Additional Systemic Therapy Research Articles

Patterns of Failure After Definitive Trimodality Therapy for Muscle-Invasive Bladder Cancer

BackgroundReal-world outcomes, especially patterns of failure, are limited for patients with muscle-invasive bladder cancer (MIBC) treated with trimodality therapy (TMT). We aim to evaluate patterns of failure after TMT for MIBC in a typical heterogeneous population. MethodsIn the national Veterans Affairs database, patients with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent definitive intent TMT between 2000-2018. Successful TMT was defined as ≥ 50% definitive radiation dose and ≥ 1 cycle chemotherapy. Endpoints of any recurrence, metastatic (nonbladder) recurrence (MR), and local (bladder) recurrence (LR) evaluated in multivariable Fine-Gray models. Times to recurrence calculated from radiation start date. ResultsIn 347 patients with MIBC treated with TMT, 65% of patients were deemed ineligible for surgery while 35% were surgically eligible but elected for TMT. Median follow-up time was 77 months. Median overall survival was 32.4 months (95% CI: 28.2-36.7). 154 (44%) patients had no recurrence. 130 (37%) patients developed MR, median time 9.9 months. 117 (34%) patients developed LR, median time 8.7 months. In multivariable models, lymph node positive (LN+) disease (HR:3.31, 95% CI: 1.45-7.55, P < .01) and pretreatment hydronephrosis (HR:1.62, 95% CI:1.11-2.36, P = .01) were associated with higher rates of MR. No patient, tumor, or treatment variables were associated with LR. ConclusionsAcross a multi-institutional and heterogeneous population, TMT is an effective treatment for many real-world patients with MIBC. However, a notable proportion of patients develop MR and/or LR which emphasizes the need for post-treatment surveillance and improved treatment pathways. Identified high risk features (LN+ disease, pretreatment hydronephrosis) and other markers should be further investigated to delineate the patients at high risk of TMT failure who therefore may potentially benefit from augmented treatment, such as additional systemic therapy.

Approach to otitis externa.

To provide family physicians with a practical evidence-based approach to management of otitis externa. The approach described is based on MEDLINE and PubMed literature published between 1993 and 2023. Otitis externa is diffuse inflammation of the external auditory canal and typically occurs from moisture exposure and trauma. Management focuses on eliminating infection, pain management, education, and preventing recurrence. The primary treatment of uncomplicated otitis externa is topical. Complicated presentations may require additional systemic therapy. History taking and physical examination can help differentiate among acute, chronic, and necrotizing otitis externa. At-risk populations, typically those who are immunosuppressed, are more likely to develop necrotizing otitis externa and should be carefully monitored.

Unraveling the role of local ablative therapies for patients with metastatic soft tissue sarcoma – A retrospective multicenter study of the Bavarian university hospitals

BackgroundLocal ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors. MethodsIn this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient. ResultsMedian overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively). ConclusionThis multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers.

"Recurrent Pleomorphic Xanthoastrocytoma Presenting with Diffuse Leptomeningeal Spread".

We have read with great interest the recent paper by Grigsby-Rocca et al regarding recurrent pleomorphic xanthoastrocytoma (PXA) with leptomeningeal dissemination. While acknowledging the challenges in managing such cases, we wish to highlight the role of radiotherapy for symptom palliation and potential life extension. We report a case of a 27-year-old woman with recurrent anaplastic PXA and diffuse leptomeningeal spread, who was offered radiotherapy to the spinal axis. Initially presenting with headaches and seizures, she underwent surgical excision, postoperative radiotherapy, and temozolomide. Despite initial disease control, subsequent recurrences required additional surgeries and systemic therapies. With disease progression to leptomeningeal spread, radiotherapy was administered, resulting in clinical stability. This case underscores the importance of considering palliative radiotherapy to improve quality of life and potentially prolong survival in patients with recurrent PXA and leptomeningeal dissemination.

Revealing patient characteristics and treatment outcomes in ultra-long biologic users for psoriasis.

Biologics are effective for psoriasis, but little is known regarding patients treated with one biologic for an "ultra-long" duration. To explore the prevalence, patient and treatment characteristics and treatment outcomes of "ultra-long users" of biologics for psoriasis. From the prospective, multicenter BioCAPTURE cohort, patients with psoriasis who received continuous treatment with the same biologic for ≥10 years were included. Baseline characteristics of these "ultra-long users" were determined and compared to the total BioCAPTURE population. Additionally, the frequency of concomitant systemic treatment use and dose adjustments administered, the trajectory of Psoriasis Area and Severity Index (PASI) scores, and drug survival rates beyond 10 years were analysed. In BioCAPTURE, 30.5% of the patients with the potential to reach a treatment episode of ≥10 years achieved this treatment duration. These patients were treated with ustekinumab, etanercept, adalimumab and infliximab. The proportion of ultra-long users was highest for ustekinumab (37%). The ultra-long user cohort had a slightly longer disease duration at registry entry, and higher proportion of males and patients diagnosed with PsA, compared to the total BioCAPTURE population. A large percentage of ultra-long users (69.5%) had ≥1 comorbidities and 66% used no additional systemic antipsoriatic therapy. Dose adjustments were often applied, varying from dose escalation (30%), dose reduction (41%), or both (14%); only 16% consistently used the standard dose. The median PASI course for ultra-long users from month 6 onwards was continuously <3, with only a small proportion achieving complete clearance of their psoriasis (3.9-13.7% at the various time points). Drug survival beyond 10 years showed >60% was still treated with the same biologic after 15 years. Ultra-long use of the same biologic in patients with psoriasis was common in real-world practice, but varied between biologics. The median PASI was around 2.5 throughout the 10-year treatment course; complete clearance was often not reached. Remarkably, ultra-long use was reached also in patients having multiple comorbidities (including PsA) and a variety of dose adjustments of the biologics was applied. These results provide clinicians with important evidence on ultra-long biological treatment, thereby improving psoriasis care and management of treatment expectations.

Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (preSINO trial): A prospective multicenter diagnostic cohort study in Asia.

196 Background: The benefit of standard esophagectomy in patients with clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) is disputable and the alternative of active surveillance should be studied. PreSANO study demonstrated that clinical response evaluations (CREs) are accurate to detect residual tumor after nCRT in patients with mainly adenocarcinoma, however, its applicability to esophageal squamous cell carcinoma (ESCC) is unknown. The preSINO trial (NCT03937362) aimed to assess the accuracy of CREs based on bite-on-bite biopsy, endoscopic ultrasonography with fine needle aspiration (EUS-FNA) of suspected lymph nodes, PET-CT in patients with ESCC, and to provide a basis for organ-sparing strategy of ESCC in Asia. Methods: Patients were eligible when they were planned for nCRT (CROSS regimen) followed by standard surgery. Patients received the first CRE (bite-on-bite biopsies) 4-6 weeks after completion of nCRT. Patients with locoregional residual tumor and without distant metastases underwent immediate surgery. In patients with a cCR at CRE-1, a second CRE (CRE-2) was done 10-12 weeks after completion of nCRT using PET-CT, bite-on-bite biopsies and EUS-FNA of suspicious lymph nodes. All patients underwent surgery irrespective of the outcome of CRE-2, in the absence of distant metastases. Circulating tumor DNA (ctDNA) analyses based on tumor-informed assay were performed at baseline and CREs for exploratory analysis. Primary endpoint was the accuracy of CREs for detecting TRG3-4 or TRG1-2 with ypN+ residual tumor. A false-negative rate (FNR) of 19.5% was considered acceptable according to the study protocol. Results: From Aug 20, 2019, to Jan 15, 2023, 309 patients were included of whom 250 patients underwent nCRT plus surgery. Eighteen of 133 patients with TRG3-4 or TRG1-2 with ypN+ residual tumor were not detected by bite-on-bite biopsies and EUS-FNA (FNR: 13.5%). Sensitivity, specificity, negative predictive value and positive predictive value of detecting any residual tumor were 82%, 93%, 69% and 97%, respectively. PET-CT detected interval distant metastases in 13 (5%) of 268 patients prior to surgery. Postoperative distant recurrence rate among patients with ctDNA-positive and ctDNA-negative during CREs were 15.1% (11/73) and 3.3% (2/59), respectively. Conclusions: Bite-on-bite biopsies and EUS-FNA for lymph nodes were accurate for detecting locoregional residual disease after nCRT in patients with ESCC. Post-nCRT ctDNA-positive during CREs may indicate an increased risk of long-term distant metastasis, potentially serving as a diagnostic tool to identify patients who would benefit from postponement of surgery and additional systemic therapy. The long-term follow-up results of this trial will further answer this question. Clinical trial information: NCT03937362 .

Otitis in paediatric practice: clinic presentation, diagnosis, role of topical therapy

The article considers the main pathological processes in the outer and middle ear, which are detected at the primary paediatric visit. A particular focus has been placed on the importance of otoscopy and the need for sustainable routing of a child with ear pain. The basic principles for the treatment of acute external and otitis media in children are outlined, and indications for additional examinations and systemic antimicrobial therapy are determined. The benefits of topical combination ear drops in the treatment of acute external and otitis media are presented. The benefits of combination ear drops in the treatment of ear pathology in children from 6 years of age are demonstrated by examples of clinical studies and retrospective analysis of clinical efficacy. Clinical cases from our own observations are presented: a 7-year-old patient with acute non-perforative otitis media and a 12-year-old patient with acute exacerbation of chronic external otitis, myringitis. The combination ear drops containing chloramphenicol, beclomethasone dipropionate (anhydrous), clotrimazole and lidocaine hydrochloride monohydrate demonstrated high clinical efficacy. The combination drug with a beneficial and clinically proven effect can help solve the issue of otitis in children from 6 years of age. The authors have developed a treatment and prevention reminder for ear pathologies in children, which will help the paediatrician explain the main principles of treatment and prevention of otitis media to parents in an easily accessible form. It was concluded that ear pathology is a current and multi-etiological challenge that requires attention and expert knowledge of a paediatrician. The active parental involvement in ear pathology prevention in their child will help their children to grow physically healthy.

Real-world economic burden associated with disease progression from metastatic castration-sensitive to castration-resistant prostate cancer on treatment in the United States.

The advent of next-generation imaging will likely reduce nonmetastatic prostate cancer (PC) prevalence and increase identification of metastatic prostate cancer cases, resulting in two predominant advanced stages in the metastatic setting. There is a need to characterize changes in health care resource utilization (HRU) and costs when metastatic castration-sensitive PC (mCSPC) progresses to metastatic castration-resistant PC (mCRPC) to identify value drivers from current and new treatments. To describe treatment patterns, HRU, and total health care costs among patients with mCSPC, before and after progression to mCRPC. Clinical data from the Flatiron Metastatic PC Core Registry (January 1, 2013, to December 1, 2021) and linked claims from Komodo Health (January 1, 2014, to December 1, 2021) were used to identify patients with progression from mCSPC to mCRPC (date of progression was the index date) and subsequently initiated first-line mCRPC therapy on/after January 1, 2017. Treatment patterns and all-cause/PC-related HRU and health care costs were described per-patient-per-month (PPPM), separately for no more than 12 months pre-index (mCSPC disease state) and post-index (mCRPC disease state). Costs (payer's perspective) included those for services/procedures from medical claims and costs from pharmacy claims. Continuous HRU and costs were compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests. Among 296 patients with mCSPC progressing to mCRPC (median age 69.0 years, 60.5% White, 15.9% Black), use of systemic therapies with androgen deprivation therapy increased dramatically from 35.1% in the mCSPC disease state to 92.9% in the mCRPC disease state, and use of androgen deprivation therapy monotherapy decreased from 25.7% to 2.4%, respectively. Although 39.2% received none of these therapies in the mCSPC disease state, this proportion decreased to 4.7% after transition to mCRPC. The mean number of days with PC-related outpatient visits increased from 1.57 to 2.16 PPPM in the mCSPC and mCRPC disease states (P < 0.001). From the mCSPC to mCRPC disease states, mean all-cause total health care costs PPPM increased from $4,424 (medical costs: $2,846) to $9,717 (medical costs: $4,654), and mean PC-related total health care costs PPPM increased from $2,859 (medical costs: $1,626) to $8,012 (medical costs: $3,285; all P < 0.001). In this real-world study of patients with disease progression from mCSPC to mCRPC in US clinical practice, nearly 2-in-3 patients did not receive treatment with additional systemic therapies before progression to castration resistance. Post-progression, mean PC-related total costs increased nearly 3-fold, with a more than 2-fold increase in PC-related medical costs. Use of additional systemic therapies may delay the time and cost associated with disease progression to castration resistance.

Abstract PO3-03-11: Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer

Abstract Background: Discordance in hormone receptor (HR) and/or HER2 status between matched primary tumors and residual specimens following neoadjuvant therapy is a known phenomenon. In the neoadjuvant setting, systemic treatment is primarily informed by the HR and HER2 status from the diagnostic biopsy. Current guidelines recommend additional adjuvant capecitabine and/or pembrolizumab and/or olaparib for patients with triple-negative breast cancer (TNBC) after neoadjuvant systemic therapy if residual disease is present at the time of surgery. Discordance in biomarker status between the initial diagnosis and residual cancer may impact postoperative systemic therapy recommendations. This study aims to investigate the discordance rate in HR and HER2 status after neoadjuvant chemotherapy (NAC) plus pembrolizumab in early-stage TNBC. Furthermore, given the emerging data in support of novel antibody-drug conjugates (ADCs) for HER2-low breast cancer, the prevalence of HER2-low disease following standard-of-care neoadjuvant therapy may have critical clinical importance. Methods: We performed a single-institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with neoadjuvant chemotherapy and pembrolizumab. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected from an institutional database. Pathologic complete response (pCR) was defined as ypT0/Tis and ypN0. HR and HER2 status before and after neoadjuvant therapy were collected. This study was approved by an Institutional Review Board. Results: Among the 94 patients included the median age was 55 years (IQR 47.0-61.8). The majority of patients had invasive ductal carcinomas (90.4%), were clinical T2 stage (68.1%), and node negative (55.3%). On the core tumor biopsy, estrogen receptor (ER) was &amp;lt; 1% in 90 (95.7%) patients and 1-10% in 4 (4.3%) of patients. Progesterone receptor (PR) was &amp;lt; 1% in 91 (96.8%) of patients and 1-10% in 3 (3.2%) of patients. HER2 was 0 by IHC in 49 (52.1%) patients, 1+ in 30 (31.9%) patients, 2+ in 11 (11.7%) patients, and not performed in 4 (4.3%) patients. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. In the 34 patients with residual disease, 29 patients had ER status evaluated at the time of surgery. Of these patients, 4 had tumors with ER &amp;lt; 1% at baseline but &amp;gt;5% at surgery. 28 patients with residual disease had PR evaluated at the time of surgery. Of these patients, all had tumors with PR &amp;lt; 1% at the time of surgery. 28 patients had residual tumors with HER2 status evaluated at the time of surgery (table). Of these patients, 18 (64.3%) tumor specimens were HER2-ultra-low, 9 (32.1%) were HER2-low-positive, and 1 (3.6%) was HER2-positive. Conclusion: Receptor discordance from the time of initial biopsy to residual disease can occur in patients with early-stage TNBC treated with NAC with pembro. As additional systemic therapy is indicated in patients who do not achieve pCR, accurate tumor marker status is critical. This study highlights the potential impact of reassessment of HR and HER2 status on the surgical tumor specimen. Clinical trials that tailor adjuvant therapy recommendations based on residual biomarker analyses may further improve outcomes for women with high risk TNBC. Table. Discordance in HER2 Status Between Primary Tumor and Residual Specimen Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-11.

Abstract PO5-20-07: A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh

Abstract Breast cancer is the most diagnosed cancer in women worldwide. The predominant cause of breast cancer mortality is metastatic disease with bone, lung, liver and brain being most common sites of metastasis. After melanoma, breast cancer is the most common cancer to have cutaneous metastatic disease and this presentation represents half of all cutaneous metastases. We are presenting a case of a 70-year-old female with distant recurrence of breast cancer to the left thigh. A 70-year-old female presented to clinic with a palpable left breast mass noted July 2022. Her medical history was notable for right sided upper lobe stage IIIB squamous cell lung cancer diagnosed in 2013 treated with chemotherapy and chest radiation (RT), menopause at 25 years old following TAH/BSO for fibroids. Family history included prostate cancer and genetic testing was negative for pathogenic mutation. Diagnostic mammogram showed a lesion in the left breast at 9:00 of 1.4 cm x 1.2 cm x1.4 cm, and biopsy showed grade 3 triple negative invasive ductal carcinoma (IDC). Her nodes were clinically and radiologically negative. She opted for breast conservation. In September of 2020 the patient had a left lumpectomy with sentinel lymph node biopsy. Final pathology (path) was pT1cN0 with two foci of IDC, grade 3, measuring 1.9 × 1.9 × 1.1 cm and 0.4 × 0.2 × 0.2 cm with negative margins. Two sentinel lymph nodes were negative for carcinoma. She received 4 cycles of doxorubicin and cyclophosphamide and started paclitaxel, but only completed 5/12 planned cycles. During these treatment cycles she was admitted twice for shortness of breath and found to have an exudative pleural effusion, repeat cytology was negative for malignancy at which point fluid did not recur. There was no CT evidence of lung nodules or plural thickening. Echocardiogram showed normal ejection fraction of 45%. PET scan was negative. Chemotherapy was stopped in February of 2021. Initial pre-operative discussion with radiation oncology indicated no contraindication to adjuvant RT. However, after simulation, it was deemed by radiation oncology that the patient was no longer a candidate for RT as during her lung cancer treatment, she had received RT of 69.4 Gy including the area of the current lumpectomy cavity. She then opted for bilateral mastectomy with immediate reconstruction in June 2021. Final path from both breasts showed no carcinoma. In November of 2021 she was admitted for shortness of breath and on CT scan was noted to have a left sided lung nodule. The patient declined biopsy and underwent a left wedge resection in January of 2022. Final path showed a 2.2. cm carcinoma consistent with breast primary that was ER 0, PR 0, and Her 2 neu 1+. She was started on capecitabine with plan for 6 months of treatment but stopped taking this after one month due to severe pain in her hands and feet. In November 2022 the patient noted a left thigh mass. Exam showed a firm, palpable thigh mass without overlying skin changes and core needle biopsy showed adenocarcinoma, favoring breast primary, ER 0, PR 0, HER 2 neu 2+ and FISH negative. PET scan showed no uptake in the chest abdomen or pelvis, however a 2.6 × 2.3 × 3.1 cm round mass in the left thigh was seen with SUV max of 8.6. She was started on traztuzumab-deruxtecan by medical oncology in December of 2022. The thigh tumor shrank significantly, however, patient discontinued after two infusions, citing intolerable hand weakness. She then received RT to the thigh. She was treated using 3D technique and 6 MV photons for a total dose of 5400 cGY, from February to March of 2023. Repeat PET June 2023 showed no avid uptake in the thigh. She has declined any additional systemic therapy. Soft tissue metastasis in distant recurrent breast cancer is uncommon and little guidance exists on clinical management. In cases of metastatic disease to the skin, hormone positive lesions can be managed with hormonal therapy. Early detection and biopsy for receptor studies may help guide therapy in cases of distant soft tissue recurrence. Citation Format: Rangel Melissa, Julia Alexieva, Alison Coogan, Lily Hussein, Elizabeth Marcus, Julie Wecsler. A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-07.

Pathologic and survival outcomes following radical cystectomy for “progressive” and “de novo” muscle-invasive bladder cancer: A meta-analysis stratified by neoadjuvant chemotherapy status

ObjectiveTo compare survival and pathologic outcomes in patients with progressive muscle-invasive bladder cancer (pgMIBC) and de novo muscle-invasive bladder cancer (dnMIBC) after radical cystectomy (RC), with a focus on the role of neoadjuvant chemotherapy (NAC). MethodsA comprehensive literature search was conducted on PubMed and EMBASE databases to identify studies comparing pgMIBC to dnMIBC. Survival outcomes, including cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS), and pathologic outcomes (rates of ≤pT1, pT0, pT3/T4, and pN+ disease) were compared between pgMIBC and dnMIBC. ResultsThe analysis included 19 cohorts from 16 studies, categorized into 3 groups based on NAC use: 1. patients who underwent RC and were all treated with NAC (RC + NAC only group); 2. patients who underwent RC, with or without NAC (RC +/- NAC group); 3. patients who only underwent RC without NAC (RC only group). Compared to dnMIBC, pgMIBC demonstrated worse outcomes for CSS, OS, and RFS. In the RC + NAC only group (3 cohorts), the hazard ratio (HR) for CSS was 1.52 (95% confidence interval [CI] = 1.05–2.2), while the HR for OS was 1.46 (95%CI = 1.05–2.02). Similarly, in the RC +/- NAC group (6 cohorts for CSS and 3 cohorts for OS), the HR for CSS was 1.27 (95%CI = 1.05–1.55), and the HR for OS was 1.27 (95%CI = 1.08–1.51). There were no significant differences observed in pathologic outcomes, including rates of ≤pT1, pT0, and pT3/T4 disease, across all subgroups. However, pgMIBC was associated with a higher risk of nodal metastatic (pN+) disease in the RC + NAC only group (4 cohorts, relative risk [RR] = 1.43, 95%CI = 1.12–1.84). ConclusionsThe findings highlight the potentially worse prognosis in patients with pgMIBC compared to dnMIBC, even with the modern use of NAC. The study emphasizes the importance of careful patient counseling, further classification of patients for treatment selection, and the consideration of additional or innovative systemic therapies for pgMIBC.

Sacituzumab Govitecan (Trodelvy)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses sacituzumab govitecan (Trodelvy), 180 mg lyophilized powder for solution for injection, for IV use. Indication: For the treatment of adult patients with unresectable, locally advanced or metastatic, HR-positive, human epidermal growth factor receptor 2-negative (immunohistochemistry [IHC] 0, IHC 1+ or IHC 2+/in situ hybridization-negative) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Patterns, timing and predictors of recurrence following pancreaticoduodenectomy for distal cholangiocarcinoma: An international multicentre retrospective cohort study

IntroductionPatients undergoing pancreaticoduodenectomy for distal cholangiocarcinoma (dCCA) often develop cancer recurrence. Establishing timing, patterns and risk factors for recurrence may help inform surveillance protocol strategies or select patients who could benefit from additional systemic or locoregional therapies. This multicentre retrospective cohort study aimed to determine timing, patterns, and predictive factors of recurrence following pancreaticoduodenectomy for dCCA. Materials and methodsPatients who underwent pancreaticoduodenectomy for dCCA between June 2012 and May 2015 with five years of follow-up were included. The primary outcome was recurrence pattern (none, local-only, distant-only or mixed local/distant). Data were collected on comorbidities, investigations, operation details, complications, histology, adjuvant and palliative therapies, recurrence-free and overall survival. Univariable tests and regression analyses investigated factors associated with recurrence. ResultsIn the cohort of 198 patients, 129 (65%) developed recurrence: 30 (15%) developed local-only recurrence, 44 (22%) developed distant-only recurrence and 55 (28%) developed mixed pattern recurrence. The most common recurrence sites were local (49%), liver (24%) and lung (11%). 94% of patients who developed recurrence did so within three years of surgery. Predictors of recurrence on univariable analysis were cancer stage, R1 resection, lymph node metastases, perineural invasion, microvascular invasion and lymphatic invasion. Predictors of recurrence on multivariable analysis were female sex, venous resection, advancing histological stage and lymphatic invasion. ConclusionTwo thirds of patients have cancer recurrence following pancreaticoduodenectomy for dCCA, and most recur within three years of surgery. The commonest sites of recurrence are the pancreatic bed, liver and lung. Multiple histological features are associated with recurrence.

Sacituzumab Govitecan: A Review in Unresectable or Metastatic HR+/HER2- Breast Cancer.

Sacituzumab govitecan (TRODELVY®) is a first-in-class trophoblast cell-surface antigen 2 (Trop-2)-directed antibody and topoisomerase I inhibitor conjugate that is approved globally as monotherapy for the treatment of adults with unresectable locally advanced or metastatic, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-; defined as immunohistochemistry 0, 1+ or 2+ and in situ hybridization-negative) breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the advanced setting. In the phase III TROPiCS-02 trial, intravenous sacituzumab govitecan demonstrated statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared with physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in adults with metastatic HR+/HER2- breast cancer. Sacituzumab govitecan had a generally manageable tolerability profile in these patients; the most common treatment-related grade ≥3 adverse events included neutropenia, diarrhoea, leukopenia, anaemia, fatigue and febrile neutropenia. Sacituzumab govitecan carries regulatory warnings for severe neutropenia and severe diarrhoea. Sacituzumab govitecan demonstrated an overall benefit in terms of health-related quality of life. Current evidence indicates that sacituzumab govitecan is an effective treatment option, with a generally manageable tolerability profile, for patients with pre-treated, unresectable locally advanced or metastatic HR+/HER2- breast cancer.

Sacituzumab Govitecan (Trodelvy)

&#x0D; CADTH recommends that Trodelvy should be reimbursed by public drug plans for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+, or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting, if certain conditions are met.&#x0D; Trodelvy should only be covered to treat adult patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have been previously treated with at least 1 taxane, at least 1 prior anticancer hormonal treatment, and at least 1 cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in any setting, have experienced treatment failure after 2 to 4 prior systemic chemotherapy regimens for metastatic disease, and have good performance status.&#x0D; Trodelvy should only be reimbursed if it is prescribed by clinicians with expertise and experience in treating breast cancer in approved centres, and if the price of Trodelvy is reduced.&#x0D;

Upfront Radiation Therapy (RT) for Post-Stem Cell Transplant Multiple Myeloma (MM) Patients with Oligo-Relapse/Progressive Disease: Factors Associated with Favorable Outcomes

Introduction: Relapsed or refractory disease post-stem cell transplant (SCT) for Multiple Myeloma (MM) can be clinically challenging. For localized relapses, radiation therapy (RT) can represent an attractive treatment modality. However, data on outcomes with RT remains scarce. We investigated the impact of RT as a treatment modality in the setting of oligo-relapse and oligo-progressive plasmacytomas after SCT and explored prognostic factors associated with favorable long-term outcome Methods: In this single-institution retrospective analysis, we identified 31 MM patients who underwent upfront RT for oligo-relapse or oligo-progressive MM after SCT between 2000 and 2021. Patients were excluded if they had received systemic therapy for evidence of concurrent biochemical relapse prior to RT start. The treatment responses to stem cell transplantation (SCT) and RT were assessed following the response criteria established by the International Myeloma Working Group (IMWG), which includes the categories: complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). Additionally, we utilized the R-ISS staging system to classify patients into Standard-Risk (R-ISS I), Intermediate-Risk (R-ISS II), and High-Risk (R-ISS III) groups, to allow for a comprehensive evaluation of treatment efficacy and outcomes. Results: Disease and treatment characteristics for the cohort are summarized inFigure 1. Of the 27 patients with imaging available prior to SCT, 67% (18) were assessed with PET, 22% (6) with skeletal survey, 3.7% (1) with MRI/CT, 3.7% with CT, and 3.7% (1) with x-ray. Following SCT, 48% (13) of patients were noted to have radiographic progression, 23% (7) had sCR, 23% (7) had a CR, 10% had a serologic CR, and 45% (14) had a VGPR. Among the 18 patients with radiographic evaluation (in addition to bone marrow biopsy and/or labs) post-SCT, 67% (12) were in radiographic CR at time of re-staging. Median times from SCT to new site of oligo-relapsed disease (20, 64.5%) and pre-existing but inactive sites of oligo-relapsed MM (4, 12.9%) were 31 months (3.2-117.5) and 9 months (3.4-15.9), respectively. Oligo-progressive MM, defined as active sites of disease both pre- and post-SCT were present in 22.6% (7) of patients. Prior to RT, 94% (29) had PET/CT imaging, with a median SUV of 4.4 (2.6-7.2) for target lesions. Solitary bone (77%) and extramedullary (23%) disease were treated to median dose of 30 Gy (8-49 Gy). At first disease response assessment post-RT, 77% (24) of which was done with PET/CT imaging , 42% (13) achieved CR. Among the 18 patients that did not achieve CR, 15 subsequently achieved CR at a median time of 7 months (1.7-44.5). A majority of patients (87%) received systemic therapy post-RT, with a median number of lines of therapy post-RT of 3 (1-17). The remaining 13% (4) of patients did not receive additional systemic therapy post-RT and did not experience progression. Median overall survival for the full cohort was 38 months (3.5-37.9). Conclusions: Utilizing modern systemic therapies in combination with post-transplant RT for patients with limited refractory or relapsed MM is a promising therapeutic approach. For those that remain refractory or relapse in a single site RT local control merits consideration supported by our report. Further investigation to identify patients at highest risk of progression and who may therefore benefit most from RT would be valuable. We plan to conduct additional analyses on the radiographic characteristics that may portend high risk disease, with the ultimate goal of developing well-defined criteria for giving RT earlier.

Machine learning based local recurrence prediction in colorectal cancer using polarized light imaging.

Current treatment for stage III colorectal cancer (CRC) patients involves surgery that may not be sufficient in many cases, requiring additional adjuvant systemic therapy. Identification of this latter cohort that is likely to recur following surgery is key to better personalized therapy selection, but there is a lack of proper quantitative assessment tools for potential clinical adoption. The purpose of this study is to employ Mueller matrix (MM) polarized light microscopy in combination with supervised machine learning (ML) to quantitatively analyze the prognostic value of peri-tumoral collagen in CRC in relation to 5-year local recurrence (LR). A simple MM microscope setup was used to image surgical resection samples acquired from stage III CRC patients. Various potential biomarkers of LR were derived from MM elements via decomposition and transformation operations. These were used as features by different supervised ML models to distinguish samples from patients that locally recurred 5 years later from those that did not. Using the top five most prognostic polarimetric biomarkers ranked by their relevant feature importances, the best-performing XGBoost model achieved a patient-level accuracy of 86%. When the patient pool was further stratified, 96% accuracy was achieved within a tumor-stage-III sub-cohort. ML-aided polarimetric analysis of collagenous stroma may provide prognostic value toward improving the clinical management of CRC patients.

Imaging and therapy targeting PSMA receptors for enhanced vision and precise treatment

SummaryIn Europe, it is estimated that more than 65,000 men die each year from the consequences of advanced and metastatic prostate cancer (PCa). Currently, approximately 3.2 million European men are living with PCa. While the majority of PCa patients have favorable outcomes, the 5‑year relative survival rate for those with metastatic PCa is only 32%. Recent advances in the diagnosis of PCa have been boosted by the introduction of the prostate-specific membrane antigen (PSMA), which might identify patients with the most aggressive form of the disease. Molecular imaging with positron emission tomography (PET) targeting PSMA receptors (PSMA-PET) has utterly revolutionized the diagnosis and staging of PCa; however, its application is still under debate. On the one hand, there has been little progress in recent years in surpassing the limitations of androgen deprivation therapy (ADT), the backbone of metastatic PCa treatment. Adding additional systemic therapy became standard in the last few decades. Current ADT is only transiently effective, and patients eventually progress during ADT treatment, a condition known as castration-resistant PCa (CRPC). On the other hand, radioligand therapy (RLT) targeting these PSMA receptors, most commonly used in the studies [177Lu]lutetium-PSMA-617, has been available for this cancer stage for nearly a decade and has been recently incorporated into the European Association of Urology (EAU) guidelines as a robust treatment option for patients with metastatic CRPC.

Clinical Presentation and Management of Prostate Cancer in the Middle East.

Prostate cancer is one of the most common malignancies worldwide and the incidence rate continues to increase in the Middle East. In the absence of large well-established cancer registries, there are no data to reflect the disease stage at initial presentation and patterns of care in this region. In order to mitigate the disease burden and help stakeholders to implement new policies to improve patient outcomes, it is important to study the disease stage at the initial presentation. The purpose of this study was to evaluate the clinical presentation and treatment of prostate cancer in the Middle East. We performed a retrospective review of 7 institutional databases in 6 Middle Eastern countries to identify patients diagnosed with prostate cancer in 2021. Demographic, clinical, and treatment variables were abstracted. Patients who missed ≥2 scheduled radiation therapy (RT) appointments (excluding planned treatment breaks) were deemed "noncompliant." A total of 1,132 patients were identified with a median age was 70 (range, 50-84). Most of the patients (78%) were diagnosed after developing symptoms and not on routine PSA screening. Diagnostic workup was completed in 87% of the patient. At time of diagnosis, 35% men presented with clinical T3 or T4 disease, 53% with metastatic disease and 42% with Gleason score ≥ 8. Mean PSA at time of presentation was 84 ng/ml. Among the nonmetastatic patients, 23% underwent a prostatectomy, 48% received definitive RT with or without androgen deprivation therapy (ADT), 9% received ADT alone and 20% received no treatment. No brachytherapy was used. Hypofractionated RT was used in 49% patients and only 8% were deemed "noncompliant". Among the metastatic patients, 74% received ADT with or without additional systemic therapy, 25% had palliative RT and 22% received no treatment. In this large cohort of prostate cancer patients in the Middle East, most men presented with symptoms and were found to have advanced-stage disease. However, substantial proportion of patients did not receive any treatment. Further interventions to optimize prostate cancer diagnosis and treatment in in the Middle East are urgently needed.

Radiation-Associated Lymphopenia in Advanced Prostate Cancer Treated with Contemporary Radiation Techniques.

Lymphocytes play a critical role in the immune system as primary effector cells for cancer control, often depleted by external beam radiation therapy (EBRT). Radiation-associated lymphopenia (RAL) has been shown to be a poor prognostic factor in the management of multiple solid tumors. We hypothesize RAL is similarly observed in advanced prostate cancer (PC) RT with contemporary techniques. We identified patients with advanced PC (high-risk or clinical/pathologic node-positive) receiving EBRT including lymph node/prostatic lesion boost on a prospective collection protocol for whom 1 baseline and ≥2 subsequent complete blood count (CBC) with differential samples were available, collected at RT end, 3-, 6-, and 12-months post-RT. Clinicopathological characteristics were retrieved from chart review. Common Terminology Criteria for Adverse Events (CTCAE)v5 was used to grade absolute lymphocyte count (ALC); RAL was defined as CTCAEv5 grade ≥2. As these patients received pelvic nodal irradiation, they were pooled with low/intermediate-risk PC cohort treated with high dose-rate (HDR) brachytherapy or prostate alone EBRT with similar CBC timepoints for univariable analysis to understand RT field size effect on RAL. Between 2019 and 2022, among 17 patients in the low/intermediate-risk PC cohort, 6 patients had grade ≥2 lymphopenia. Among 25 patients in the advanced PC cohort, all received androgen deprivation therapy (ADT), 6 received lymph node boost, and 5 received prostatic lesion boost. At RT end, leukopenia was prominently observed (median nadir count 75.1% of baseline), with ALC as major driver (median nadir count 27.3% of baseline). Grade ≥2 lymphopenia was observed in 76% of patients (n = 19) Of 19 advanced PC patients who reached 6 months post-RT follow-up, median ALC was 53.0% of baseline, and Grade ≥2 lymphopenia remained in 37% (n = 7) of patients. Of 8 advanced PC patients who reached 12 months post-RT follow-up, median ALC was 55.6% of baseline. When evaluating whether RT dose or field size contributed to lower nadir ALC counts, combining the low/intermediate-risk and advanced PC cohorts (n = 42), univariable analysis demonstrated Gleason grade group (p = 0.009), RT field size (p = 0.020), ADT use (p = 0.020), baseline ALC (p = 0.037), and baseline hemoglobin (p = 0.009) were independent predictors of Grade ≥2 lymphopenia. Age, prostatic lesion/lymph node boost, and equivalent dose in 2 Gy/fraction (EQD2) were nonsignificant. Grade ≥2 RAL was observed in patients with advanced PC at end of RT, irrespective of age, RT boost, or EQD2. Lymphocyte recovery from baseline can be prolonged even at 12 months post-RT. Ongoing analyses include expanding data with additional serial CBC, increasing cohort size, and integrating effect of additional systemic therapies. RAL has downstream implications for future chemotherapy/radiopharmaceuticals.