation therapy following comprehensive inguinal lymphadenectomy may not be associated with a survival benefit for patients with early-stage SCC of the vulva and single lymph node metastasis.

Abstract CT564: KEYNOTE-992: A randomized phase 3 trial of pembrolizumab versus placebo in patients with muscle-invasive bladder cancer receiving concurrent chemoradiotherapy

Abstract Background: Concurrent chemoradiotherapy (CRT) is recommended as a bladder-preserving treatment option for selected patients with muscle-invasive bladder cancer (MIBC). Pembrolizumab has shown clinical activity across many stages of bladder cancer, and ongoing phase 2 studies (ANZUP 1502, NCT02662062; NCT02621151) of pembrolizumab + CRT are promising. The global, randomized, double-blind, placebo-controlled, multicenter, phase 3 KEYNOTE-992 study (NCT04241185) will be conducted to evaluate the safety and efficacy of pembrolizumab + CRT in patients with previously untreated MIBC who opt for bladder preservation. Methods: Key patient eligibility criteria are age ≥18 years, histologically confirmed cT2-T4a, nonmetastatic MIBC, and decision to pursue bladder-preserving therapy. Approximately 636 patients will be randomly assigned 1:1 to receive CRT + either pembrolizumab 400 mg or placebo. Pembrolizumab or placebo will be administered intravenously (IV) every 6 weeks for up to 9 doses. Patients will be stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 or 1 vs 2), PD-L1 combined positive score (&amp;lt;10 vs ≥10), T stage (T2 vs T3 or T4), and geographic region (US vs Europe vs rest of world). CRT regimen must be determined before randomization. The following radiotherapy (RT) regimens are permitted: conventional RT consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated RT consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). The following radiosensitizing chemotherapy regimens are permitted: cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m2 on day 1), and gemcitabine monotherapy (27 mg/m2 IV twice weekly). Efficacy will be assessed by cystoscopy (± biopsy), by CT or MRI with blinded independent central review, and by urine cytology at 10 weeks after CRT, then every 12 weeks until the end of year 2, and every 24 weeks thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause. The key secondary end point is overall survival. Additional secondary end points are metastasis-free survival, time to any non-muscle-invasive bladder cancer, time to cystectomy, and safety. The study is enrolling at sites in Asia, Australia, Europe, North America, and South America. Citation Format: Neal D. Shore, Nicholas D. James, Michiel Simon Van der Heijden, Arjun Vasant Balar, Xiao Fang, Ekta Kapadia, Jeff M. Michalski, Shahrokh F. Shariat, Andrew James Weickhardt. KEYNOTE-992: A randomized phase 3 trial of pembrolizumab versus placebo in patients with muscle-invasive bladder cancer receiving concurrent chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT564.