Improvement In Recurrence-free Survival Research Articles

Extended pelvic lymph node dissection in muscle invasive bladder cancer.

Bilateral pelvic lymph node dissection (PLND) at the time of radical cystectomy (RC) provides important staging information and oncologic benefit in patients with bladder cancer. The optimal extent of the PLND remains controversial. Our aim is to highlight nodal mapping studies and the data that guides optimization of both staging and oncologic outcomes. We then review contemporary randomized trials studying the extent of PLND. A recent randomized trial (RCT) powered for a 15% improvement in recurrence-free survival (RFS) of extended (e) over limited (l)PLND was completed but failed to identify this large difference in outcome. Concerns over study design limit the ability to interpret the oncologic results. Importantly, ePLND minimally changed surgical morbidity. An ongoing, similar RCT (SWOG S1011) powered to detect a 10% difference in RFS has completed accrual, but no published outcomes are available. RC and ePLND can provide cure in 33% of LN positive bladder cancer patients. Current data support a 5% improvement in RFS if ePLND is routinely used in MIBC patients. Two randomized trials powered to identify much larger (15 and 10%) improvements in RFS are unlikely to identify such an ambitious benefit by extending the PLND.

Neoadjuvant chemotherapy and radical cystectomy in patients with bladder cancer

Background. Bladder cancer is the ninth most common malignant neoplasm worldwide. Hidden metastases at the time of diagnosis are the main reason muscle-invasive bladder cancer has poor prognosis. Even after radical cystectomy, muscleinvasive bladder cancer mostly progresses within 2 years with a recurrence rate of over 50 %. At stages II–IV of the disease, drug treatment is indicated before radical cystectomy. The main goal of neoadjuvant chemotherapy is to affect micrometastases, which may be present at the beginning of disease development. The response to ongoing chemotherapy can serve as a predictor of long-term survival.Aim. To increase effectiveness of bladder cancer treatment.Materials and methods. A total of 231 patients with bladder cancer were included in the study. The main contingent consisted of men over 60 years old with locally advanced tumors at stage Т2–Т4. Drug therapy was carried out in neoadjuvant mode before surgical treatment. Standard regimens were used: cisplatin + gemcitabine and MVAC (methotrexate, vinblastine, adriamycin, cisplatin). After four courses of neoadjuvant chemotherapy, the results were evaluated. With complete normalization of a patient’s condition, the issue of surgical treatment – radical cystectomy with one of the types of urinary diversion – was decided.Results and conclusion. The follow-up period for patients after treatment was 62 months. In patients who underwent neoadjuvant chemotherapy, the median overall survival was 44.9 months, in patients without neoadjuvant treatment – 36.8 months with improvement in recurrence-free survival from 32.5 to 39.8 months (p = 0.08). Overall survival after neoadjuvant chemotherapy improved by 8.1 months (p = 0.09).

Disease Recurrence during Adjuvant Immune Checkpoint Inhibitor Treatment in Metastatic Melanoma: Clinical, Laboratory, and Radiological Characteristics in Patients from a Single Tertiary Referral Center.

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.

Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial

The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data. IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete. Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths. Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease. Bristol-Myers Squibb.

LBA39 Final 5-year results of the phase II, multicenter, randomized, open-label trial of talimogene laherparepvec (T-VEC) neoadjuvant treatment (Tx) plus surgery vs immediate surgery in patients (pts) with resectable stage IIIB-IVM1a melanoma (MEL)

The risk of recurrence after resection remains high for pts with advanced MEL. Neoadjuvant therapies before surgery shrink tumors, reduce recurrence risks, and potentially improve long-term outcomes. T-VEC, an intralesional oncolytic viral immunotherapy, selectively replicates in MELs and enhances the antitumor immune response. The primary analysis (NCT02211131) reported a 2-y recurrence-free survival (RFS) of 29.5% for T-VEC + surgery and 16.5% for surgery alone (overall HR 0.75; 80% CI 0.58-0.96) in pts with resectable stage IIIB-IVM1a MEL, persisting at 3 y (overall HR 0.74; 80% CI 0.57-0.95) (Dummer Nat Med 2021). Here, we report the final 5-y analysis. Pts with resectable stage IIIB-IVM1a MEL and ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions were randomized 1:1 to six doses of neoadjuvant T-VEC, then surgery (Arm 1) or immediate surgery alone (Arm 2). T-VEC was administered at standard doses until surgery, no remaining injectable tumors, or intolerance. The investigator’s choice adjuvant Tx was allowed and used similarly in both arms. The final RFS was analyzed 5 y after randomization. As of May 30, 2022, the median follow-up for all 150 pts was 63.3 mo (range 0.1-86.8). For Arm 1 vs Arm 2, the 5-y KM estimates of RFS were 22.3% and 15.2% (HR 0.76, 80% CI 0.60-0.97), the 5-y KM estimates of EFS were 43.7% and 27.4% (HR 0.57, 80% CI 0.43-0.76), and the 5-y KM estimates of OS were 77.3% and 62.7% (HR 0.54, 80% CI 0.36-0.81). HRs for local RFS, regional RFS, and distant metastases-free survival (DMFS) were 0.82 (80% CI 0.64-1.06), 0.81 (80% CI 0.62-1.05), and 0.73 (80% CI 0.57-0.94), respectively. No new safety signals were detected. In the final readout of the largest randomized trial of neoadjuvant Tx in pts with resectable stage IIIB-IVM1a MEL, we report durable improvements in RFS, EFS, DMFS, and OS at 5 y with neoadjuvant T-VEC + surgery vs standard surgery. These results provide proof of concept that an intratumorally administered oncolytic agent can elicit a meaningful long-term systemic effect and support the use of neoadjuvant T-VEC + surgery in this pt population.

Surgery combined with photodynamic therapy versus surgery alone for the treatment of non-melanoma skin cancer and actinic keratosis: A retrospective cohort study.

Photodynamic therapy (PDT) is an effective treatment for some non-melanoma skin cancers (NMSC) and actinic keratosis. To compare recurrence-free survival (RFS) rates between surgery alone and surgery with postoperative PDT in patients with NMSC in China. This retrospective cohort study included patients with pathologically confirmed NMSC or actinic keratosis treated by surgical excision with/without PDT. A total of 125 patients were included, including 72 patients (43 females) aged 57-75 years in the surgery alone group and 53 patients (32 females) aged 61-76 years in the surgery+PDT group. The most common NMSC types were squamous cell carcinoma and basal cell carcinoma, the most common lesion site was the head and neck, and the vast majority of patients had a primary disease and solitary lesions. There were no significant differences between groups in baseline characteristics. RFS rates in the surgery alone and surgery+PDT groups were, respectively, 100.0% and 98.1% at 1week, 98.6% and 98.1% at 4 weeks, 97.2% and 98.1% at 8 weeks, 97.2% and 98.1% at 12 weeks, and 90.3% and 90.4% at 24 weeks, with no significant differences between groups. Adjuvant PDT after surgical excision of NMSC or actinic keratosis does not provide short-term improvement in RFS, but the results need to be confirmed by a formal randomized controlled trial.

Abstract 6116: Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival

Abstract Introduction: The liver is a common site of metastases of colorectal cancer. Tumor infiltrating lymphocytes (TILs) play an important role in the process of colorectal cancer liver metastasis (CRCLM). A comprehensive investigation into TILs will provide more prognostic information for patients with colorectal liver metastases after liver resection. Methods: 15 CRC patients with liver metastases from our hospital were enrolled in the study. The density and percentage of the TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+etc.] in the liver metastasis samples from operation were analyzed by multiplex immunofluorescence technique (3DMedcines Inc.). The level of the density and percentage of immune cells were determined by dichotomy method. The correlation between recurrence free survival (RFS) and immune cells were analyzed using the Kaplan-Meier curve and Log-rank test. Results: The existence of dim CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0461). The median RFS was 26.1 months (95% CI, 14.9 to 33.5) with the existence of dim CD56+ NK cells in the stroma versus 1.7 months (95% CI, -18.0 to 32.4) without dim CD56+ NK cells in the stroma. Nevertheless, dim CD56+ NK cells in the tumor-enriched segments was not significantly associated with improved outcome. The existence of bright CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0307) but not in the tumor-enriched segments. The median RFS was 34.6 months (95% CI, 15.0 to 35.2) with the existence of bright CD56+ NK cells in the stroma versus 7.9 months (95% CI, -5.3 to 23.1) without bright CD56+ NK cells in the stroma. However, low FoxP3+ cells in the tumor-enriched segments (p=0.0037) was significantly associated with improved outcome but not in the stroma. The median RFS was 36.5 months (95% CI, 23.1 to 40.1) with low FoxP3+ cells versus 8.2 months (95% CI, 0.5 to 21.8) with high FoxP3+ cells in the tumor-enriched segments. Low CD3+CD4+FoxP3+ cells (p=0.074) and the existence of PD-L1+CD68+ cells (p=0.0524) in the tumor-enriched segments showed a trend towards better RFS. No significant correlation was achieved for CD8+, CD3+, CD3+CD4+, CD20+, CD68+CD163+, CD68+CD163-, PD-1, PD-1+CD8+ cells either in the tumor-enriched segments nor in the stroma. Conclusion: We identified that CD56+ NK cells in stroma are associated with improved outcome in CRCLM. Nevertheless, FoxP3+ cells are associated with poor prognosis in CRCLM. Citation Format: Jiamin Zhou, Weiqi Xu, Miao Wang, Siqi Zhang, Ding Zhang. Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival [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 6116.

EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study (SWOG S0931, NCT01120249).

LBA4500 Background: Patients (pts) who undergo resection of renal cell carcinoma (RCC) with curative intent remain at risk for disease relapse. We conducted a phase III, double-blind, placebo (PB)-controlled, intergroup study to determine the effect of adjuvant treatment with the mTOR inhibitor everolimus (EVE) on recurrence-free survival (RFS). Methods: Pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to EVE 10 mg PO daily x 54 weeks or PB within 12 weeks of radical or partial nephrectomy. Randomization was stratified by risk group, histology (clear vs. non-clear cell), and performance status (0 vs. 1). RFS was the primary end point; secondary endpoints included overall survival (OS) and adverse events (AEs). The study was designed to detect an 18% reduction in the risk of RFS with EVE compared to PB, corresponding to an improvement of median RFS from 6.75 (based on E2805 ASSURE) to 8.23 years. Final analysis, using a stratified logrank test, was to occur after 804 total events or by 3/2022, whichever occurred first. Results: Between 4/2011 and 9/2016, 1545 pts were randomized to EVE (n = 775) or PB (n = 770). Overall pt characteristics included: intermediate high-/very high-risk 45%/55%; clear cell/non-clear cell 83%/17%. The DSMC recommended study continuation after each of 4 pre-specified interim analyses. 556 DFS events among 1499 eligible pts occurred by the time of final study analysis on 2/23/2022. The median follow-up was 76 months. RFS was improved with EVE vs. PB (HR 0.85, 95% CI, 0.72 – 1.00; P1-sided= 0.0246), narrowly missing the pre-specified, one-sided significance level of 0.022 which accounted for interim analyses. Median RFS was not reached; the 6-year RFS estimate was 64% for EVE and 61% for PB. RFS improvement with EVE vs. PB was observed in the very high-risk group (HR 0.79, 95% 0.65-0.97; P1-sided= 0.011) but not in the intermediate high-risk group (HR 0.99, 95% CI 0.73-1.35, P1-sided= 0.48) ( P for interaction = 0.22). With 290 deaths, OS was similar between arms (HR 0.90, 95% CI, 0.71 – 1.13; P1-sided= 0.178). Fewer pts completed all 54 weeks of study treatment in the EVE group (45% v 69%). In the EVE group, 37% withdrew due to AEs (vs 5% in PB). Grade 3-4 AEs occurred in 46% of pts treated with EVE and 11% with PB. The most common grade 3-4 AEs were mucositis (14% v 0%), hypertriglyceridemia (11% vs. 2%), and hyperglycemia (5% vs. 0%). Conclusions: Adjuvant EVE improved RFS in RCC pts after nephrectomy, but the nominal significance level was narrowly missed. The RFS improvement was seen despite a high rate of early treatment discontinuation. A 21% improvement in RFS with EVE was observed in pts with very high-risk disease, a group for whom adjuvant therapy may be most relevant. Clinical trial information: NCT01120249.

The GERMELATOX-A (Dermatologic Cooperative Oncology Group): Study attitude of German melanoma patients towards toxicity during adjuvant treatment.

e21597 Background: Trials of adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in recurrence-free survival (RFS) with a very similar relative risk reduction. Both treatment modalities are characterized by specific side effects. Therefore the decision for or against a treatment modality is very often driven by the risk for toxicity. This study addressed for the first time the attitudes and preferences of German and Swiss patients and physicians for adjuvant treatment with ICI and TT. Methods: In this multicenter study („GERMELATOX-A“) patients with low-risk melanoma (pT1a, AJCC stage I, familiar with cancer diagnosis but no adjuvant treatment planned), and dermatooncologists from 11 German and 1 Swiss skin cancer centers were asked to fill out a questionnaire. Here, side effect scenarios typical for each ICI and TT with mild-to-moderate or severe toxicity and also melanoma recurrence leading to cancer death were described. We asked patients and physicians about the reduction in melanoma relapse (relapse-free survival, RFS) and the survival increase (overall survival, OS) at 5 yrs they would expect to tolerate defined side-effects. Results: Data were obtained from 136/107 patients/physicians, respectively (median age: 59 yrs/32 yrs, 56.2%/67.6% female).Overall, by visual analog scale, patients valued a melanoma relapse worse than all scenarios of side-effects during adjuvant treatment with ICI or TT. In general patients required higher risk reductions for DFS and OS for both ICI and TT and their drug related side effects compared to physicians to accept this treatment. In case of severe side effects, patients needed a 20% higher reduction of relapse rate at 5 yrs for ICI compared to TT (71.4%/50.0%). Physicians required identical relapse reduction rates for ICI and TT in case of severe side effects (42.9%). Conclusions: This study demonstrated a pronounced variation of German and Swiss patient preferences on adjuvant treatment related to drug class specific side effects and outcomes and a clear difference between patients' and physicians' attitudes. This difference might influence decision making for adjuvant treatment options and should therefore also be investigated in further trials for current adjuvant treatment modalities. As adjuvant melanoma treatment with ICI and TT will possibly be implemented in earlier stages soon, precise knowledge of the patient perspective can be helpful for the process of decision making.

SALVO: Single-arm trial of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma.

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection &lt;90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.

Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic CTNNB1 mutation on recurrence-free survival

ObjectiveThe primary objective of this study was to determine whether women whose tumors harbor a somatic CTNNB1 mutation have longer recurrence-free survival if they receive traditional adjuvant therapy strategies compared...

Adjuvant chemotherapy and radiation for patients with high-risk stage I endometrial cancer treated with curative intent surgery: impact on recurrence and survival

BackgroundSurvival benefits of post-operative systemic and radiation therapy in high-risk stage I endometrial cancer are uncertain.ObjectiveTo compare recurrence patterns and survival outcomes of post-surgical treatment in patients with high-risk stage...

Surgical results of non-ampullary duodenal cancer: a nationwide survey in Japan.

As non-ampullary duodenal cancer is relatively rare, the optimal treatment strategy, including the appropriate surgical procedure and efficacy of adjuvant chemotherapy, remains unclear. This nationwide survey aimed to clarify the actual lymph node spread pattern and determine the optimal treatment strategy for this disease, using a large-scale database. We used a questionnaire and a retrospective registry of 1083 patients with non-ampullary duodenal cancer who had undergone surgery during 2008-2017 in 114 high-volume Japanese Society of Hepatobiliary and Pancreatic Surgery-certified training institutions. Propensity score-matched analyses were conducted to minimise background bias. Cox regression was performed to identify covariates associated with recurrence-free survival. There were distinct disparities in the nodal dissection rate according to the predominant tumor location and tumor invasion depth. Metastases were frequently observed in the peripancreatic nodes and those along the superior mesenteric artery, irrespective of tumor location. Their dissection seemed to be beneficial for improved survival. In the overall cohort, no survival benefit was observed in patients who received adjuvant chemotherapy when compared with that in patients who underwent surgery alone. Nevertheless, in the matched cohort, adjuvant chemotherapy for > 6months was associated with a significant improvement in recurrence-free survival (median: 43.5 vs. 22.5months, p = 0.016), particularly in patients with tumor invasion of the subserosa or deeper tumor invasion, lymph node metastasis, or elevated serum carbohydrate antigen 19-9 levels. Pancreatoduodenectomy should be the standard procedure for advanced non-ampullary duodenal cancer. Adjuvant chemotherapy for > 6months, especially for advanced tumors, significantly improves survival.

Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma

BackgroundNivolumab (an anti–programmed death-1 antibody) is an adjuvant standard of care for patients with high-risk resected melanoma, although a watch-and-wait strategy remains an option. In the absence of head-to-head evidence, an indirect treatment comparison (ITC) of adjuvant nivolumab versus placebo, the proxy for a watch-and-wait strategy, was conducted in patients with high-risk resected melanoma. MethodsAn ITC using the Bucher method compared nivolumab with placebo using intention-to-treat population data from the phase III CheckMate 238 (nivolumab vs ipilimumab; minimum follow-up, 4 years; NCT02388906) and European Organisation for Research and Treatment of Cancer (EORTC) 18071 (ipilimumab vs placebo; minimum follow-up, ≈4.5 years; NCT00636168) trials. The end-points were recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS). To account for cross-trial differences in staging and subsequent therapy, additional analyses examined patients with stage IIIB/IIIC disease and adjusted post-recurrence survival in EORTC 18071, respectively. ResultsNivolumab versus placebo was associated with clinically meaningful improvements in RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.42–0.68) and OS (HR, 0.63; 95% CI, 0.45–0.89). Nivolumab versus placebo was also associated with clinically meaningful improvements in RFS (HR, 0.53; 95% CI, 0.40–0.69), DMFS (HR, 0.62; 95% CI, 0.46–0.83) and OS (HR, 0.67; 95% CI, 0.47–0.97) in patients with stage IIIB/IIIC disease and in OS (HR, 0.65; 95% CI, 0.46–0.92) in the overall population after adjusting post-recurrence survival in EORTC 18071. ConclusionThis ITC shows that adjuvant nivolumab provides clinically meaningful improvements in RFS, DMFS and OS versus a watch-and-wait strategy in high-risk resected melanoma.

Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial

AimThe Cher-LOB randomised phase II study showed that the combination of lapatinib-trastuzumab plus chemotherapy increases pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here, we report the post hoc survival analysis as per treatment arm, pCR and biomarkers. MethodsThe Cher-LOB study randomised 121 patients with human epidermal growth factor receptor 2–positive, stage II–IIIA breast cancer. A specific protocol to collect recurrence-free survival (RFS) and overall survival (OS) data was designed. Tumour-infiltrating lymphocytes (TILs) and PAM50-intrinsic subtyping were evaluated at baseline. ResultsAt 9-year median follow-up, a trend towards RFS improvement with lapatinib-trastuzumab over trastuzumab was observed (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.18–1.05). Combining treatment arms, pCR was significantly associated with both RFS (HR 0.12, 95% CI 0.03–0.49) and OS (HR 0.12, 95% CI 0.03–0.49). TILs were significantly associated with RFS (HR = 0.978 for each 1% increment). Luminal-A subtype was a significant and independent predictor of improved RFS as compared with other PAM50-based intrinsic subtypes at the multivariate analysis including the most relevant clinicopathologic variables (HR 0.29, 95% CI 0.09–0.94, p = 0.040). ConclusionsCher-LOB trial survival analysis confirmed the prognostic role of pCR and TILs and showed a signal for a better outcome with lapatinib-trastuzumab over trastuzumab. Trial registrationNCT00429299.

Impact of pathological response after neoadjuvant chemotherapy on adjuvant therapy decisions and patient outcomes in gastrointestinal cancers.

BackgroundNeoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC.AimTo evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence‐free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC.Methods and resultsMedical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty‐six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0–1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11–0.72) and OS (HR 0.13; 95% CI 0.2–0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2–3) after NAC, was not associated with improved RFS or OS.ConclusionsGIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. Merck Sharp & Dohme.

Perioperative chemotherapy for upper tract urothelial carcinoma: show me the evidence.

Perioperative chemotherapy for upper tract urothelial carcinoma: show me the evidence.

Is there an oncological benefit to extended lymphadenectomy for muscle-invasive bladder cancer?

The full optimal extent of a pelvic lymph node dissection (PLND) at time of radical cystectomy (RC) has not yet been determined. The diagnostic role of LND is clear and is extremely important for identifying those who may benefit from adjuvant therapy. While retrospective analyses have demonstrated improved survival when the number of lymph nodes is increased and extended LNDs (eLNDs) are performed, these results have yet to be borne out in prospective randomized phase III trials. The recently published LEA AUO AB 25/02 trial is a promising attempt to determine the efficacy of eLND, but unfortunately falls short because of its limited design and therefore, did not demonstrate an improvement in recurrence-free survival (RFS). In an era of increased utilization of neoadjuvant chemotherapy (NAC) providing survival benefit, the ability to demonstrate improved survival with eLND is even more challenging. Currently, we are awaiting the results of SWOG S1011, expectations of achieving a positive trial with improved RFS remains unlikely.

Adjuvant breast radiotherapy, endocrine therapy, or both after breast conserving surgery in older women with low-risk breast cancer: Results from a population-based study

Background and PurposeThe relative benefit of adjuvant radiotherapy (RT) alone in older women with low-risk early breast cancer (EBC) remains unclear. It is hypothesized that adjuvant RT-alone can improve outcomes of older patients with low-risk EBC, similar to endocrine therapy (ET) alone or combination of RT + ET. MethodsIn this population based study, we identified all women aged ≥70 with T1–2, N0, ER+ve, Her-2/neu−ve EBC treated with breast conserving surgery (BCS), followed by adjuvant treatments (RT-alone, ET-alone, or RT + ET combination) from 2005 to 2015. Primary outcome measures were recurrence-free survival (RFS), overall survival (OS), and breast cancer specific survival (BCSS). Treatment details were collected and Charlson Comorbidity Index (CCI) was calculated. ResultsA total of 1166 patients were identified. Median follow-up was 76.5 months. Adjuvant treatments: BCS only 130 (11%), RT 378 (32.5%), ET 161 (14%), and RT + ET 497 (42.5%). Less than 60% of women completed 5-years of ET. Compared to BCS alone, RT resulted in significant improvement in RFS (HR = 0.174; p < 0.001), similar to ET (HR = 0.414; p = 0.007) and RT + ET (HR = 0.236; p < 0.001). Determinants of OS were age, tumor grade, comorbidities, and adjuvant therapy. Increased comorbidity scores (0 vs. 1; 0 vs. ≥2) were associated with reduced OS (HR = 1.40; p = 0.013 and HR = 1.98; p < 0.001), without impact on RFS or BCSS. ConclusionsAdjuvant RT-alone is a reasonable alternative to ET or RT + ET for older women with biologically favorable EBC. No difference in RFS or BCSS was noted between RT, ET, and RT + ET. Comorbidity was independently associated with reduced overall survival.