Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk.Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.     

Recent advances in localized RCC: A focus on VEGF and immuno-oncology therapies

Recent advances in advanced renal cell cancer (RCC) research have produced new drugs and therapies for patients with metastatic disease leading to higher response rates, improvements in progression-free survival, and longer overall survival. These advances have yet to be realized in patients with early-stage kidney cancer, and to date, no drug has been approved for the adjuvant treatment of localized kidney cancer. The current standard of care for localized high-risk kidney cancers is resection of the primary tumor. Here, we review the results of recently completed adjuvant vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) trials in RCC that have been reported, or are awaiting results. Further, we discuss the new immune checkpoint inhibitor adjuvant trials planned. There is hope that these trials may lead to new options and longer survival for patients with localized high-risk kidney cancer.     

Management of High-Risk Localised Prostate Cancer

ContextHigh-risk localised prostate cancer (PCa) is defined as significant likelihood of death from PCa or development of distant metastases. It is important to identify patients at high risk of progression who may benefit from neoadjuvant or adjuvant therapies.ObjectiveTo review definitions for high-risk localised PCa and review outcomes of different treatment modalities.Evidence acquisitionRandomised and nonrandomised clinical trials addressing the characterisation of patients with high-risk PCa and treatment options for this patient population were reviewed, mainly focusing on comparison of monotherapy with multimodality approaches.Evidence synthesisRadical prostatectomy (RP) represents a treatment option for selected high-risk patients and can result in long-term progression-free survival (PFS) in a subset without hormone therapy (HT). HT prior to RP is not considered as a standard treatment in high-risk, clinically localised PC, because survival advantage has never been conclusively demonstrated. Adjuvant “early” androgen-deprivation therapy (ADT) is not recommended for patients with high-risk disease except for pathologically confirmed nodal disease. Adjuvant radiotherapy (RT) after RP in patients with adverse risk factors decreases biochemical recurrence risk with improved local control but without a clear advantage in overall survival (OS). RT with long-term adjuvant HT improves OS. However, the exact period of HT is still controversial, and one must consider the cardiovascular comorbidity status of the patients before initiating ADT. Neoadjuvant chemotherapy can be administered safely in patients with high-risk disease prior to definitive therapy. Although complete responders are very rare, prostate-specific antigen (PSA) responses were present in a substantial number of patients. Early results of adjuvant chemotherapy trials are promising, but ongoing phase 3 trials should be completed to establish any survival advantage.ConclusionsIntegrating local and systemic therapies may be beneficial in the management of high-risk localised or locally advanced PCa.     

Identification of Risk Factors for Recurrence in High-Risk Stage II Colon Cancer

To identify risk factors for recurrence in patients with stage II colon cancer, Cox proportional hazards regression analysis was performed in 194 patients with stage II colon cancer who underwent curative surgery between April 1997 and December 2008. Thirteen clinical and pathologic factors, including use of fluoropyrimidine-based adjuvant chemotherapy in 113 of the patients (58.2%), were assessed. By multivariate analysis, only obstruction, perforation, and T4-level invasion were identified as independent risk factors affecting disease-free survival (DFS) (P < 0.01). The 5-year DFS rate was 70.6% in patients with one or more risk factors (n = 68) and 96.0% in patients with no risk factors (n = 126) (P < 0.01). These results suggest that obstruction, perforation, and T4-level invasion are suitable candidates for prediction of tumor recurrence in patients with stage II colon cancer. The oxaliplatin-based adjuvant chemotherapy, which has been reported to be effective in stage III colon cancer patients, may improve the prognosis in high-risk stage II colon cancer patients.     

Sequential versus concurrent anthracyclines and taxanes as adjuvant chemotherapy of early breast cancer: a meta-analysis of phase III randomized control trials

PurposeWe performed a meta-analysis of Phase III randomized trials to compare treatment outcomes for early-stage breast cancer patients receiving adjuvant chemotherapy with sequential or concurrent anthracyclines and taxanes.MethodsAll Phase III randomized trials comparing adjuvant chemotherapy of sequential or concurrent anthracyclines and taxanes in early-stage breast cancer patients were considered eligible. A total of three trials that enrolled 8728 women were analyzed. A pooled analysis was accomplished and event-based risk ratios (RR) with 95% confidence intervals (95%CI) were derived. The significant differences in disease-free survival (DFS) and overall survival (OS) were explored. A heterogeneity test was applied as well.ResultsAmong three eligible trials, significant differences in favor of sequential regimen were seen in DFS (RR: 0.90; 95%CI: 0.84 to 0.98; P = 0.01) and in OS (RR: 0.88; 95%CI: 0.79 to 0.98; P = 0.02).ConclusionConsidering all the available Phase III trials, sequential adjuvant chemotherapy for early breast cancer seems to add a significant benefit in both DFS and OS over concurrent regimens.     

Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk,nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial

Introduction and objectiveWith a limited number of prognostic and predictive biomarkers available, carbonic anhydrase-IX (CAIX) has served as an important prognostic biomarker for patients with clear cell renal cell carcinoma (ccRCC). However, studies have recently called into question the role of CAIX as a biomarker for ccRCC. To investigate this uncertainty, we quantified the association of CAIX with lymphatic involvement and survival using data from ARISER study (WX-2007-03-HR)—a prospective trial involving subjects with high-risk nonmetastatic ccRCC.Methods and materialsWe reviewed the records of 813 patients enrolled in the ARISER study. Central review of histology, grade, and CAIX staining (frequency and intensity) was performed. CAIX score was derived by multiplying the staining intensity (1–3) by percent positive cells (0%–100%), yielding a range of 0 to 300. We quantified the association of CAIX expression and score with lymphatic spread and survival (disease-free survival [DFS] and overall survival [OS]) using Kaplan-Meier and multivariable propensity score adjusted Cox regression analyses.ResultsMedian follow-up of the cohort was 54.2 months. Although 56% of subjects with lymphatic involvement had CAIX>85%, only 33% had CAIX score≥200. On multivariable analysis, CAIX>85% was not a statistically significant predictor of DFS and OS (P = 0.06 and P = 0.15, respectively). However, CAIX score≥200, when compared with CAIX score≤100, was associated with improved DFS and OS (P = 0.01 and P = 0.01, respectively) on multivariable analysis.ConclusionsThe largest, multicenter, prospective analysis of patients with high-risk nonmetastatic ccRCC demonstrates the utility of CAIX score as a statistically significant prognostic biomarker for survival. We recommend that CAIX score be quantified for all patients with high-risk disease after nephrectomy.     

Management of high-risk localized prostate cancer: the integration of local and systemic therapy approaches

Using a combination of PSA, Gleason score, and clinical stage, it is possible to identify a group of patients with prostate cancer who have a high risk of relapse following initial treatment (e.g., radiotherapy or radical prostatectomy). For these patients, multi-modal therapy may result in improved outcomes. We reviewed published literature to identify methods to identify high-risk patients as well as options for adjuvant or neoadjuvant therapy to reduce risk of disease recurrence. At the present time, the most promising adjuvant therapy is hormonal therapy following radiotherapy for locally advanced disease (T3-T4, or N1). In phase III trials in these patients, survival is improved. For all other applications, including adjuvant and neoadjuvant hormonal therapy, chemotherapy, or radiotherapy, the benefits are unclear. Perhaps most promising at this time, and the subject of a current phase III trial, is the utility of adjuvant chemotherapy in high-risk patients. It will be through the conduct of phase III trials that the benefits of multi-modal therapy will be evaluated. Patients with high-risk prostate cancer undergoing radiotherapy or surgery should be offered participation in these clinical trials.     

Avances en uro-oncología «OncoForum»: lo mejor del 2019

ObjectiveReview the latest evidence on urologic oncology on kidney, bladder and prostate tumors.MethodsAbstracts on kidney, bladder and prostate cancer presented at the 2019 congresses (EAU, AUA, ASCO and ESMO) and the publications with the greatest impact in this period, with the highest evaluation by the OncoForum committee, are reviewed.ResultsIn patients with metastatic kidney cancer, regimens including immunotherapy (nivolumab + ipilimumab, pembrolizumab) have been shown to be superior to sunitinib in terms of survival. In patients with non-muscle invasive bladder cancer, pembrolizumab has been shown to be an effective alternative in those refractory to bacillus Calmette-Guérin, while in patients with metastatic urothelial cancer, third-line enfortumab vedotin achieved a significant response rate (44%). In patients with localized prostate cancer (PCa), ultrafractionated external radiotherapy did not show any greater acute toxicity than fractionated or hypofractionated radiotherapy. The benefit of enzalutamide and apalutamide associated with castration has been confirmed in M1 PCa patients, regardless of disease volume. In patients with castration-resistant M0 PCa, treatment with enzalutamide, apalutamide or darolutamide has been associated with a delay in the occurrence of metastasis and prolonged survival. Cabazitaxel has demonstrated a survival benefit in patients with metastatic CRPC, while olaparib showed anti-tumor activity after chemotherapy in those tumors with mutations in DNA repair genes.ConclusionsThese data show the implementation of immunotherapy as a novel alternative against renal and bladder cancer. The arrival of new agents for advanced urothelial carcinoma should be highlighted, and the efficacy of enzalutamide and apalutamide in de novo metastatic prostate cancer is established. In metastatic CRPC, cabazitaxel and olaparib (targeting mutations) are promising therapeutic options.     

Radiotherapy before and after radical prostatectomy for high-risk and locally advanced prostate cancer

ObjectivesMen with localized high-risk prostate cancer carry significant risk of prostate cancer–specific mortality. The best treatment approach to minimize this risk is unclear. In this review, we evaluate the role of radiation before and after radical prostatectomy.Methods and materialsA critical review of the literature was performed regarding the application of external radiation therapy (RT) in combination with prostatectomy for high-risk localized prostate cancer.ResultsUp to 70% of men with high-risk localized disease may require adjuvant therapy because of adverse pathologic features or biochemical recurrence in the absence of systemic disease. The utility of adjuvant RT among men with adverse pathologic features are well established at least regarding minimizing biochemical recurrence risk. The optimal timing of salvage radiation is the subject of ongoing studies. Neoadjuvant RT requires further study but is a potentially attractive method because of decreased radiation field sizes and potential radiobiologic benefits of delivering RT before surgery. Salvage prostatectomy is effective at treating local recurrence after radiation but is associated with significant surgical morbidity.ConclusionsCombining local therapies including radical prostatectomy and RT can be a reasonable approach. Care should be taken at the initial presentation of high-risk localized prostate cancer to consider and plan for the likelihood of multimodality care.     

p21-Activated kinase 4 predicts early recurrence and poor survival in patients with nonmetastatic clear cell renal cell carcinoma

Backgroundp21-Activated kinase 4 (PAK4), a serine/threonine kinase implicated in the cytoskeleton organization to orchestrate cell morphology, adhesion, and motility, is associated with angiogenesis and vessel branching, which are important events in the progression of clear cell renal cell carcinoma (ccRCC). We investigated the effect of PAK4 expression on recurrence and survival among patients with nonmetastatic ccRCC following surgery.MethodsPAK4 expression was assessed, using immunohistochemistry, in 376 patients with nonmetastatic ccRCC after nephrectomy, where data of 187 patients were obtained from 2013 to 2014 and of 189 patients were obtained from 2008. Kaplan-Meier and Cox regression analyses were used to associate PAK4 expression with overall survival and recurrence-free survival.ResultsOverall, 41.2% and 36.5% of specimens exhibited high PAK4 expression in 2 cohorts. Patients with high PAK4 expression were prone to possess high Fuhrman grade and tumor necrosis. Moreover, high PAK4 intensity was significantly associated with poor overall survival and recurrence-free survival. PAK4 expression remained an independent adverse prognosticator after adjusting for other well-established factors. Furthermore, in subgroups stratified by Fuhrman grade or T category, patients with high PAK4 intensity had an increased risk of recurrence and death. After adjusting for age, high PAK4 expression was an adverse prognostic marker in subgroup of low Fuhrman grade and in subgroup of early T category.ConclusionPAK4 expression is an independent adverse prognostic biomarker for recurrence and survival among patients with low-risk ccRCC after nephrectomy.     

Clinical complete response after nivolumab administered as a third-line treatment for unresectable advanced gastric cancer with peritoneal dissemination: A case report

Introduction and importanceNivolumab, which is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has been recommended as a third-line treatment based on the results of the ATTRACTION-2 study involving patients with unresectable advanced gastric cancer.Case presentationA 69 year-old woman was referred to our department with a diagnosis of gastric cancer based on an upper gastrointestinal endoscopy during a medical examination. The endoscopy, along with various tests, helped establish a diagnosis of unresectable advanced gastric cancer (cT4aN3aM1P1c, cStage IV) with peritoneal dissemination. The first and second-line chemotherapy administered was S-1 plus oxaliplatin followed by ramucirumab and nab-paclitaxel, respectively. In this case, the disease was evaluated as progressive disease due to increased peritoneal dissemination. Nivolumab was administered as the third-line treatment. The patient developed interstitial pneumonia after nine courses of nivolumab, for which chemotherapy was discontinued and prednisolone treatment was initiated. The patient had a complete response to treatment endoscopically, 9 months after the last administration of nivolumab. After that, there was no recurrence of the cancer, despite there being no treatment for 5 months.Clinical discussionIt was suggested that the therapeutic effect of nivolumab could be maintained for a long period after discontinuation of its administration. In addition, a correlation has been reported between the treatment efficacy and immune-related adverse events associated with nivolumab.ConclusionsThe synergistic effect of the sustained effect of nivolumab and later-line treatment may contribute to the prolongation of survival after discontinuation of nivolumab in patients who are refractory or intolerant to treatment.     

Impact of chronic kidney disease on oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who underwent adjuvant bacillus Calmette-Guérin therapy

ObjectivesTo investigate the impact of chronic kidney disease (CKD) on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who underwent adjuvant induction bacillus Calmette-Guérin (BCG) therapy after transurethral resection of bladder tumor (TURBT).Materials and MethodsWe conducted a multi-institutional retrospective study assessing 209 patients with high-risk NMIBC who underwent TURBT and subsequent adjuvant induction BCG therapy from December 1998 to April 2019. Patients were divided into 2 groups: those with preoperative estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m² (non-CKD group), and those with eGFR < 60 ml/min/1.73 m² (CKD group). Primary endpoints were intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival. Background-adjusted multivariate analyses with the inverse probability of treatment weighting (IPTW) method using the propensity score were performed to evaluate the impact of CKD on intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. Moreover, multivariable analyses were performed to assess the impact of CKD on intravesical recurrence and MIBC progression, adjusting for the competing risk of death using the Fine-Gray competing risk regression model.ResultsMedian age and follow-up period after TURBT were 72 years and 45 months, respectively. Of 209 patients, 71 (34%) were diagnosed with CKD before TURBT. Background-adjusted multivariate analyses with the IPTW method indicated that CKD was significantly associated with shorter intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. In the Fine-Gray competing risk regression model, CKD showed significantly higher probabilities of intravesical recurrence and MIBC progression, with an adjusted subdistribution hazard ratio of 1.886 (95% confidence interval 1.069–3.330, P = 0.028) and 3.740 (95% confidence interval 1.060–13.20, P = 0.040), respectively.ConclusionsCKD presents a risk factor of poor oncological outcomes in patients with high-risk NMIBC who underwent adjuvant induction BCG therapy after TURBT.     

Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck

BACKGROUND: Australians have the highest rate of skin cancer in the world. Merkel cell carcinoma (MCC) is the most aggressive skin cancer reported, with a high propensity for relapse. The purpose of this study was to report the patterns of recurrence after initial treatment, the outcomes, and any predictors for survival. METHODS: We identified 37 patients who were diagnosed with MCC of the head and neck between 1980 and 2002. In this retrospective analysis, multivariate analysis was performed by use of Cox regression analysis. Disease-free survival (DFS) and overall survival (OS) were calculated with Kaplan-Meier survival curves. RESULTS: The median age at diagnosis was 75 years (range, 46-89 years), with 24 men and 13 women. The median duration of follow-up was 26 months (range, 7-104 months). Twenty-nine patients (78%) initially were seen with a primary lesion, and eight (22%) had a primary lesion and clinical nodal disease. A total of 24 (65%) of 37 patients had a relapse, with regional relapse the most common site of the first relapse (12 of 37). The rates of local relapse were similar for patients undergoing local surgery (three of 17; 18%) or surgery and adjuvant radiotherapy (two of 19; 11%). Nodal relapse developed in seven (50%) of 14 patients not receiving regional treatment compared with six (26%) of 23 patients receiving regional treatment of some type. Patients treated with surgery and adjuvant radiotherapy experienced a significantly longer median DFS than did those undergoing surgery alone (23 months vs 6 months; p < .01). The 3-year OS and DFS rates for the entire study population were 66% and 25%, respectively. CONCLUSION: MCC is an aggressive skin cancer. There is a sufficient body of evidence, including this study, to consider the addition of adjuvant locoregional radiotherapy as best practice in markedly improving freedom from relapse.     

Selective use of whole breast radiotherapy after breast conserving surgery for invasive breast cancer and DCIS

BackgroundRadiotherapy following breast conservation is routine in the treatment of invasive breast cancer and is commonly used in ductal carcinoma in situ to decrease local recurrence. However, adjuvant breast radiotherapy has significant short and longer-term side effects and consumes substantial health care resources. We aimed to review the randomised controlled trials and attempted to identify clinico-pathological factors and molecular markers associated with the risk of local recurrence.MethodsA literature search using the Medline and Ovid databases between 1965 and 2011 was conducted using the terms ‘breast conservation’ and radiotherapy, and radiotherapy and DCIS. Only papers with randomised clinical trials published in English in adult were included. Only Level 2 evidence and above was included.ResultsThree meta-analyses and 17 randomised controlled trials have been published in invasive disease and one meta-analysis and four randomised controlled trials for DCIS. Overall, adjuvant radiotherapy provides a 15.7% decrease in local recurrence and 3.8% decrease in 15-year risk of breast cancer death. The key clinico-pathological factors, which enable stratification into high, intermediate or low risk groups include age, oestrogen receptor positivity, use of tamoxifen and extent of surgery. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories are 7.8%, 1·1%, and 0·1% respectively Adjuvant radiotherapy provides a 60% risk reduction in local recurrence in DCIS with no impact on distal metastases or overall survival. Size, pathological subtype and margins are major risk factors for local recurrence in DCIS.ConclusionsAdjuvant radiotherapy consistently decreases local recurrence across all subtypes of invasive and in-situ disease. While it has a survival advantage in those with invasive disease, this is not seen with DCIS and is minimal in invasive disease where the risk of local recurrence is low. This group includes women over 70 with node negative, ER positive tumours<2 cm.     

Optimizing the Safe Washout Period for Liver Transplantation Following Immune Checkpoint Inhibitors with Atezolizumab,Nivolumab, or Pembrolizumab

BackgroundUsing immune checkpoint inhibitors (ICIs) as a downstaging therapy for liver transplantation (LT) has improved outcomes for patients with advanced hepatocellular carcinoma (HCC). However, this therapy carries a risk of post-transplant graft rejection. The washout (WO) period between the last ICI dose and LT seems critical in preventing postoperative rejection. This study aimed to optimize the WO period by balancing tumor burden suppression and rejection prevention using ICIs before LT.MethodsWe reviewed published case reports or series from March 2020 to December 2022 regarding LT for HCC after downstaging or bridge therapy with ICIs and included 4 of our cases. Most patients received atezolizumab, nivolumab, or pembrolizumab; these ICIs shared a half-life of around 28 days. Therefore, we excluded cases without definite WO period data and those using non-atezolizumab/nivolumab/pembrolizumab ICIs and ultimately enrolled 22 patients for analysis. We compared their clinical outcomes and estimated the rejection-free survival for every 0.5 half-life interval.ResultsMost study subjects received nivolumab (n = 25). Six patients had severe rejections (nivolumab group, n = 5) and needed rescue management. Of the 6 cases, 1 patient died after rejection, and 2 underwent re-transplantation. The median WO period in these 6 patients was 22 days (IQR: 9–35 days). In addition, we found that a 1.5 half-life (42 days) was the shortest safe WO period associated with significant rejection-free survival (P = .005).ConclusionsOur results showed that 42 days was the safest WO period before LT for HCC after ICI with atezolizumab, nivolumab, or pembrolizumab.     

Treatment of Intermediate-Risk Non–Muscle-Invasive Bladder Cancer (NMIBC)

ObjectivesReview treatment of NMIBC, particularly intermediate-risk NMIBC.MethodsSearch of published literature on conventional adjuvant treatment of low-, intermediate-, and high-risk NMIBC, and novel treatment modalities.ResultsA considerable percentage of patients with intermediate-risk NMIBC, and especially high-risk NMIBC, are at risk of disease recurrence and progression. Of currently used adjuvant therapies, chemotherapy and especially immunotherapy are effective in reducing the risk of recurrence in the short term, but are suboptimal in the long term. In contrast to chemotherapy, BCG slightly decreases the risk of progression in patients with high-risk tumours. New agents, like gemcitabine and apaziquone, and device-assisted therapies, like thermochemotherapy and EMDA, are promising, but need further evidence on long-term efficacy.ConclusionsThere still is a clear need for novel or improved adjuvant treatment modalities for patients with NMIBC. These modalities should be able to better reduce the risk of recurrence of NMIBC and progression to muscle-invasive disease, so as to reduce disease burden, preserve a patient's bladder, and improve disease-specific survival.     

Cost-effectiveness analysis of neoadjuvant immune checkpoint inhibition vs. cisplatin-based chemotherapy in muscle invasive bladder cancer

BackgroundMultiple single-arm clinical trials showed promising pathologic complete response rates with neoadjuvant immune checkpoint inhibitors (ICIs) in muscle-invasive bladder cancer. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with cisplatin-based chemotherapy (CBC).MethodsWe applied a decision analytic simulation model with a health care payer perspective to compare neoadjuvant ICIs vs. CBC. For the primary analysis we compared pembrolizumab with ddMVAC. We performed a secondary analysis with gemcitabine/cisplatin as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICI. We input pathologic complete response rates from trials or meta-analysis and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed.ResultsThe incremental cost of pembrolizumab compared with ddMVAC was $8,041 resulting in an incremental improvement of 1.5% in 2-year RFS for an ICER of $522,143 per 2-year RFS. A 21% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required an 89% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC.ConclusionsICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments.     

The disease-free interval in breast cancer trials: scientific or spurious?

Reports that stem from the National Surgical Adjuvant Breast and Bowel Project clinical trials have had a major influence on the trend toward adjuvant chemotherapy. These reports use life-table analysis to report survival or disease-free survival (DFS). DFS is reported more frequently than survival, and most studies report an increase in DFS with adjuvant therapy but no difference in survival. This means a shorter time between recurrence (end of DFS) and death. A conceptual model is presented herein with five possible explanations for this observation: (1) Bias exists in randomizing (entrance); (2) bias is introduced by the examining physician (exit end point); (3) the spectrum of micrometastases is selectively affected; (4) the sites of systemic recurrence (macrometastases) are affected; (5) treatment after recurrence (salvage) is less effective in the previously treated group; probably because of the induction of resistance to antineoplastic therapy. Hypothesis 5 seems most probable, and if so, the benefit of chemotherapy should be reserved for those women who need it rather than rendering everyone less treatable. The disease-free interval, with its doctor-determined end point, is insufficiently reliable to be used for major decisions regarding adjuvant therapy.