Node-positive Disease Research Articles

Prognostic Significance of Lymph Node Density in Pathological Node Positive Urothelial Carcinoma of the Bladder -Upfront Surgery and Post Neoadjuvant Chemotherapy Cohorts

AimTo validate the role of lymph node density as a prognostic marker in patients undergoing primary surgery and postneoadjuvant therapy in pathological node-positive urothelial bladder carcinoma. Materials and MethodsRetrospective analysis of 503 patients who underwent radical cystectomy from 2006 to 2019 for muscle-invasive urothelial bladder carcinoma, of which 152 patients with pathological node-positive disease were analyzed. Demographic details, pathological findings, treatment details, disease-free, and overall survival were documented. X tile program analysis was used to divide patients with positive lymph nodes into 3 groups: LD1: <= 7, LD2 :>7 to <15, LD3: >15, and the optimal cut-off value obtained was 15%. To evaluate the impact of lymph node ratio, patients with positive lymph nodes into 3 categories for each cut-off point estimation method, the application generates the histogram, Kaplan–Meier plot and calculates hazard ratio, confidence intervals and P-values. Univariate and multivariate cox regression analysis was done with a P-value of <.05, considered significant. ResultsOne hundred fifty-two patients (30.2%) had pathological nodal metastasis, with 87 of them having perinodal extension. Ninety-six underwent primary surgery, and 56 were postneoadjuvant chemotherapy. The median follow-up was 55.42 months. 68 of the 152 node-positive patients died of the disease. Median number of lymph nodes removed was 17.11. Lymph node density divided into tertiles were LD1 <7%, LD2 7-<15%, LD3 >15% showed 5-year RFS 40.5%,29.3%, 22.6% and 5 year OS was 55.5%, 42.4%,32.1% respectively. Cox regression analysis showed that age less than 55 years ,higher tumor stage, lymphovascular invasion, and higher lymph node ratio were significant in univariate and multivariate analysis. The lymph node density cut-off value of 15% was substantial among node-positive patients (P = .027), and subgroup analysis in upfront surgery with the adjuvant treatment group and postneoadjuvant chemotherapy group was also significant (P =.021). ConclusionPathological higher T stage, Age <55 years, Lymphovascular invasion, adjuvant chemotherapy , adjuvant radiation treatment and lymph node density had prognostic significance in both cohorts of patients who underwent upfront surgery and neoadjuvant chemotherapy. Lymph node density cut-off value of <15% was prognostically significant.

Efficacy of Targeted Axillary Dissection With Radar Reflector Localization Before Neoadjuvant Chemotherapy

IntroductionFor clinically node positive breast cancer patients treated with neoadjuvant chemotherapy (NAC), targeted axillary dissection (TAD) can be used to stage the axilla. TAD removes the sentinel lymph node (SLN) and tagged positive nodes, which can be identified via radar reflector localization (RRL). As it can be challenging to localize a previously positive node after NAC, we evaluated RRL prior to NAC. MethodsWe performed a retrospective chart review of breast cancer patients with node positive disease treated with NAC who underwent TAD with RRL. We compared retrieval of radar reflector and clip, timing of localization, and, if a node was positive, whether the radar reflector node or SLN was positive. ResultsSeventy-nine patients fulfilled inclusion criteria; 32 were placed pre-NAC (mean 187 d before surgery) and 47 were placed post-NAC (mean 7 d before surgery). For pre-NAC placement, 31 of 32 radar reflectors and 31 of 32 clips were retrieved. For post-NAC placement, 47 of 47 radar reflectors and 46 of 47 clips were retrieved. There was no significant difference in radar reflector or clip retrieval rates between pre-NAC and post-NAC groups (P = 0.41, P = 1, respectively). Thirty of 32 patients with pathologic complete response avoided an axillary lymph node dissection. Of 47 patients with a positive lymph node, 32 were both the SLN and radar reflector node, 11 were radar reflector alone, and four were the SLN. ConclusionsRRL systems are an effective way to guide TAD, and RRL makers can be safely placed prior to NAC.

Optimization of supraclavicular lymph node clinical target volume delineation in high-risk breast cancer: a single center experience and recommendation

BackgroundProphylactic irradiation of supraclavicular lymph node drainage areas can improve the regional control rate of lymph node-positive or lymph node-negative disease but a locally-advanced stage breast cancer, and it can reduce breast cancer-related mortality. However, many controversies exist in the clinical target volume delineation of supraclavicular lymph node drainage in patients with breast cancer.MethodsWe retrospectively analyzed 42 patients with breast cancer and supraclavicular lymph node metastasis at our hospital between January 2017 and December 2021. Among these cases, 32 were locally advanced and 10 were stage IV at initial treatment. A patient with breast cancer who did not undergo dissection of the supraclavicular and infraclavicular lymph nodes at our hospital was selected as a standard patient. A contrast-enhanced computed tomography (CT) scan for positioning was used as a template image, and blood vessels, muscles, and bony landmarks were used as references for positioning. The metastatic supraclavicular lymph nodes were identified in all enrolled patients and projected into the template CT images.ResultsThe metastastic pattern of supraclavicular lymph node in breast cancer was proposed: distribution along the posterolateral border of the internal jugular vein (medial supraclavicular group) and along the transverse jugular vein (lateral supraclavicular group). We theorized that the lateral and posterior borders of the clinical target volume in the supraclavicular region should include the lymph nodes in the posterior triangle of the neck (level V) in high-risk individuals. If the metastatic axillary lymph node is extensive, then the superior border of the supraclavicular region should be moved upward appropriately.ConclusionsThis study analyzed patients with breast cancer and supraclavicular lymph node metastasis at initial treatment, explored the metastastic pattern of supraclavicular lymph node, and applied anatomical knowledge to further optimize the target volume delineation of supraclavicular lymph node drainage area in high-risk breast cancer.

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed. To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC. This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022. Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles. Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay. Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group. The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC. ClinicalTrials.gov Identifier: NCT03639948.

Sentinel-node biopsy in apparent early stage ovarian cancer: final results of a prospective multicentre study (SELLY)

AimTo evaluate the sensitivity and specificity of sentinel-lymph-node mapping compared with the gold standard of systematic lymphadenectomy in detecting lymph node metastasis in apparent early stage ovarian cancer. MethodsMulticenter, prospective, phase II trial, conducted in seven centers from March 2018 to July 2022. Patients with presumed stage I-II epithelial ovarian cancer planned for surgical staging were eligible. Patients received injection of indocyanine green in the infundibulo-pelvic and, when feasible, utero-ovarian ligaments and sentinel lymph node biopsy followed by pelvic and para-aortic lymphadenectomy was performed. Histopathological examination of all nodes was performed including ultra-staging protocol for the sentinel lymph node. Results174 patients were enrolled and 169 (97.1 %) received study interventions. 99 (58.6 %) patients had successful mapping of at least one sentinel lymph node and 15 (15.1 %) of them had positive nodes. Of these, 11 of 15 (73.3 %) had a correct identification of the disease in the sentinel lymph node; 7 of 11 (63.6 %) required ultra-staging protocol to detect nodal metastasis. Four (26.7 %) patients with node-positive disease had a negative sentinel-lymph-node (sensitivity 73.3 % and specificity 100.0 %). ConclusionsIn a multicenter setting, identifying sentinel-lymph nodes in apparent early stage epithelial ovarian cancer did not reach the expected sensitivity: 1 of 4 patients might have metastatic lymphatic disease unrecognized by sentinel-lymph-node biopsy. Nevertheless, 35.0 % of node positive patients was identified only thanks to ultra-staging protocol on sentinel-lymph-nodes.

Time to extend the indication for sentinel node biopsy in vulvar cancer? Results from a prospective nationwide Swedish study

ObjectiveTo assess detection rates and negative predictive values of sentinel node biopsy in vulvar squamous cell carcinoma with tumors ≥4 cm, multifocal tumors, and in locally recurrent disease.MethodsBetween December 2019...

Circulating Tumor DNA and Risk of Venous Thromboembolism in Locally Advanced Rectal Cancer

Venous thromboembolism (VTE) is a common complication in cancer patients, which negatively affects treatment delivery and, consequently, prognosis. The pathophysiology of cancer-associated thrombosis (CAT) is extremely complex, relying on cytokine release in response to interactions between tumor cells and macrophages, thus leading to endothelial damage and activation of coagulation. Several risk factors may contribute to VTE risk, including tumor types, advanced stage, and anti-cancer treatments. Anti-angiogenic agents or combination of systemic chemotherapy and concomitant radiotherapy (CT-RT), for instance, are well-established risk factors across different malignancies. Colorectal cancer (CRC) is not listed as a high-risk VTE tumor according to pivotal risk assessment models, although retrospective studies showed a VTE rate of around 20%. Consequently, considering the high prevalence of the disease, VTE in CRC represents a main burden in terms of morbidity, increased healthcare costs, and mortality. Rectal cancer (RC) comprises approximately 30% of all CRC. The treatment of locally advanced disease (LARC) consists of a multimodal approach which includes chemotherapy, radiotherapy, and surgery. In the context of CRC management, circulating tumor DNA (ctDNA) is a fast-growing tool able to detect minimal residual disease, useful for improving patients' stratification and prognosis. Moreover, its determination at the time of diagnosis may represent a surrogate of tumor burden, potentially increasing the risk of VTE compared to ctDNA negative patients. Due to the paucity of prospective data of VTE in LARC, the aim of this analysis is to describe the rate of VTE and the potential association between ctDNA levels at baseline and VTE occurrence. We conducted a prospective observational study enrolling patients with LARC managed with neoadjuvant CT-RT (capecitabine 1650 mg/m2 concomitant with 50,4 Gy pelvic long course radiotherapy), surgery, plus/minus adjuvant chemotherapy at European Institute of Oncology (IEO) between November 2014 and November 2019. Blood samples for ctDNA were obtained at pre-planned timepoints: baseline (T0), end of CT-RT (T1), after surgery (T2), end of adjuvant chemotherapy (T3). ctDNA was extracted from plasma and mutations detected on tumor biopsy (KRAS, NRAS, BRAF, PIK3CA) were evaluated on ctDNA. Among other clinical information, VTE events were collected, including pulmonary embolism (PE), deep vein thrombosis (DVT) and visceral venous thrombosis (VVT). VTE was counted when occurred after or whitin 30 days before LARC diagnosis. The ctDNA value, defined as variant allele frequency (VAF) in a targeted mutation, was analyzed for correlation with clinical outcomes and VTE events. Median baseline ctDNA value was set as threshold to subdivide patients in VAF high and VAF low. We enrolled 111 patients. Sixty-one (55%) patients harboring tumoral tissue mutations underwent liquid biopsy. KRAS mutation was the most frequent one (42%), followed by NRAS (7%) and PIK3CA (5%). Fifty-one patients (83%) had a clinical node positive disease. Baseline Khorana Score (KS) was 0 in 54 patients (88%) and 1 in 7. Median ctDNA value at T0 was 0.11 ng/2ml (range: 0.00 - 17.40). After a median follow up of 82 months, 9 VTE events (15%) were diagnosed, 4 PE, 3 DVT and 2 VVT. The median time from diagnosis to VTE event was 14 months (IQR 6 - 51). VTE occurrence was associated with VAF high at baseline, even though not statistically significant (Hazard Ratio [HR]: 2.85; 95% CI: 0.71-11.4, p value = 0.14). Looking specifically at KRAS mutant patients, 6 VTE events were observed, all experienced by VAF high patients (HR not estimable, p value = 0.001). Considering the overall population, VTE rate was 14% and no statistical differences were observed for VTE development according to mutational profile. In our prospective study on LARC patients, VTE was associated with high levels of ctDNA at diagnosis, although not statistically significant. However, the association was significant in KRAS mutant tumors, which may represent a subset of patients with higher risk of thromboembolic complications. Prospective translational studies using deeper molecular techniques and wider populations are required to define the role of ctDNA as additional predictive tool to stratify VTE risk in cancer patients.

The Use of Trimodality Treatment in Patients With Locally Advanced Oesophageal Squamous Cell Carcinoma: An Experience From a Large Cancer Centre in Pakistan.

Introduction Esophageal cancer is one of the most common cancers worldwide. Neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for locally advanced squamous cell carcinoma (SCC). Pathological complete response (pCR) after surgery is associated with better outcomes in terms of overall survival and disease-free survival. We aim to determine the effectiveness of neoadjuvant chemoradiotherapy in patients with locally advanced SCC at our institute, the largest purpose-built cancer center in Pakistan. We also aim to identify various factors influencing pCR, such as chemotherapy regimen, total radiation dose, clinical stage at presentation, and gender. Materials and methods This is a retrospective review of all patients with esophageal SCCpresented between January 2019 and 2021 to the institute for treatment. Patients received neoadjuvant chemoradiotherapy (nCRT) as per the CROSS trial protocol, followed by surgery. We assessed the pCR rate. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22 (Released 2013; IBM Corp., Armonk, New York). pCR was studied alongside associated factors such as age, gender, stage of disease, chemotherapy regimen, and total dose of radiotherapy. A p-value of <0.05 was considered statistically significant. The chi-square test was used to compare categorical variables. Univariate and multivariate logistic regression was employed to evaluate factors affecting pCR. Results A total of 218 patients were included in the study. pCR was achieved in 64.2% of the patients. The female gender was associated with better outcomes, as 70.4% (n=81) of female patients achieved a complete pathological response, compared to 57.3% (n=59) of males, with a p-value of 0.03. On univariate analysis, the complete pathological response was 69.6% (n=94) in the age group of 45 years and below, whereas it was 55.4% (n=46) in the age group above 45 years, with a p-value of 0.024. Though statistically insignificant, outcomes were slightly better for those with node-negative disease, as 67.2% (n=41) achieved complete pathological response compared to those with node-positive disease at 63.1% (n=99). Univariate logistic regression analysis identified gender (p=0.044, OR=1.77, 95% CI:1.016-3.108) and age group (p=0.034, OR=1.844, 95% CI: 1.046-3.252) as significantly associated with pCR. Female patients were 77% more likely to achieve pCR compared to male patients (OR=1.77, 95% CI:1.016-3.108). Younger patients (≤45 years) were 84.4% more likely to achieve pCR compared to the older age group (OR=1.844, 95% CI:1.046-3.252). However, these did not maintain significance in multivariate logistic regression analysis. Conclusion Our study indicated a high rate of pCR with nCRT in patients with esophageal SCC compared to other studies. The achievement of pCR was higher among females and younger patients, which was statistically significant on univariate logistic regression analysis. Our study also concluded that a higher dose of RT (50Gy/25#) is not superior to a lower dose (45Gy/25#) in terms of pCR achievement but was statistically insignificant. Similarly, CARBO/PAC was not superior to CIS/CAP in terms of pCR achievement and was also statistically insignificant.

Axillary management in breast cancer after neoadjuvant chemotherapy in the modern era: A national cancer database analysis

BackgroundAxillary management for node-positive breast cancer continues to evolve. Data further supporting targeted axillary dissection after neoadjuvant chemotherapy was published in 2016 and may have induced changes in practice. MethodsPatients included in the National Cancer Database from 2014 to 2017 with clinical T1 to T4 and node-positive disease who underwent neoadjuvant chemotherapy before surgical axillary management were evaluated. Patients were divided into the following 3 groups: selective axillary dissection, minimal axillary dissection, and maximal axillary dissection, according to surgical axillary management and pathological node status. ResultsPatients who underwent selective axillary dissection were younger (52.4 years ± 12.4, P < .0001) compared to maximal axillary dissection (55.1 ± 12.7) and minimal axillary dissection (54.6 ± 12.7). Patients with higher clinical stage more frequently underwent maximal axillary dissection, and those with lower tumor grade more frequently underwent minimal axillary dissection (P < .0001). Community cancer programs were more likely to perform maximal axillary dissection compared to all other types of programs and had the slowest rate of adoption of selective axillary dissection. Integrated Network Cancer Programs had the lowest proportion of maximal axillary dissection performed and the highest proportion of selective axillary dissection. Uninsured patients were more likely to receive maximal axillary dissection, and those with private insurance were more likely to undergo selective axillary dissection (P < .0001). Selective axillary dissection rates increased from 29.8% of procedures in 2016 to 41.5% in 2017, and MaxAD rates decreased from 62.4% in 2016 to 47.9% in 2017. ConclusionUtilization of selective axillary dissection has increased since 2016; however, discrepancies in surgical axillary management after neoadjuvant chemotherapy still exist.

The Role of Nodes and Nodal Assessment in Diagnosis, Treatment and Prediction in ER+, Node-Positive Breast Cancer.

The majority of breast cancers are oestrogen receptor-positive (ER+). In ER+ cancers, oestrogen acts as a disease driver, so these tumours are likely to be susceptible to endocrine therapy (ET). ET works by blocking the hormone's synthesis or effect. A significant number of patients diagnosed with breast cancer will have the spread of tumour cells into regional lymph nodes either at the time of diagnosis, or as a recurrence some years later. Patients with node-positive disease have a poorer prognosis and can respond less well to ET. The nodal metastases may be genomically similar or, as is becoming more evident, may differ from the primary tumour. However, nodal metastatic disease is often not assessed, and treatment decisions are almost always based on biomarkers evaluated in the primary tumour. This review will summarise the evidence in the field on ER+, node-positive breast cancer, including diagnosis, treatment, prognosis and predictive tools.

Surgery with or Without Darolutamide in High-risk and/or Locally Advanced Prostate Cancer: The SUGAR (CCAFU-PR2) Phase 2 Trial Rationale and Protocol

BackgroundHigh-risk prostate cancer (PCa) patients frequently experience recurrence and progression after radical prostatectomy (RP). Neoadjuvant androgen deprivation therapy (ADT) has not demonstrated a clear oncological benefit and is not currently recommended. ObjectiveThe SUGAR trial is the first phase 2, randomised, controlled, multicentre, noncommercial, open-label study investigating single-agent perioperative darolutamide compared with the standard of care (ie, upfront RP, without neoadjuvant ADT). Design, setting, and participantsSUGAR aims to randomise 240 men affected by nonmetastatic PCa, with the major eligibility criteria being International Society of Urological Pathology grade group ≥4, seminal vesicle invasion at magnetic resonance imaging and/or clinically node-positive disease. Patients in the experimental arm will undergo neoadjuvant darolutamide monotherapy, RP, and adjuvant darolutamide, completing 9 mo of treatment. Outcome measurements and statistical analysisThe primary endpoint is noncurable recurrence-free survival, an innovative and clinically meaningful measure; the secondary endpoints encompass safety; recurrence-free, metastasis-free, and overall survival; pathological response; and quality of life. A predictive biomarker analysis will also be performed. Results and limitationsInitial data suggest that intensified neoadjuvant treatment with androgen receptor signalling inhibitors (ARSIs) is associated with a sustained pathological response and may improve outcomes, via tumour downstaging and micrometastasis eradication. ARSI monotherapy could further enhance tolerability. ConclusionsSUGAR will provide efficacy and safety information on perioperative darolutamide monotherapy compared with upfront RP, in a contemporary high-risk PCa population undergoing surgery. Patient summaryThe on-going SUGAR clinical trial evaluates 9 mo of darolutamide treatment in addition to radical prostatectomy, in men affected by prostate cancer with specific high-risk characteristics. It investigates whether this hormonal treatment can lower the rates of noncurable recurrences, maintaining a favourable tolerability profile.

Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

Fragmented care in localized pancreatic cancer: Is commission on cancer accreditation associated with improved overall survival?

BackgroundPrior studies of fragmentation of care in pancreatic cancer have not adjusted for indicators of hospital quality such as Commission on Cancer accreditation. The effect of fragmentation of care has not been well defined. MethodsWe queried the National Cancer Database to identify patients undergoing pancreaticoduodenectomy and distal pancreatectomy with perioperative systemic therapy for clinical stages I–III pancreatic cancer between 2006 and 2019. Patients who received systemic therapy at a center different than the center performing surgery were categorized as having fragmentation of care. Patients having fragmentation of care were further categorized on the basis of whether (fragmentation of care Commission on Cancer) or not (fragmentation of care non-Commission on Cancer) systemic therapy was administered at a facility accredited by the Commission on Cancer. ResultsA total of 11,732 patients met inclusion criteria; 5,668 (48.3%) underwent fragmentation of care, and 3,426 (29.2%) fragmentation of care non-Commission on Cancer. Patients undergoing fragmentation of care non-Commission on Cancer were less likely to receive neoadjuvant systemic therapy than those undergoing fragmentation of care Commission on Cancer or non-fragmented care (27.7% vs 40.1% vs 36.8%, P < .001). On Cox analysis, advanced age, comorbid disease, node-positive disease, and facility type were associated with risk of overall survival. Fragmentation of care was not (adjusted hazard ratio = 0.99, 95% confidence interval [0.94–1.06], P = .8). On Kaplan-Meier analysis, there were no significant differences in 5-year overall survival between treatment cohorts. ConclusionIn patients undergoing fragmentation of care for localized pancreatic cancer, those treated with systemic therapy in Commission on Cancer accredited facilities are more likely to be given neoadjuvant therapy but demonstrate no significant improvement in survival relative to those undergoing non-fragmented care or those undergoing fragmentation of care but receiving systemic therapy in nonaccredited facilities.

Predictive Value of Genomic Classifier Scores and Transcriptomic Data for Prostate Cancer Distant Metastasis Risk: A Multicenter Retrospective Study.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has a greater specificity and sensitivity for detection of extraprostatic prostate cancer than conventional imaging. The Decipher genomic classifier is an established prognostic biomarker being evaluated for its ability to predict systemic treatment intensification. The relationship between Decipher scores and PSMA-based spread remains unknown, as do differences in transcriptomic patterns of PSMA PET-based spread in the de novo vs. recurrent setting. We retrospectively identified patients who (a) had undergone staging with a PSMA PET prior to treatment or for evaluation of recurrence post-radical prostatectomy (RP) at two institutions and (b) had transcriptomic data available from the Genomics Resource for Intelligent Discovery (GRID) database from either biopsy or RP specimens. We classified the PSMA PET pattern of spread using molecular imaging (mi) staging as localized (miT+N0M0), node-positive (miN1M0), distant metastasis (miM1a-c), or negative/non-diagnostic. We used logistic regression to calculate the odds ratios (OR) with 95% confidence intervals (CI) for distant metastasis risk based on Decipher score both pre-treatment and post-RP. As an exploratory analysis, we compared each of the staging groups for differences in important transcriptomic signatures. Kruskal-Wallis and Pearson chi-squared tests were used for continuous and categorical variables, respectively. A total of 315 patients were included in this analysis (n = 164 pre-treatment, n = 151 post-RP). Eighty PSMA PET scans were negative, while 147 were miT+N0M0, 45 were miN1M0, and 43 were miM1a-c. A higher Decipher score was associated with distant metastasis (miM1a-c) on PSMA PET both pre-treatment (OR 1.3 [95% CI: 1.0-1.7] per 0.1 increase in Decipher score, P = 0.05) and post-RP (OR 1.2 [1.0-1.4] per 0.1 increase in Decipher score, P = 0.04). There were higher TP53 mutation (P = 0.01) and cell cycle progression (P = 0.04) signature scores in miM1a-c patients compared to miN1M0 or miT+N0M0 patients. Basal subtype was more prevalent per PAM50 in miM1a-c or miN1M0 patients (36%) than miT+N0M0 patients (19%, P=0.01). Patients with de novo miN1M0 or miM1a disease (n = 19) had higher Decipher scores (0.85 vs 0.57, P = 0.10) and IFNa response (P = 0.08) than patients with recurrent miN1M0 or miM1a disease (n = 35). Higher Decipher scores were associated with distant metastasis on PSMA PET in both the de novo and recurrent setting. Transcriptomic differences in pathways related to proliferation, p53 status, and PAM50 classification were seen when comparing localized, node-positive, and distant metastatic disease. Patients with de novo miN1M0 or miM1a disease may harbor more aggressive disease than those with miN1M0 or miM1a disease at recurrence.

First Results of the Primary Outcome of a Phase II Prospective Clinical Trial to Assess the Feasibility of Preoperative Radiation Boost in Breast Cancer Patients

A radiation boost targeted at the tumor bed is an important component of breast-conserving therapy (BCT) and has been shown to improve outcomes in patients with early-stage breast cancer. This is a prospective phase II study (NCT04871516) to assess the feasibility of delivering the radiation boost pre-operatively. This approach allows more accurate targeting of the high radiation dose at the tumor that may spare more normal breast tissue. We hypothesize wound complication rates to be comparable to standard treatment. The study design was a prospective phase II with a planned accrual of 55 patients. Women with non-metastatic node negative breast cancer or DCIS who were eligible for BCT were included. Patients were treated with pre-operative radiation boost of 1332 cGy in 4 fractions, followed by lumpectomy and adjuvant hypofractionated whole breast radiation to 3663 cGy in 11 fractions. The primary outcome of the study was to demonstrate that the incidence of grade 3 or more wound complications was not inferior to the current standard of care with conventional lumpectomy, postoperative whole breast radiation and a postoperative boost (6- 20%). Secondary outcomes included cosmetic outcome, local-regional control, and immunologic biomarkers induced by the preoperative radiation boost. We report here the results of the primary outcome of the study. Fifty-five women were enrolled between June 2021 and October 2022. Of those, 48 patients had at least 1 month follow up and were included in the analysis. Median age was 64 years-old, (range 40-77). Median follow up time was 2 months, (range 1-15). Forty-three patients (90%) had invasive cancers and 5 (10 %) had DCIS. Median clinical tumor size was 13 mm, (range 5-26). Median pathologic tumor size was 9 mm, (range 0-27). Margins were negative in 47 patients (98%). Two patients were found to have node positive disease on final pathology. Grade 3 wound dehiscence requiring surgical revision occurred in one patient (2%). There were no other grade 3 adverse side effects reported. Three patients (6%) had grade 2 wound infections requiring antibiotics. Cosmetic outcome at 1st follow up was available for 45 patients and was very good or excellent in 39 patients (87%). No patient had a poor cosmetic outcome. The use of a pre-operative radiation boost prior to lumpectomy followed by whole breast radiation as administered in this prospective trial resulted in an acceptable primary outcome with a similar rate of post-operative wound complications as the standard of care. We are currently enrolling patients on an expansion cohort to assess longer term cosmetic outcomes and performing a panel of immunologic markers to assess immune response to the preoperative boost.

Risk-Stratification using the 40-Gene Expression Profile (40-GEP) Test Identifies Patients with Node Negative Cutaneous Squamous Cell Carcinoma (cSCC) at Higher Risk of Metastasis Who May Benefit from Adjuvant Radiation Therapy (ART)

ART is a standard treatment used to reduce the risk of metastasis and recurrence in moderate‒to‒high-risk cSCC patients. Indications for ART have been largely based on pathologic risk factors and informed by staging systems, and while radiation oncologists generally designate a >10% risk threshold for usage of ART, there is no consensus on which groups of tumors may benefit from ART. The 40-GEP test has been independently validated to predict a cSCC patient's risk for regional/distant metastasis in patients with one or more high-risk clinicopathologic factors and reports three biologic risk groups: Class 1 (low, ∼7%), Class 2A (moderate, 20-25%), and Class 2B (high risk, >50%) for metastasis. This study aims to evaluate whether a biomarker informed risk stratification approach using a 40-GEP result could refine the ability to select patients with node negative cSCC at higher risk of metastasis who are most likely to benefit from ART. In this retrospective study, all patients had primary cSCC tissue with verified clinicopathologic information of tumors with one or more high-risk factors, met clinical testing criteria, were comprehensively staged, and had outcomes data (n = 954). Patients with node positive disease, or those with nodal failure within 3 months of diagnosis were excluded (n = 19). From the n = 935, an intermediate risk population wherein ART is often considered was defined as Brigham and Women's Hospital (BWH) ≥T2a (n = 489). Kaplan-Meier survival analysis and log-rank test were used to assess metastasis free survival (MFS). Univariate Cox regression compared metastasis rates between 40-GEP results. The 3-year MFS rate for this eligible for ART cohort was 82.4% The 40-GEP demonstrated statistically significant risk stratification with MFS rates of 92.4%, 76.1% and 59.4% for Class 1, Class 2A and Class 2B, respectively (p<0.0001). Cox regression was significant for Class 2A and 2B compared to Class 1, with a 3.2-fold and 6.4-fold increase in metastasis, respectively (p<0.0001). 64% (59/92) of all metastases received a Class 2A result, and 44% (14/32) of Class 2B patients metastasized. 46% (223/489) of the cohort received a Class 1 result. Of patients staged BWH T1 (n = 446), those with a Class 2A and 2B had an 88.7% and 66.7% MFS rate, respectively. Within this eligible for ART population, patients with Class 2A or 2B 40-GEP results have inferior rates of MFS, while Class 1 patients have <10% risk of metastasis. Nearly half of this population received a 40-GEP Class 1 result and could be considered for treatment de-intensification trials. Conversely, patients with low-risk BWH T1 stage, who are traditionally not considered for ART, that received a Class 2A or 2B (>10% risk of metastasis) could be considered for adjuvant therapy.

Prognostic value of pretreatment inflammatory markers in localised prostate cancer before radical prostatectomy

PurposeThere is growing evidence of an association between inflammatory processes and cancer development and progression. In different solid tumor entities, a pronounced inflammatory response is associated with worse oncological outcome. In this study, we aim to evaluate the prognostic role of clinically established pretreatment inflammatory markers in patients with localised prostate cancer (PCa) before radical prostatectomy (RP).MethodsA total of 641 men met our inclusion criteria and were followed prospectively for a median of 2.85 years. Univariable logistic and Cox regression analysis were performed to analyse associations between preoperative inflammatory markers and tumor characteristics, and biochemical recurrence free survival (BRFS).ResultsMedian age at RP was 64 years. Gleason Score (GS) 7a (263, 41%) was the most prevalent histology, whereas high-risk PCa (≥ GS 8) was present in 156 (24%) patients. Lympho-nodal metastasis and positive surgical margin (PSM) were detected in 69 (11%) and 180 (28%) patients, respectively. No statistically relevant association could be shown between pretreatment inflammatory markers with worse pathological features like higher tumor stage or grade, nodal positive disease or PSM (for all p > 0.05). Additionally, pretreatment inflammatory markers were not associated with a shorter BRFS (p > 0.05). Known risk factors (tumor grade, tumor stage, nodal positivity and positive surgical margins) were all associated with a shorter BRFS (for all p < 0.0001).ConclusionIn this large prospective cohort, preoperative inflammatory markers were not associated with worse outcome.

Speculation on optimal numbers of examined lymph node for early-stage epithelial ovarian cancer from the perspective of stage migration.

In early-stage epithelial ovarian cancer (EOC), how to perform lymphadenectomy to avoid stage migration and achieve reliable targeted excision has not been explored in depth. This study comprehensively considered the stage migration and survival to determine appropriate numbers of examined lymph node (ELN) for early-stage EOC and high-grade serous ovarian cancer (HGSOC). From the Surveillance, Epidemiology, and End Results database, we obtained 10372 EOC cases with stage T1M0 and ELN ≥ 2, including 2849 HGSOC cases. Generalized linear models with multivariable adjustment were used to analyze associations between ELN numbers and lymph node stage migration, survival and positive lymph node (PLN). LOESS regression characterized dynamic trends of above associations followed by Chow test to determine structural breakpoints of ELN numbers. Survival curves were plotted using Kaplan-Meier method. More ELNs were associated with more node-positive diseases, more PLNs and better prognosis. ELN structural breakpoints were different in subgroups of early-stage EOC, which for node stage migration or PLN were more than those for improving outcomes. The meaning of ELN structural breakpoint varied with its location and the morphology of LOESS curve. To avoid stage migration, the optimal ELN for early-stage EOC was 29 and the minimal ELN for HGSOC was 24. For better survival, appropriate ELN number were 13 and 8 respectively. More ELNs explained better prognosis only at a certain range. Neither too many nor too few numbers of ELN were ideal for early-stage EOC and HGSOC. Excision with appropriate numbers of lymph node draining the affected ovary may be more reasonable than traditional sentinel lymph node resection and systematic lymphadenectomy.

Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC)

Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy. Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy×5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2). The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%). PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial.

The management concept of breast cancer with clinically node-negative/imaging node-positive disease.

The management concept of breast cancer with clinically node-negative/imaging node-positive disease.