Recurrence-free Survival Benefit Research Articles

Treatment Strategy for Dialysis Patient with Urothelial Carcinoma

To investigate postoperative complications and oncologic outcomes of prophylactic nephroureterectomy and/or cystectomy in dialysis patients with urothelial carcinoma (UC), we retrospectively reviewed the records of dialysis patients with UC and a final status of complete urinary tract extirpation (CUTE, i.e., the removal of both kidneys, ureters, and bladder) between January 2004 and December 2015. Patients undergoing dialysis after initial radical nephroureterectomy and/or cystectomy were excluded. Eighty-four and 27 dialysis patients, undergoing one-stage and multi-stage CUTE, were enrolled in this study, respectively. Demographic, medical, perioperative, and pathologic features were collected to determine variables associated with oncologic outcomes. Although there was no significant difference in mortality between the 2 groups (p = 0.333), all 5 (4.5%) patients with Clavien–Dindo grade 5 complications were from the one-stage CUTE group. On multivariate logistic regression analysis, advanced age (p = 0.042) and high Charlson comorbidity index (CCI) (p = 0.000) were related to postoperative major complications. Compared with multi-stage CUTE, one-stage CUTE had no overall, cancer-specific, and recurrence-free survival benefits (all p > 0.05). According to multivariate analysis with Cox regression, age > 70 years (HR 2.70, 95% CI 1.2–6.12; p = 0.017), CCI ≥ 5 (HR 2.16, 95% CI 1.01–4.63; p = 0.048), and bladder cancer stage ≥ 3 (HR 12.4, 95% CI 1.82–84.7; p = 0.010) were independent, unfavorable prognostic factors for the overall survival. One-stage CUTE is not associated with superior oncologic outcomes, and all perioperative mortalities in our series occurred in the one-stage CUTE group. Our data do not support prophylactic nephroureterectomy and/or cystectomy for uremic patients with UC.

The effect of lymphadenectomy and adjuvant chemotherapy on survival in stage I, grade 1 and 2 endometrioid ovarian carcinoma

Objectives: To determine the effect of lymphadenectomy and adjuvant chemotherapy on survival in stage I, grade 1 (G1) and 2 (G2) endometrioid ovarian cancer (EnOC) as there is limited evidence in this population. Methods: Retrospective cohort study of patients with stage I, G1 and G2 EnOC, treated at two cancer centers between 2001-2019. Demographic, surgical and follow up data was collected. Recurrence free survival (RFS) and overall survival (OS) were calculated from the Kaplan-Meier curves. Cox Proportional Hazard was used to evaluate predictive factors. Results: There were 192 G1 and G2 EnOC, 129 had stage I disease upon presentation. Twenty-nine patients were upstaged after surgery: 25 patients were stage II and 4 patients were stage III based on omental or bowel involvement. Nine patients had CT findings concerning for advanced stage, but were found to be stage I following surgery. In total, there were 131 patients with stage I disease. The median age for the stage I patients (n=131) was 54 (26-90) years, 80 patients had G1 and 51 had G2 disease, 84 patients were stage IA, 5 were IB and 42 were stage IC. Complete staging lymphadenectomy was performed in 34/131 (26.0%) whereas 97 had either partial (n=22) or no (n=75) surgical staging. Adjuvant chemotherapy was given in 30 patients. Median (95% CI) follow-up was 51.5 months (44.3-57.2). Median RFS was 48.2 (42.3-54.0) months and median OS time was 51.5 (44.3-57.2) months. In the univariate analysis, including age, complete staging, and chemotherapy, only grade was found to be significant with G2 more likely recurrence, compared to G1 patients (p=0.03). This was further validated in the multivariable analysis (p=0.04; HR=3.42 95% CI 1.03-11.38). There was no difference in RFS (p=0.57) and OS (p=0.30) in patients who underwent complete surgical staging compared to those that did not. None of the 56 patients that had complete (n=34) or partial (n=22) lymphadenectomy had positive lymph nodes. For a subgroup of 70 patients with stage IA/IB that did not have complete surgical staging, adjuvant chemotherapy was given to 10 patients. Sixty patients had no adjuvant treatment. Median (95% CI) follow-up was 58.0 (48.2-69.3) months. Median RFS was 56.7 (46.9-67.4) and median OS was 58.0 (48.2-69.3) months. There was no benefit in RFS (p=0.08) for stage IA/IB patients who received adjuvant chemotherapy (Figure 1). There was a trend toward no chemotherapy being superior to adjuvant chemotherapy in OS (p=0.05). Twelve patients had recurrence. One patient recurred in a lymph node and the peritoneum, 8 had a pelvic recurrence, 2 had peritoneal recurrence only, and 1 patient with fertility sparing surgery recurred in the remaining ovary. Three patients were salvageable at the time of recurrence and are alive with no disease. Conclusions: Patients with Stage I, G1 and G2 EnOC have excellent prognosis and staging lymphadenectomy does not improve RFS or OS. Morover, patients with stage IA/IB who did not have complete staging lymphadenectomy, did not benefit from adjuvant chemotherapy. Download : Download high-res image (70KB) Download : Download full-size image

Role of Radiation Therapy for Newly Diagnosed Retroperitoneal Sarcoma.

Soft tissue sarcomas (STS) are rare, aggressive, and heterogenous tumors, comprising approximately 1% of adult cancers with over 50 different subtypes. The mainstay of treatment for retroperitoneal sarcomas (RPS) includes surgical resection. The addition of radiation therapy (RT), either preoperatively or postoperatively, has been used to potentially decrease the risk of local recurrence. The recently published results from STRASS (EORTC-STBSG 62092-22092), which randomized patients to receive or not receive preoperative radiation, indicate no abdominal recurrence-free survival benefit (primary endpoint) nor overall survival benefit to date from the addition of preoperative RT prior to surgical resection in patients with RPS. Keeping in mind caveats of subgroup analyses, the data show a significant reduction in local recurrence with radiation therapy in resected patients and non-significant trends toward improved abdominal recurrence-free survival in all patients and improved local control and abdominal recurrence-free survival in patients with liposarcoma and low-grade sarcoma. Given the high rate of local failure with surgery alone, it is possible that higher RT dose and/or selective RT dose painting may improve outcomes. Prior to treatment, the authors encourage multidisciplinary review and discussion of management options at a sarcoma center for patients with RPS. Selective use of RT may be considered for patients at high risk of local recurrence.

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

The prognostic value of the interferon-gamma (IFNγ) signature in patients with macroscopic stage III melanoma treated with and without adjuvant systemic therapy.

9579 Background: Recently, trials have shown the benefit of adjuvant aPD-1 therapy in macroscopic stage III melanoma patients. This treatment has been incorporated in daily clinical practice, however, a substantial part of patients still does not benefit from this therapy, as they develop recurrences. The aim of this study is to evaluate the results of adjuvant aPD-1 therapy and the potency of the IFNγ signature as a prognostic or predictive marker, as it has proven to be predictive of response in neoadjuvant trials. Methods: Patients participating in an ongoing biobank study and naïve for systemic therapy were included, between 10-2017 and 06-2020, after complete resection of macroscopic stage III melanoma. Approval and reimbursement of adjuvant therapy in the Netherlands started in 12-2018, resulting in 2 cohorts of similar high risk patients: prior to availability of adjuvant aPD-1 (cohort A) and thereafter (cohort B). Data cut-off for clinical data was January 1st 2021. Transcriptome sequencing was performed on samples of stage III melanoma by CeGaT GmbH, IFNγ signature was determined on these data with the median as cut-off. Clinical data were compared between cohort A and B as intention-to-treat population, including patients with a recurrence before adjuvant therapy start (n=10). Results: In total, 99 patients were included: 50 in cohort A and 49 in cohort B. Majority of included patients had thick primary melanomas (Breslow >2mm in 59.6%) and stage IIIC/IIID disease (83.3%) according to AJCC 8th edition. At a median follow-up of 20.6 months (95% confidence interval [CI] 16.6-24.7), median recurrence-free survival (RFS) was 6.1 months (95%CI 3.9-8.4) versus 22.8 months (95%CI 8.7-36.9), significantly in favor of cohort B (p=0.011). Median overall survival (OS) was not reached in both patient groups, but was overall significantly different (p=0.040), favoring cohort B. RNA sequencing was performed in 25 patients who received adjuvant therapy and in 24 who did not, excluding patients with an early recurrence (<12 weeks). In both treatment groups median (p=0.003) and 12-months RFS (p<0.001) was significantly higher for IFNγ high patients, but both IFNγ low and high patients show higher RFS rates when receiving adjuvant aPD-1 therapy (Table). Conclusions: Our study confirms RFS and OS benefit of adjuvant aPD-1 for patients with macroscopic stage III melanoma. IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy, as both patients with IFNγ high and low signatures show benefit from adjuvant therapy.[Table: see text]

Current management of melanoma patients with nodal metastases.

The management of melanoma patients with nodal metastases has undergone dramatic changes over the last decade. In the past, the standard of care for patients with a positive sentinel lymph node biopsy (SLNB) was a completion lymph node dissection (CLND), while patients with palpable macroscopic nodal disease underwent a therapeutic lymphadenectomy in cases with no evidence of systemic spread. However, studies have shown that SLN metastases present as a spectrum of disease, with certain SLN-based factors being prognostic of and correlated with outcomes. Furthermore, the results of key clinical trials demonstrate that CLND provides no survival benefit over nodal observation in positive SLN patients, while other clinical trials have shown that adjuvant immune checkpoint inhibitor therapy or targeted therapy after CLND is associated with a recurrence-free survival benefit. Given the efficacy of these systemic therapies in the adjuvant setting, these agents are now being evaluated and utilized as neoadjuvant treatments in patients with regionally-localized or resectable metastatic melanoma. Multiple options now exist to treat melanoma patients with nodal disease, and determining the best treatment course for a particular case requires an in-depth knowledge of current data and an informed discussion with the patient. This review will provide an overview of the various options for treating melanoma patients with nodal metastases and will discuss the data that supported the development of these treatment options.

Daily practice in guideline adherence to adjuvant chemotherapy in stage III colon cancer and predictors of outcome

IntroductionAlthough guidelines recommend adjuvant chemotherapy for stage III colon cancer patients, many patients do not receive adjuvant chemotherapy. The aim of this study was to identify reasons for guideline non-adherence and assess the effect on patient outcomes in a multicenter cohort of stage III colon cancer patients who received surgery plus adjuvant chemotherapy or surgery alone. MethodsPatients who underwent surgery between 2007 and 2017 were included. Reasons for non-adherence were determined. Propensity score analyses with inverse probability weighting were performed to adjust for confounding factors. Cox proportional hazards regression and risk stratified analyses were performed to assess the association of guideline adherence and other potential predictors with recurrence free survival (RFS). ResultsData of 575 patients were included of whom 61% received adjuvant chemotherapy. In 87 of 222 patients (39%) who did not receive adjuvant chemotherapy, no reason was documented. Only age was predictive for receiving chemotherapy. Patients who received adjuvant chemotherapy had longer RFS (HR 0.42, 95%CI 0.29–0.62, p < 0.001). High T- and N-stage were associated with poorer RFS HR 2.0 (95%CI 1.58–2.71, p < 0.001) and HR 2.19 (95%CI 1.60–2.99, p < 0.001) respectively. Risk groups were identified with distinct prognosis and treatment effect and a nomogram is presented to visualize individualized RFS differences. ConclusionThis study shows considerable variation in guideline adherence to adjuvant chemotherapy and poor documentation on reasons for non-adherence. Optimizing adherence and gaining insight in reasons for non-adherence is advocated as this can lead to significant RFS benefit, especially in patients with high T-and N-stage tumors.

Identifying tumor-related risk factors for simultaneous adrenalectomy in patients with cT1 - cT2 kidney cancer during robotic assisted laparoscopic radical nephrectomy.

Background In some cases, preservation of adrenal gland could be at risk in patients with cT1 and cT2 RCC. The aim of this study was to evaluate tumor-related factors that can potentially increase the risk of simultaneous adrenalectomy during robotic-assisted laparoscopic radical nephrectomy (RALRN) in patients with cT1-cT2 disease and the impact of performing such procedure on recurrence-free survival (RFS) and complication rates. Methods We used a multi-institutional kidney cancer database where we identified patients who underwent RALRN with or without adrenalectomy. We evaluated the tumor-related characteristics that could potentially increase the risk of adrenal gland resection of these patients. We also reported RFS at 12-24 months of follow-up, which was compared with an inverse probability of treatment weighted (IPTW) multivariable cox proportional hazards regression model and postoperative complications, which was compared with an IPTW multivariable logistic regression model. Results Tumor size, cT stage, pT stage, histologic subtype, sarcomatoid differentiation, BMI, lymph node involvement, metastatic disease, Fuhrman grade do not increase the risk of simultaneous adrenalectomy during RALRN. Moreover, RALRN with adrenalectomy had no significant benefit in RFS. No differences in post-operative complications were noted. Conclusions Our evaluated tumor-related characteristics did not show to impact the incidence of simultaneous adrenalectomy. Adrenal gland resection T does not provide significant benefit in recurrence-free survival. We consider that RALRN with adrenalectomy should be reserved only for patients with adrenal compromise as stated previously regardless that it has shown to be a safe procedure.

Weight gain during neoadjuvant therapy is associated with improved recurrence-free survival for patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma

Presenter: Jonathan Hue MD | Case Western Reserve University School of Medicine Background: Weight loss commonly precedes the diagnosis of pancreatic ductal adenocarcinoma (PDAC). There is growing emphasis on neoadjuvant treatment for patients with localized disease. The severity and impact of weight loss during neoadjuvant therapy is not well studied. We hypothesized that weight loss during neoadjuvant chemotherapy would be associated with poor short- and long-term outcomes. Methods: We performed a single institution retrospective cohort study of patients with histologically confirmed PDAC who received neoadjuvant chemotherapy (with or without radiotherapy) and underwent a pancreatectomy between 2009-2021. We abstracted patient weights within 1 year preceding diagnosis, as well as at diagnosis, chemotherapy start, and before pancreatectomy. Patients were categorized based on weight change from start of chemotherapy to surgery: weight gain (≥5%), stable ( < 5% gain to < 5% loss), and weight loss (≥5%). The association between weight change and pathologic, perioperative, and long-term outcomes was analyzed. Results: A total of 127 patients received neoadjuvant therapy followed by pancreatectomy during the study period, of whom 95 had raw weights recorded at the specified time points and were included in the analysis. The median weight loss prior to diagnosis was 7.9% (range: 0.5% gain to 24.1% loss). Thirty patients (31.6%) lost weight during neoadjuvant chemotherapy, 56 (59.0%) had stable weight, and nine (9.5%) gained weight. Patients who lost weight were more likely to have locally advanced disease compared to patients with stable weight or weight gain (26.7% vs 8.9% vs 11.1%, p=0.12). CA19-9 levels were similar at the time of diagnosis and prior to pancreatectomy across groups. There was no difference between the three groups in the number of chemotherapy cycles administered, chemotherapeutic regimens, rate of neoadjuvant radiotherapy, or the time from initiation of chemotherapy to surgery. There was no difference in pathologic (tumor size, lymph node positivity, margin positivity, pathologic response to therapy) or perioperative (in-hospital complication rate, length of stay, discharge disposition) outcomes based on degree of weight loss during therapy. Utilization of adjuvant chemotherapy and adjuvant radiotherapy was also similar between groups. Median overall survival of patients who gained weight during neoadjuvant therapy was longer than that of patients with stable weight or weight loss (38.4 vs 25.8 vs 26.7 months, p=0.58), but this did not reach statistical significance. Median recurrence-free survival of patients who gained weight during neoadjuvant therapy was longer than that of patients with stable weight or weight loss (29.5 vs 9.6 vs 14.0 months, p=0.07, Figure). After controlling for clinical and treatment factors as well anatomic stage, weight gain was associated with improved recurrence-free survival benefit compared to weight loss (HR=0.15, 95% CI 0.03-0.81). A similar association was not identified when analyzing overall survival (HR=1.17, 95% CI 0.28-4.80). Conclusion: Weight trends during neoadjuvant therapy are variable, but the majority of patients maintain weight or lose weight. Patients who gain weight during neoadjuvant therapy may have improved recurrence-free survival. The association between weight and overall survival is less clear. Future studies may validate weight as a predictor of survival among patients receiving neoadjuvant therapy for localized PDAC.

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P =0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P =0·047) and systemic (HR 0·56, 0·33 to 0·94; P =0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P =0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P =0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P =0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy.

The current state of adjuvant therapy of melanoma.

Melanoma adjuvant therapy targets residual micrometastatic disease destined for future recurrence. In patients with resected stage III or IV melanoma, adjuvant therapy was shown to reduce the risk of recurrence, death, or both, leading to the regulatory approval of several agents since 1995: IFNα, pegylated-IFNα, checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab, and BRAF and MEK inhibitors dabrafenib and trametinib. 1 Kirkwood JM Manola J Ibrahim J et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004; 10: 1670-1677 Crossref PubMed Scopus (456) Google Scholar , 2 Kirkwood JM Ibrahim JG Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19: 2370-2380 Crossref PubMed Scopus (783) Google Scholar , 3 Eggermont AM Suciu S Testori A et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012; 30: 3810-3818 Crossref PubMed Scopus (208) Google Scholar , 4 Eggermont AM Chiarion-Sileni V Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16: 522-530 Summary Full Text Full Text PDF PubMed Scopus (856) Google Scholar , 5 Tarhini AA Lee SJ Hodi FS et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020; 38: 567-575 Crossref PubMed Scopus (51) Google Scholar , 6 Eggermont AMM Blank CU Mandala M et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378: 1789-1801 Crossref PubMed Scopus (929) Google Scholar , 7 Long GV Hauschild A Santinami M et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017; 377: 1813-1823 Crossref PubMed Scopus (799) Google Scholar Key adjuvant trials, their outcomes, and current standard of care status are summarised in the appendix. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trialAt a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Full-Text PDF

The comparison of different antiviral therapies on the prognosis of hepatitis B virus-related hepatocellular carcinoma after curative treatments

The purpose of this study was to evaluate the efficacy of different nucleos(t)ide analogues in the prognosis of HBV-related hepatocellular carcinoma (HCC) patients after curative treatment by network meta-analysis. Literature retrieval was conducted in globally recognized databases, namely, PubMed, EMBASE, Cochrane Library databases, and Science Citation Index Expanded, to address relative studies investigating nucleot(s)ide analogues for HBV-related HCC patients after curative resection. Relative parametric data, including 1-, 3-, and 5-year overall survival rate and 1-, 3-, and 5-year recurrence-free survival rate were quantitatively pooled and estimated. The inconsistency factor, the cumulative ranking curve, and the publication bias were evaluated. Fourteen observational studies of 2481 adults performed between 2000 and 2019 were eligible. In terms of overall survival, ADV (Adefovir dipivoxil) (Odds ratio (OR): 2.35, 95% confidence interval (CI): 1.17-4.73), Lamivudine (OR: 2.08, 95% CI: 1.78-5.58), and Entecavir (OR: 2.14, 95% CI: 1.59-2.88) were found to be more beneficial than control group while ADV has the highest probability of having the most efficacious treatment (SCURA values 66.3) for 5-year overall survival. In late recurrence-free survival, ADV (OR = 1.88, 95% CI: 1.77-4.60), Entecavir (OR = 1.96, 95% CI: 1.36-2.55), and Lamivudine (OR = 1.73, 95% CI: 1.06-2.82) all had better significant prognosis than patients without antiviral therapy postoperatively and patients with ADV as postoperative antiviral therapy has significantly recurrence-free survival benefit at 5-year follow-up compared to those undertaking Entecavir (OR = 1.96, 95% CI: 1.52-7.38) and Lamivudine (OR = 1.39, 95% CI: 1.09-3.01). Moreover, the application of ADV possessed the highest possibility of having the best clinical effects on 1- (surface under the cumulative ranking probabilities (SUCRA), 64.7), 3- (SUCRA, 64.7), and 5-year (SUCRA, 70.4) recurrence survival rate for HBV-related HCC patients. Patients with postoperative nucleos(t)ide analogues antiviral therapy had better survival benefit than those without antiviral therapy for HBV-related HCC patients after curative treatment. Additionally, nucleotide analogues like ADV and Tenofovir disoproxil fumarate has better impact on early and late recurrence-free survival of patients after curative treatment than those undertaking nucleoside analogues.

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS5101 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013 .

Toxicities with combination BRAF and MEK inhibition in resected stage III melanoma.

e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS765 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of October 18, 2019, 317 patients have been enrolled. Clinical trial information: NCT03055013.

Benefit of oxaliplatin in stage III colon cancer according to IDEA risk groups: Analysis of MOSAIC and C-07 trials.

118 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. Patients were classified into low-risk and high-risk, suggesting low-risk patients may be offered only 3 months of treatment. In our previously published analysis using retrospective data from the National Cancer Database (NCDB) we showed similar benefit for oxaliplatin in both low and high IDEA risk groups. In the current study, we aimed to test our hypothesis using data from the two large clinical trials assessing the benefit of oxaliplatin in the adjuvant setting, namely, MOSAIC and C-07. Methods: Using the MOSAIC and C-07 previously published studies, we identified 1,754 low-risk and 1,302 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. The analysis was adjusted for age, primary tumor sidedness, tumor stage, tumor grade and lymph node ratio. Results: Individuals with IDEA low-risk derived overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios (HRs) of 0.78 (0.65-0.94), 0.75 (0.63-0.89) and 0.74 (0.62-0.90). Similarly, individuals with IDEA high-risk derived OS, DFS and RFS benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted HRs of 0.84 (0.71-0.99), 0.81 (0.69-0.95) and 0.82 (0.69-0.97). Conclusions: IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer, according to analysis of the MOSAIC and C-07 studies. Funding: NCI U10CA-180868, NCI U10CA-180822.

The efficacy of sorafenib in preventing hepatocellular carcinoma recurrence after resection: a systematic review and meta-analysis.

hepatocellular carcinoma (HCC) recurrence after liver resection remains a major threat for patients' survival. Sorafenib is recommended as an adjuvant treatment for patients after a liver resection. The objective of this meta-analysis was to estimate the therapeutic value of sorafenib in patients who underwent a HCC resection. relevant reports were retrieved from electronic databases. All eligible studies were carefully reviewed and the required data were extracted. Outcome with regard to overall survival (OS), recurrence-free survival (RFS), recurrence rate, mortality rate, OS time (months) and RFS time (months) were analyzed. nine trials were included. The results of the meta-analysis revealed that sorafenib did not exert a significant superior effect on OS (sorafenib as reference: hazard ratio [HR] = 2.15; 95% CI, 0.91-5.08, p = 0.80; control as reference: HR = 0.56; 95% CI, 0.31-1.02; p = 0.059), OS time in months (weighted mean differences [WMD] = 4.96; 95% CI, -1.21-11.13; p = 0.115) and RFS time in months (WMD = 7.58; 95% CI, -1.36-16.53; p = 0.097). Nevertheless, the use of sorafenib was associated with a significantly higher RFS (HR = 0.53; 95% CI, 0.31-0.90; p = 0.018), and a lower recurrence rate (risk ratio [RR] = 0.72; 95% CI, 0.60-0.86; p < 0.001) and mortality rate (RR = 0.74; 95% CI, 0.57-0.95; p = 0.20). according to the present meta-analysis, sorafenib showed a significant benefit in RFS, recurrence rate and mortality rate. The effect of sorafenib for the prevention of HCC recurrence seems to be encouraging. However, more evidence is still needed before reaching a definitive conclusion.

A nomogram predicting the recurrence of hepatocellular carcinoma in patients after laparoscopic hepatectomy

BackgroundPatients with hepatocellular carcinoma (HCC) undergoing surgical resection still have a high 5-year recurrence rate (~ 60%). With the development of laparoscopic hepatectomy (LH), few studies have compared the efficacy between LH and traditional surgical approach on HCC. The objective of this study was to establish a nomogram to evaluate the risk of recurrence in HCC patients who underwent LH.MethodsThe clinical data of 432 patients, pathologically diagnosed with HCC, underwent LH as initial treatment and had surgical margin > 1 cm were collected. The significance of their clinicopathological features to recurrence-free survival (RFS) was assessed, based on which a nomogram was constructed using a training cohort (n = 324) and was internally validated using a temporal validation cohort (n = 108).ResultsHepatitis B surface antigen (hazard ratio [HR], 1.838; P = 0.044), tumor number (HR, 1.774; P = 0.003), tumor thrombus (HR, 2.356; P = 0.003), cancer cell differentiation (HR, 0.745; P = 0.080), and microvascular tumor invasion (HR, 1.673; P =0.007) were found to be independent risk factors for RFS in the training cohort, and were used for constructing the nomogram. The C-index for RFS prediction in the training cohort using the nomogram was 0.786, which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification (C-index, 0.698) and the Barcelona Clinic Liver Cancer staging system (C-index, 0.632). A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve. An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis, which was also confirmed in the validation cohort compared to other systems.ConclusionsWe constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients, which can be clinically implemented in assisting the planification of individual postoperative surveillance protocols.

Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial

BackgroundSince 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial. Patients, methods and resultsA total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63–0.88; P < 0.001), DMFS (HR 0.76, 0.64–0.90; P = 0.002) and OS (HR 0.73, 0.60–0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups. ConclusionsAdjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups.

Adjuvant systemic therapy in high-risk melanoma.

In resected high-risk melanoma (stage IIB/C-III) the risk of locoregional and/or distant recurrence is substantial and so far adjuvant therapies have been fairly unsuccessful. Interferon showed slight improvements in recurrence-free survival (RFS) but failed to convincingly improve overall survival (OS). In these patients, adjuvant therapy with treatments that show promising results in stage IV disease is arising. Studies using immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 agents reveal convincing RFS benefits. OS rates, however, are not mature yet in most studies. Only ipilimumab has shown an OS benefit but at a high cost of toxicity. Also in studies with adjuvant targeted therapy using BRAF and MEK inhibitors, ensuring results are reported regarding RFS. As possible toxicity cannot be ignored, it is crucial to identify patients who would benefit most from these adjuvant therapies. In patients with clinically detectable lymph node metastases, studies using neoadjuvant schedules of immunotherapy and targeted therapy have been performed. In phase I and II studies the most optimal schedule of combination immunotherapy was identified and further research on this front will follow in the coming years. Concluding, after decades of scarce options for patients with high-risk melanoma, recent developments in adjuvant therapy have changed the standard of care for these patients.