Favorable Pathologic Response Research Articles

Neoadjuvant immunotherapy or chemoimmunotherapy in non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundIn recent years, a series of clinical trials have explored the application of neoadjuvant immunotherapy or chemoimmunotherapy in non-small cell lung cancer (NSCLC). However, no randomized control trials comparing neoadjuvant immunotherapy with chemoimmunotherapy have yet been reported. This study aimed to summarize and compare the efficacy and safety of neoadjuvant immunotherapy and chemoimmunotherapy in NSCLC.MethodsLiterature focusing on the efficacy and safety of neoadjuvant immunotherapy or chemoimmunotherapy in NSCLC published before June 2021 was retrieved from PubMed, Embase, and the Cochrane Library. Study endpoints included major pathological response (MPR), complete pathological response (pCR), treatment-related adverse events (TRAEs), severe adverse events (SAEs), resection rate, surgical delay rate, and conversion to thoracotomy. The risk of bias was assessed using the Cochrane bias risk assessment tool. Subgroup and sensitivity analyses were further performed.ResultsA total of 988 patients from 16 studies were included in this meta-analysis. For patients who received neoadjuvant immunotherapy with single/combined ICIs or chemoimmunotherapy, the pooled MPR rate was 43.5% and the pooled pCR rate was 21.9%. The pooled incidence of TRAEs and SAEs were 54.8% and 15.3%, respectively. The pooled resection rate was 85.8%, the surgical delay rate was 7.4%, and the conversion rate was 17.4%. Patients who received neoadjuvant chemoimmunotherapy had remarkably improved pathological response (MPR rate: 53.3% vs. 28.6%; pCR rate: 28.6% vs. 9.9%) compared with those receiving neoadjuvant single-agent immunotherapy, while the incidence of SAEs (18.0% vs. 12.3%) and surgical delay rate (3.8% vs. 7.4%) did not significantly increase. Neoadjuvant nivolumab combined with ipilimumab also achieved a high pCR rate (28.6%) with tolerable toxicity. Nivolumab- and pembrolizumab-based neoadjuvant therapy showed a higher MPR rate (nivolumab 51.5%, pembrolizumab 46.8%) and pCR rate (nivolumab 29.1%, pembrolizumab 31.5%). Besides, patients with positive programmed death-ligand 1 (PD-L1) expression [tumor proportion score (TPS) ≥1%] exhibited favorable pathological responses than PD-L1 negative patients.DiscussionOverall, neoadjuvant immunotherapy or chemoimmunotherapy is effective and safe in NSCLC. Compared with single-agent immunotherapy, neoadjuvant chemoimmunotherapy provides a significant improvement in pathological response without increasing the incidence of SAEs or surgical delay. These results need further confirmation by more large-scale randomized controlled trials.

The baseline oral microbiota predicts the response of locally advanced oral squamous cell carcinoma patients to induction chemotherapy: A prospective longitudinal study

PurposeAmong oral squamous cell carcinoma (OSCC) patients who receive docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy, those with a favorable pathological response tend to obtain satisfactory clinical outcomes, while the total population exhibit no survival benefit. Thus, there is an urgent need to improve the therapeutic effect of TPF by applying personalized treatment according to distinct biomarkers. Methods and materialsIn the present study, we collected oral rinse samples from 44 OSCC patients enrolled in our prospective multicenter random phase II trial before TPF induction chemotherapy to conduct 16S rRNA gene sequencing and metagenomic analysis. Patients were administrated with two cycles of TPF induction chemotherapy (75 mg/m2 cisplatin and 75 mg/m2 docetaxel on day 1 and 750 mg/m2 fluorouracil from the first to the fifth day), and then divided into responsive and nonresponsive groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ResultsIn the 16S rRNA gene sequence analysis, Fusobacterium and Mycoplasma were more enriched in the nonresponsive group, while Slackia was more enriched in the responder group at the genus level. In the metagenomic shotgun sequencing analysis, Fusobacterium nucleatum was more enriched in the nonresponsive group. Functional analysis showed that the platinum drug resistance pathway and microRNAs in cancer and RNA degradation pathways were remarkably associated with patient sensitivity to induction chemotherapy. ConclusionsOur data suggest that the oral microbiome may play an important role in the OSCC patient sensitivity to TPF induction chemotherapy and offer novel potential biomarkers for predicting the response to TPF induction chemotherapy.

Predictive value of red blood cell distribution width level on histological response and prognosis in colorectal liver metastases.

The red blood cell distribution width (RDW) level is a potential prognostic factor for solid tumours. We aimed to investigate the predictive value of pre-neoadjuvant chemotherapy (pre-NAC) RDW, preoperative RDW and the change in RDW on the pathological response and prognosis of patients with colorectal liver metastasis (CRLM), which was helpful for treatment decision-making, surveillance and prognostication. This retrospective study analyzed clinicopathologic data, treatments and outcomes of 150 CRLM patients treated with NAC followed by liver resection at our hospital. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The secondary outcome was postoperative major complications. The RDW level was presented as the RDW-SD level and the RDW-CV level. The optimal cut-off of RDW level was determined by X-tile analysis. The change in RDW was scored as 0 (decreased pre-NAC RDW and decreased preoperative RDW), 2 (elevated pre-NAC RDW and elevated preoperative RDW), or 1 (all other combinations). Multivariable logistic regression analysis was performed to determine the relationships between the tumour characteristics and pathological response and the postoperative major complications. A multivariate Cox proportional hazards model was used to evaluate the prognostic factors associated with survival. The optimal cut-off values of the RDW-CV and RDW-SD levels for survival were 13.5% and 42.2 fl, respectively. The multivariate analysis showed that a preoperative RDW-CV ≥13.5% (OR =3.215, 95% CI: 1.299-7.958, P=0.012) significantly predicted a favorable pathological response. The multivariate analysis revealed that a pre-NAC RDW-CV ≥13.5% (OR =2.462, 95% CI: 1.080-5.615, P=0.032) significantly predicted postoperative major complications. In the multivariate analysis, an RDW-CV change =2 (HR =0.487, 95% CI: 0.309-0.768, P=0.002) was a significant predictor of better PFS. The multivariate analysis also revealed that an RDW-SD change =2 (HR =0.532, 95% CI: 0.332-0.854, P=0.009) were an independent predictor of better OS. This study revealed that pre-NAC RDW, preoperative RDW and RDW changes may be reliable markers that could predict a pathological response and prognosis in CRLM patients receiving NAC followed by liver resection.

Prospective trial of immuno(chemo)therapy before resection, definitive chemoradiotherapy or palliative therapy in patients with locally advanced or oligometastatic non-small cell lung cancer without a primary curative option

BackgroundRecent phase II–III trials of immuno(chemo)therapy before resection in locally advanced resectable non-small cell lung cancer (NSCLC) report high rates of pathological response and promising survival. However, primarily, patients who did not undergo resection were excluded from these studies. Moreover, there are no data on chemoradiotherapy (CRT) after immuno(chemo)therapy in patients who are primarily not amenable to CRT. We hypothesised that induction immuno(chemo)therapy may enable patients with NSCLC with a potentially curative stage (III–IVA), for whom primary curative treatment (either resection or CRT) is not possible for anatomical or functional reasons, to receive curative treatment. Patients and methodsWe enrolled 35 patients with NSCLC with aforementioned characteristics into a prospective real-world trial of induction immuno(chemo)therapy followed by morphologic and metabolic reassessment and multidisciplinary board-guided curative treatment (resection [preferred] or CRT) or palliative therapy. The primary end-point was the proportion of patients receiving curative treatment. ResultsThirty-two patients (91%) received curative treatment (11 resections and 21 CRT). 73% and 64% of patients who underwent resection had a major or complete pathological response, respectively. There were 14 recurrences: 2 (18%) in patients who underwent resection, 9 (43%) in patients who received CRT and 3 (100%) in patients who received palliative therapy (median follow-up 17 months). Eight tumour-related deaths occurred: 5 (24%) in patients who received CRT; and 3 (100%) in patients who received palliative therapy. There were no treatment-related deaths. ConclusionsIn locally advanced or oligometastatic NSCLC without a primary curative option, induction immuno(chemo)therapy results in a high rate of curative treatment with promising early survival data. patients who underwent resection achieved a high rate of prognostically favourable pathological response.

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.

Post-radical prostatectomy (RP) outcome for patients with high-risk prostate cancer treated with intense neoadjuvant hormone therapy (NHT): Results of a pooled analysis of contemporary clinical trials.

238 Background: Patients with high-risk prostate cancer have an increased risk of recurrence and death from prostate cancer. Intense NHT prior to RP has been associated with favorable pathologic responses in a subset of patients with high-risk disease. We conducted a pooled analysis of post-RP outcomes of four, multicenter, randomized, clinical trials of intense NHT prior to RP. Methods: All patients included were enrolled on trials evaluating intense NHT followed by RP. The primary endpoint was time to biochemical recurrence (BCR), defined as the time from RP to prostate specific antigen (PSA) >0.1 ng/mL or start of first post-RP therapy. Secondary endpoints included metastasis-free survival (MFS), overall survival (OS), and time to testosterone recovery. We evaluated outcomes in the overall population, favorable responders (defined as a pathologic complete response or minimum residual disease ≤ 5 mm at RP), and non-responders. We correlated pathologic parameters, including RP pathologic response, PTEN status, ERG status, and presence of intraductal carcinoma with BCR. Results: 121 patients were included of whom 78.5% (n=95) had high-risk disease by NCCN risk categories. Following NHT, 20.7% (n=25) had 0-5 mm of residual tumor (including 9.1%, n=11, with pathologic complete response). Overall, 52 patients (43.0%) experienced BCR, of whom two were exceptional responders (Table). Testosterone recovery was observed in 94.0% of patients (n=109/116). PTEN loss and presence of intraductal carcinoma were associated with shorter time to BCR. Conclusions: In this pooled analysis of clinical trials, we demonstrate that patients who achieve a favorable pathologic response to NHT prior to RP experienced a decreased PSA relapse rate and prolonged time to BCR. Larger residual tumor volumes and tissue-based parameters, including PTEN loss and intraductal carcinoma, were associated with BCR. Additional follow-up is warranted to evaluate the impact on long-term outcomes. Clinical trial information: NCT00298155; NCT00924469; NCT01547299; NCT02268175 . [Table: see text]

Pathological responses to low-dose irradiation and Pepleomycin in Oral squamous cell carcinoma are predictive of Locoregional control

BackgroundThe prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence.MethodsWe retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3–4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato.ResultsEight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100 and 56.6% in patients with favorable and unfavorable pathological responses, respectively.ConclusionsThe present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Can 68Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography Predict Pathological Response of Primary Prostate Cancer to Neoadjuvant Androgen Deprivation Therapy? A Pilot Study.

We explored the role of 68Ga-PSMA-11 positron emission/computerized tomography as a predictor of pathological response to neoadjuvant androgen deprivation therapy combined with abiraterone for high risk prostate cancer. A total of 45 patients with localized high risk prostate cancer who had serial 68Ga-PSMA-11 positron emission tomography/computerized tomography scans before and after 6 months of androgen deprivation therapy plus abiraterone neoadjuvant treatment followed by radical prostatectomy were included in this study. Complete pathological response or minimal residual disease <5 mm on whole mount histopathology was defined as favorable pathological response. The diagnostic performance of prostate specific antigen response and positron emission tomography/computerized tomography response for favorable pathological response was calculated. Univariable and multivariable logistic regression analyses of clinical and imaging variables were also performed to identify favorable pathological response. Compared to the prostate specific antigen response, positron emission tomography/computerized tomography response had a significantly higher specificity in diagnosing favorable pathological response (89.7% vs 62.1%, p=0.043). Preoperative nadir prostate specific antigen (OR 0.121, 95% CI 0.028-0.529, p=0.005), posttreatment maximum standardized uptake value (OR 7.072, 95% CI 2.035-24.579, p=0.002) and posttreatment tumor volume (OR 7.896, 95% CI 1.415-44.054, p=0.018) measured on positron emission tomography/computerized tomography were significantly associated with favorable pathological response in univariable logistic regression analysis. On multivariable logistic regression analysis, only posttreatment maximum standardized uptake value was found to be an independent predictor of favorable pathological response (OR 9.69, 95% CI 1.439-65.242, p=0.020). 68Ga-PSMA positron emission tomography/computerized tomography has a better diagnostic performance of pathological response to neoadjuvant treatment compared with prostate specific antigen, with maximum standardized uptake value being an independent predictive factor. This pilot study suggests that prostate specific membrane antigen positron emission tomography/computerized tomography may serve as a potential predictor of pathological response to neoadjuvant treatment.

Lauren Classification Is A Predictor For Pathological Response Of Preoperative Chemoradiotherapy Compared With Preoperative Chemotherapy In Patients With Locally Advanced Gastric Cancer

To investigate the predictive value of Lauren classification to tumor pathological response after preoperative chemoradiotherapy (CRT) vs. preoperative chemotherapy (ChT) in locally advanced gastric adenocarcinoma (LAGC). From June 2013 to Dec, 2019, 182 patients in our hospital were enrolled into an ongoing multicentric phase III clinical trial comparing preoperative CRT (induction XELOX × 1 + 45Gy/25f with concurrent dose-reduced XELOX × 2) with preoperative ChT (XELOX × 3) in LAGC (NCT01815853). The clinical stage should be cT3N2-3M0, cT4aN+M0, or cT4bNanyM0. There were 124 males and 58 females, median age was 60 yrs (range 26-75 yrs). The interval between end of RT and surgery was 6-8 weeks. 65 out of 91 patients in the ChT group and 61 out of 91 patients in the CRT group had completed the preoperative treatments and the following radical D2 gastrectomy. Pathological response of primary tumor was categorized with NCCN tumor regression grade (TRG). Favorable pathological response (FPR) was defined as TRG0-1 with ypN0. At enrollment, patients’ baseline and tumor characteristics were well-balanced between the two groups. Proximal GC was in 58.2% (53/91) and 50.5(46/91) of the CRT and ChT group, respectively. Intestinal type (IT) GC was identified in 33(36.3%) patients of the ChT group, and in 36(39.6%) patients of the CRT group (X2 = 0.51, p = 0.916). After D2 gastrectomy, proportions of IT were 32.3% (21/65 pts) in the ChT group, and 50.8% (31/61 pts) in the CRT group, showing obvious shift towards resectability favoring IT vs. non-intestinal (n-IT, diffused plus mixed) type (X2 = 8.61, P = 0.035) after CRT. CRT group achieved higher rate of pCR (21.3% vs 3.1%, P = 0.002). There were 30, 37, and 22 patients obtained TRG0-1, ypN0, and FPR, respectively in the CRT group, while only 10, 14, and 5 patients did in the ChT group (P<0.001 for all). In the CRT group, ypN0 and FPR were observed in 80.6% and 45.2% of patients with IT tumor, but only in 35.7% and 21.4% with n-IT tumors (ypN0:P<0.001; FPR: P = 0.054), respectively. Logistic regression revealed IT tumor with higher probability of achieving ypN0 (OR = 7.500, 95%CI: 1.838-30.730; P = 0.005) than n-IT tumors. In contrast, no such differences were observed in the ChT group. Primary tumor locations were not predictive for ypN0 or TRG. In all patients with IT tumors, CRT was associated with higher rates of TRG0-1 (51.6% vs. 14.3%, P = 0.006), ypN0 (80.6% vs. 19.0%, P<0.001), FPR (45.2% vs. 0%, P<0.001) , pCR (22.6% vs. 0%, P = 0.033), and upstage 0-II (93.5% vs. 50.0%, P = 0.001) than ChT, while in patients with n-IT GC, only TRG showed significant improvement favoring CRT than ChT(TRG0-1: 42.9% vs. 15.9%, P = 0.011). Intestinal type gastric adenocarcinomas showed better responses to preoperative CRT vs. preoperative ChT than diffuse or mixed type GC did. This is the first set of data to date suggesting the predictive value of Lauren classification to tumor response after preoperative treatment in gastric cancer.

From the completion of neoadjuvant chemotherapy to surgery for colorectal cancer liver metastasis: What is the optimal timing?

BackgroundNeoadjuvant chemotherapy (NAC) has been widely performed in the treatment of colorectal cancer liver metastasis (CRLM) patients, but the optimal timing of surgery after NAC is unclear. The aim of this study was to investigate the optimal timing of surgery.MethodsFrom December 2010 to May 2018, 101 consecutive patients who received NAC followed by liver resection for CRLM were included in this study. The main outcome parameters were pathological response, progression‐free survival (PFS), and overall survival (OS). The effect of time to surgery (TTS) on patient outcomes, defined as a high TTS and a low TTS according to an X‐tile analysis, was investigated. To adjust for potential selection bias, propensity score matching at 1:2 was performed with two high TTS patients matched to one low TTS patient. Kaplan‐Meier curves, logistic regression analyses, and Cox regression models were used for the data analysis.ResultsThe optimal cut‐off value for the TTS was 5 weeks by X‐tile analysis. The patients in this study were divided into low (≤5 weeks, n = 27) and high (>5 weeks, n = 74) TTS groups. Patients with a high TTS were more likely to have an unfavorable pathological response (75.7% vs 48.1%, P = .008). In multivariate analysis, a low TTS significantly predicted a better pathological response (OR = 3.397, 95% CI: 1.116‐10.344, P = .031). Compared to patients with a high TTS, patients with a low TTS had significantly better PFS (P < .001, mPFS: 16 months vs 7 months) and better OS (P = .037, mOS: not reached vs 36 months). Multivariate analysis revealed that a TTS > 5 weeks was an independent predictor of decreased PFS (HR = 2.041, 95% CI: 1.152‐3.616, P = .014) but not OS. After propensity matching, the patients with a low TTS had significantly better PFS (P < .001, mPFS: 18.2 months vs 10 months) and an equivalent OS (P = .115, mOS: not reached vs 41 months). Multivariate analysis revealed that a TTS > 5 weeks was an independent predictor of decreased PFS (HR = 3.031, 95% CI: 1.494‐6.149, P = .002) but not OS.ConclusionThe longer TTS after the completion of NAC may be disadvantageous for a favorable pathological response and long‐term PFS. These results should be validated prospectively in a randomized trial.

Efficacy and safety of neoadjuvant immunotherapy in patients with microsatellite instability-high gastrointestinal malignancies: A case series

IntroductionImmune checkpoint inhibitors (ICIs) have been approved for the late-line treatment of unresectable gastrointestinal tumors, but their efficacy and safety in the neoadjuvant setting have not been described. Whether dMMR/MSI-H populations benefit from preoperative ICIs plus surgery remains undefined. Materials and methodsSix consecutive patients managed at our institution received neoadjuvant ICIs and surgery for advanced, resectable, and MSI-H gastrointestinal tumors. All patients underwent thorough clinical evaluations and radiographic investigations before and during treatment. Next-generation sequencing (NGS), immunohistochemical (IHC) staining, and in situ hybridization (ISH) were also performed for each patient’ s biopsy section to generate their molecular profiling. ResultsNeoadjuvant immunotherapy was efficient and well-tolerated in patients with dMMR/MSI-H gastrointestinal tumors. Pathologic responses were observed in 6/6 (100%) dMMR/MSI-H tumors, with 5/6 (83%) complete responses. The other patient was also confirmed to demonstrate a TNM downstaging after treated with ICIs. Three patients (50%) developed grade I/II adverse events. All enrolled patients underwent timely operations without the occurrence of unexpected perioperative or postoperative complications. No disease recurrence was identified during the follow-up so far. ConclusionsNeoadjuvant immunotherapy results in favorable pathologic responses and minor adverse effects among patients with MSI-H gastrointestinal tumors. This pre-operative measure does not compromise subsequent surgery. There is an urgent need to warrant large-cohort clinical trials to examine the utility of neoadjuvant ICIs in resectable, dMMR/MSI-H gastrointestinal malignancies.

Results of a phase II trial of intense androgen deprivation therapy prior to radical prostatectomy (RP) in men with high-risk localized prostate cancer (PC).

5503 Background: Patients with high-risk localized PC have an increased risk of recurrence and death despite treatment. Abiraterone acetate (AA), a potent CYP17 inhibitor, and apalutamide, a next generation anti-androgen, have each demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial we investigate the impact of intense androgen deprivation on RP pathologic response (NCT02903368). Methods: Eligible patients had a Gleason score ≥4+3=7, PSA &gt;20 ng/mL or T3 disease (by prostate MRI) and lymph node &lt;20 mm. During Part 1 of the study, patients were randomized 1:1 to AA + prednisone + apalutamide + leuprolide (APAL) or AA + prednisone + leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of a pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 118 patients were enrolled at four sites. Median age was 61 (range 46-72) years. The majority of patients had NCCN high-risk disease [n=111, 94%; T3 n=73 (62%), Gleason 8-10 n=84 (71%), PSA &gt;20 ng/mL n=28 (24%)]. 114 (97%) patients completed 6 therapy cycles followed by RP. Median PSA nadir was &lt;0.01 versus 0.02 ng/mL and time to nadir was 4.2 versus 4.6 months in the APAL and APL arms, respectively. RP outcomes are displayed in Table. The combined pCR or MRD rate was 21.8% in the APAL arm and 20.3% in the APL arm (p=0.85). 13 (11%) patients (8 in APAL; 5 in APL) experienced grade 3 treatment-related adverse events (TrAEs). The most common grade 3 TrAEs were hypertension (5%), elevated ALT (3%) and elevated AST (3%). No grade 4 or 5 TrAE was reported. Conclusions: Intense neoadjuvant hormone therapy followed by RP in men with high-risk PC resulted in favorable pathologic responses (&lt;5 mm residual tumor) in 21% of patients. Pathologic responses were similar between the treatment arms. Follow-up is necessary to evaluate the significance of a pathologic response on recurrence rates. Part 2 of this trial will investigate the impact of an additional 12 months of APAL post-RP on biochemical recurrence. A phase 3 trial investigating neoadjuvant apalutamide + leuprolide prior to RP is ongoing. Clinical trial information: NCT02903368 . [Table: see text]

Pathologic response and surgical outcomes in patients undergoing nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.

e16102 Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. Four patients experienced any complication, including 3 that were addressed with a single interventional radiology procedure. One patient died of progressive disease &gt; 3 months after surgery, and one patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants attention.

Neo-adjuvant Chemotherapy-Induced Neutropenia Is Associated with Histological Responses and Outcomes after the Resection of Colorectal Liver Metastases

BackgroundNeutropenia, the major adverse event in chemotherapy, is associated with favourable clinical outcome in several solid tumours. We aimed to investigate the predictive value of neo-adjuvant chemotherapy (NAC)–induced neutropenia for the pathological response and prognosis in colorectal liver metastases (CRLM) patients. MethodsA retrospective review was performed in 141 CRLM patients receiving NAC followed by liver resection. A logistic regression was applied to analyse potential predictors. A Cox proportional hazards analysis was used to analyse survival. ResultsNeutropenia due to NAC was observed in 42.6% (60/141) of all patients, and grade 3/4 neutropenia was noted in 31.7% (19/60). A pathological response (tumour regression grade (TRG) 1–3) was reported in 46.1% (65/141) of patients. Multivariate analysis showed that neutropenia significantly predicted the favourable pathological response (OR = 3.718, 95% CI 1.716–8.329, P = 0.001), as well as targeted therapy, good differentiation and preoperative CEA < 10 ng/ml as independent predictors of favourable histological response. Of the patients, 54.6% (77/141) had postoperative complications, including 28 major complications (28/77, 36.4%). Severe neutropenia significantly predicted postoperative major complications in multivariate analysis (OR = 4.077, 95% CI 1.184–14.038, P = 0.026). Compared to patients without neutropenia, patients with neutropenia had significantly better progression-free survival (PFS) (P = 0.007; mPFS, 10.2 months vs. 6.7 months). Patients with histological response had significantly better PFS than patients with no histological response (P = 0.001; mPFS, 10.0 months vs. 5.5 months). According to multivariate analyses, neutropenia was a significant predictor for better PFS (HR = 0.613, 95% CI 0.406–0.925, P = 0.020) but not OS. ConclusionsFor CRLM patients receiving NAC followed by liver resection, NAC-induced neutropenia was a significant predictor of favourable pathological response, postoperative major complications and better prognosis, which makes it useful for CRLM patients in guiding treatment approaches and prognosis assessments.

Safety and feasibility of nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.

619 Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 98 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. One patient died of progressive disease &gt; 3 months after surgery; one patient required thoracentesis and another required paracentesis of a sterile fluid collection in the hepatic resection bed. No complications were noted in the remaining 7 patients, none of whom required readmission. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, use of neoadjuvant ICI for selected patients may warrant attention.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreas cancer.

370 Background: Management for borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) is controversial. Multiagent chemotherapy (CT) followed by SBRT may allow for tumor downstaging and the ability to perform an R0 resection. Methods: We retrospectively evaluated BRPC and LAPC patients (pts) treated on our multidisciplinary treatment pathway. Pts underwent 2-3 months of CT. Pts without systemic progression received five fractions of SBRT, delivered every other day, to a dose of 30-33 Gy. After restaging, pts underwent surgery if resectable. Overall survival (OS), distant metastasis free survival (DMFS) and local progression free survival (LPFS) were estimated and compared by Kaplan-Meier and log-rank methods. Results: We identified 80 pts with BRPC (65) or LAPC (15) treated with neoadjuvant CT + SBRT between 2011-2017. Median follow up was 20 months. CT primarily included FOLFIRINOX (65%) and gemcitabine/nab-paclitaxel (30%). Of pts completing CT + SBRT, 67 (84%) went to surgery and 53 (79%) of those pts underwent definitive surgery including seven LAPC patients. The remaining 14 pts underwent palliative or exploratory surgery due to intraoperative metastases (43%) or vascular involvement (57%). Of pts undergoing definitive surgery, 51 had R0 resection (96%) and 5 (9%) had a complete pathologic response (PR) to CT + SBRT. The R0 resection rate of the cohort was 64%. OS was 24.5 months. Pts with a complete or marked (14%) PR had significantly better OS than those with a moderate (40%) PR (41.3 vs 30 months, p = 0.04) and pts unable to undergo definitive surgery (18.2 months, p &lt; 0.001). Zero of 11 pts who had a marked or complete PR had local progression, significant compared to those with moderate PR (p = 0.012). DMFS between these two groups was not statistically significantly different. Conclusions: Neoadjuvant CT + SBRT are associated with favorable PR rates and R0 resection rates. Marked or complete PR was associated with improved LPFS and OS compared to moderate PR and pts who did not undergo definitive surgery. DMFS was not significantly different between complete and marked PR compared to those with moderate PR.

Histological tumor response assessment in colorectal liver metastases after neoadjuvant chemotherapy: impact of the variation in tumor regression grading and peritumoral lymphocytic infiltration.

Background: The objective of this study was to evaluate the prognostic value of the variation in tumor regression grade (TRG) and peritumoral lymphocytic infiltration of colorectal liver metastases (CRLMs) after neoadjuvant chemotherapy (NACT).Methods: A retrospective review was performed in 98 patients with CRLMs who underwent NACT between 2010 and 2016. The TRG scores and counts of TILs at the tumor-normal interface were assessed in all 176 resected liver metastases to determine their association with prognosis. According to the variation in TRG scores, 40 patients with more than one liver metastasis were divided into a decreased TRG group and a stable TRG group. An additional independent cohort of 64 patients with 106 resected liver specimens was established to validate our main findings.Results: In the derivation cohort of 98 patients, 41.8% patients had a favourable pathological response to NACT (TRG 1-3), which were significantly associated with improved prognosis. Seventeen patients (42.5%) showed decreased TRG scores, and the remaining patients had stable scores. The multivariate analysis indicated that patients with decreased TRG scores had a better recurrence-free survival (RFS) compared with those with stable TRG scores (HR=0.42, P=0.034), and a similar trend was observed in the validation cohort (P=0.068). Dense TILs surrounding the metastases were present in 55.1% of the derivation cohort and associated with pathological response (P=0.008). Among patients with a pathological response to NACT, those with dense TILs had a superior RFS compared to those with weak TILs in both cohorts (derivation: HR=0.36, P=0.035; validation: HR=0.34, P=0.016).Conclusions: Variation in TRG scores and peritumoral lymphocytic infiltration may be proposed as secondary pathological parameters to evaluate the pathological response to NACT and predict the risk of recurrence after liver surgery.

Comparison of efficacy and safety of preoperative Chemoradiotherapy in locally advanced upper and middle/lower rectal cancer

BackgroundWe aimed to explore the efficacy and safety profile of preoperative neoadjuvant chemoradiation (NACRT) in locally advanced rectal cancer (LARC) in upper rectum versus middle/lower rectum.MethodsThe study included 173 patients with stage II or III (T2-4b, N0-2b) LARC who underwent NACRT followed by total mesorectal excision (TME) between January 2011 and October 2016. Cox regression, log-rank test, and Kaplan–Meier curves were calculated.ResultsAmong the 173 patients, 58 had lesions in the upper rectum and 115 patients had lesions in middle/lower rectum. In a median follow-up of 35 months (range, 6–73 months), the 5-year disease-free survival (DFS) and overall survival (OS) were 84% and 88% for the patients with upper rectal cancer and 77% and 68% for those with middle/lower rectal cancer (P = 0.251 and P = 0.058, respectively). The 5-year DFS (P = 0.012) and OS (P = 0.003) were better in the NACRT responders [tumor regression grade (TRG) 0 or 1] compared with nonresponders (TRG 2 or 3). The independent prognostic factor of favorable response to NACRT was the FOLFOX regimen (P = 0.004).ConclusionsPatients with LARC in the upper rectum who underwent NACRT followed by TME had similar DFS and a trend toward longer OS, compared with those who had middle/lower rectal lesions. Furthermore, FOLFOX may yield superior results than fluoropyrimidine based regimen during NACRT. NACRT might be an alternative option for patients with LARC in the upper rectum as it has a favorable pathological complete response rate and comparable clinical outcomes when compared with patients with LARC in middle/lower rectum.

Correlation Between Standardized Uptake Value in Preneoadjuvant and Postneoadjuvant Chemoradiotherapy and Tumor Regression Grade in Patients With Locally Advanced Esophageal Cancer.

To investigate whether positron emission tomography/computed tomography (PET/CT) initial and restaging imaging predicts for pathologic response measured by tumor regression grade (TRG) after preoperative chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer. A retrospective review of 220 patients with stage II-III esophageal cancer treated with neoadjuvant CRT followed by surgery was performed. In total, 187 patients were eligible for statistical analysis. Pretreatment and posttreatment PET/CT scans were reviewed. Maximum standard uptake value (SUV) at the site of the primary tumor was recorded before and 6 weeks after neoadjuvant therapy. Upon completion of surgery, TRG was determined by a specialized site-specific gastrointestinal pathologist. Spearman correlation was used to compare pre, post, and change in maximum SUV, TRG, and overall survival. The median follow-up was 24 months. Although no significant correlation was found between pretreatment SUV and TRG (r=0.073, P=0.32), post-CRT SUV, however, showed a significant positive correlation with TRG (r=0.374, P<0.01). There was no significant correlation between the absolute change in fluorodeoxyglucose uptake after CRT and TRG (r=0.057, P=0.44); however, the rate of SUV change showed a significant correlation with TRG (r=0.178, P=0.017). Similar to previous studies, our study showed a significant difference in overall survival between TRG groups (log-rank test, P=0.019). Patients with TRG 3 showed prominently worse survival with median survival of 27.4 months. Patients with favorable pathologic responses were those whose scans demonstrated a metabolic response defined as a decrease in SUV≥70%. Changes in SUV uptake on PET/CT scans after CRT have prognostic value in predicting pathologic response of esophageal cancer after neoadjuvant therapy. Further studies are needed to validate the integration of PET/CT as a decision-making tool.

Impact of RAS/BRAF mutation status in locally advanced rectal cancer treated with preoperative chemotherapy.

Our sincere hope is to establish the predictive factors of neoadjuvant chemotherapy (NAC) response and provide patients with greater certainty regarding treatment outcomes. The aim of this study was to assess the response to NAC and survival in patients with locally advanced rectal cancer (LARC) according to their RAS/BRAF mutation status. Data on 57 patients with LARC who received NAC between 2009 and 2016 were analyzed retrospectively. The patients were classified into two groups based on their mutation status: wild-type in both RAS and BRAF (WT) or mutant-type in either RAS or BRAF (MT). Twenty-three patients were classified as WT, and the remaining 34 patients were MT. Histological response to NAC was similar in both groups. In responders, the 3-year relapse-free survival (RFS) was better compared with the non-responders (92 and 66%, respectively). In the WT group, the 3-year RFS was 95% which was significantly better than that in the MT group (59%, p=0.011). The MT group was further subdivided into the following 2 groups by the pathological response; the MT responders (n=10) and MT non-responders (n=24). The 3-year RFS was 50% in the MT non-responders, which was significantly worse compared to that in the remaining patients (92%, p=0.001). RAS/BRAF mutations did not affect the response to NAC. However, the RFS was likely to be poor for those in the MT group who did not achieve favorable pathological response. In contrast, the RFS was favorable in the WT group regardless of the pathological response.