Frequency of surgical resection after starting neoadjuvant chemoradiotherapy in patients with esophageal cancer: A population-based cohort study

BackgroundNeoadjuvant chemoradiotherapy (nCRT) for resectable esophageal cancer is accompanied by the risk of treatment-related toxicity. The aim of this population-based cohort study was to provide insight in patients who do not proceed to surgical resection after starting nCRT.MethodsPatients who started nCRT for primary esophageal cancer diagnosed in 2015 and 2016 were selected from the nationwide population-based cancer registry. Outcome measurements included omission from surgical resection, reasons for omission of surgical resection, mortality during nCRT (≤90 days after ending nCRT) and 1-year overall survival. Multivariable logistic regression analyses were performed to identify predictive factors for omission of surgical resection.ResultsA total of 1521 patients were included, of whom 215 (14.1%) did not undergo surgical resection after starting nCRT. Age (OR:1.04, 95%CI:1.01–1.06), BMI (OR:0.95, 95%CI:0.90–0.99), WHO performance status (WHO 1: OR:1.62, 95%CI:1.16–2.62 and WHO 2: OR:3.53, 95%CI:1.68–7.41) and clinical N status (cN2: OR:1.57, 95% CI:1.04–2.37 and cN3: OR:2.52, 95%CI:1.14–5.55) were significantly associated with omission from surgery. The most frequently reported reasons for omission from surgery were disease progression (44.3%) and physical functioning (22.8%). During nCRT or within the subsequent waiting period to surgery, 38 patients (2.5%) deceased. One year overall survival of the patients who underwent nCRT followed by surgical resection was 94.9%, and 73.5% in the patients who did not undergo surgical resection following nCRT.ConclusionsOne in 7 patients who started nCRT for esophageal cancer do not proceed to surgical resection and have a decreased one year overall survival compared to patients who do proceed to surgical resection. Mortality during nCRT is considerable.     

Stage for stage comparison of recurrence patterns after definitive chemoradiotherapy or surgery for oesophageal carcinoma

AimsDefinitive chemoradiotherapy (dCRT) has been advocated as an alternative treatment for oesophageal carcinoma, but received criticism for perceived poorer locoregional disease control when compared with surgery. The aim of this study was to determine the relative incidence and pattern of oesophageal carcinoma recurrence after dCRT and surgery in patients receiving stage-directed therapy with curative intent.Materials and methodsIn total, 623 consecutive patients with oesophageal carcinoma (207 squamous cell carcinoma, 416 adenocarcinoma) were studied. The primary outcome measure was disease-free survival, adjusted for baseline differences in gender, age and histological cell type.ResultsThree hundred and eleven patients deemed unsuitable for surgery on the grounds of performance status (n = 137), bulky local disease (n = 121) or personal choice (n = 53) received dCRT and 312 surgery (200 received neoadjuvant chemotherapy). Oesophageal carcinoma recurrence was diagnosed in 44.1% of patients after dCRT compared with 40.7% after surgery (P = 0.222). Locoregional recurrence was more common after dCRT than after surgery (24.1% versus 9.3%, P < 0.0001). In contrast, distant metastases were more common after surgery than after dCRT (22.8% versus 12.9%, P = 0.001). The median time to recurrence in patients receiving dCRT and surgery were 15 and 17 months, respectively (P = 0.052). Stage-related disease-free 2 year survival for dCRT versus surgery was: stage I (68.6 versus 85.6%, P = 0.069), stage II (36.9 versus 47.4%, P = 0.011), stage III (31.0 versus 28.6, P = 0.878), stage IVa (21.4 versus 26.3%, P = 0.710).ConclusionsThese findings provide further support for a randomised trial of dCRT versus surgery in both oesophageal squamous cell carcinoma and adenocarcinoma.     

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer

BackgroundStudies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database.Patients and methodsData for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (<70 versus ≥70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors.ResultsOf 1172 patients included, 295 (25%) were ≥70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68–1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46–1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88–1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99–1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98–1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00–1.03, P = 0.04).ConclusionsElderly patients (≥70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.     

局部进展期食管癌新辅助治疗研究进展

术前新辅助治疗是近年来局部进展期食管癌治疗领域的研究热点,越来越多的证据显示新辅助治疗联合手术较单纯手术治疗能明显改善局部进展期食管癌患者的生存,其中新辅助化疗和新辅助放化疗的重要作用已逐步达成共识,并纳入指南推荐。对于局部进展期食管癌,尤其是对于食管腺癌,新辅助化疗和新辅助放化疗都较单纯手术显著改善了患者的生存。两者相比,放疗的参与能否给患者带来更多的获益仍是当前研究的热点。此外,学者一般认为手术在新辅助治疗结束后的2-8周进行,但具体间隔多长时间更为合理,尚无统一定论。本文将就近年来关于局部进展期食管癌术前新辅助治疗的研究进展和存在的问题综述如下。     

A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction

BackgroundNeoadjuvant therapy improves long-term survival after oesophagectomy, treating oesophageal cancer, but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types, chemotherapy (nCT) or chemoradiotherapy (nCRT), is more beneficial. We aimed to compare the effects of nCT with those of nCRT.Patients and methodsThis multicentre trial, which was conducted in Sweden and Norway, recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were candidates for curative-intended treatment. The primary end point was histological complete response after neoadjuvant treatment, which has been shown to be correlated with increased long-term survival. Study participants were randomized to nCT or nCRT, followed by surgery with two-field lymphadenectomy. Three cycles of platin/5-fluorouracil were administered in both arms, whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm.ResultsThe trial met the primary end point, histological complete response being achieved in 28% after nCRT versus 9% after nCT (P = 0.002). Lymph-node metastases were observed in 62% in the nCT group versus 35% in the nCRT group (P = 0.001). The R0 resection rate was 87% after nCRT and 74% after nCT (P = 0.04). There was no difference in overall survival between the treatment arms.ConclusionThe addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate, higher R0 resection rate, and a lower frequency of lymph-node metastases, without significantly affecting survival.clinicaltrials.govNCT01362127 (https://clinicaltrials.gov; The full study protocol was registered in the Clinical Trials Database).     

Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis

BACKGROUND: Resectable oesophageal cancer is often treated with surgery alone or with preoperative (neoadjuvant) chemoradiotherapy or chemotherapy. We aimed to clarify the benefits of neoadjuvant chemoradiotherapy or chemotherapy versus surgery alone by a meta-analysis of randomised trial data. METHODS: Eligible trials were identified first from earlier published meta-analyses and systematic reviews. We also used MEDLINE, Cancerlit, and EMBASE databases to identify additional studies and published abstracts from major scientific meetings since 1980. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios if available or estimates from other survival data or survival curves. Treatment effects by type of tumour and treatment sequencing were also investigated. FINDINGS: Ten randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and eight of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable oesophageal carcinoma were identified. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumour types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those with adenocarcinoma (0.78 [0.64-0.95]; p=0.014). INTERPRETATION: A significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus. The findings provide an evidence-based framework for the use of neoadjuvant treatment in management decisions.     

Surgically treated oesophageal cancer developed in a radiated field: Impact on peri-operative and long-term outcomes

BackgroundThe objectives of this study were to compare peri-operative and long-term outcomes from oesophageal cancer (EC) (i) that arose in a previously radiated field (ECRF) versus primary (PEC) and among ECRF patients and (ii) radiotherapy-induced (RIEC) versus non-radiotherapy–induced EC (NRIEC).MethodsData were collected from 30 European centres from 2000 to 2010. Two thousand four hundred eighty nine EC patients surgically treated were included in the PEC group and 136 in the ECRF group, NRIEC group (n = 61) and RIEC group (n = 75). Propensity score matching analyses were used to compensate for differences in baseline characteristics.ResultsCompared to the PEC group, the ECRF group was characterised by less use of neoadjuvant chemoradiotherapy (0% versus 29.5%; P < 0.001), less pathological stage III/IV (31.6% versus 39.2%, P = 0.036), greater incidence of R1/2 margins (21.3% versus 10.9%; P < 0.001), increased in-hospital mortality (14.0% versus 7.1%; P = 0.003) and overall morbidity (68.4% versus 56.4%, P = 0.006). After matching, 5-year overall (28.8% versus 50.5%; hazard ratio [HR] = 1.53, 95% confidence interval [CI]: 1.15–2.04; P = 0.003) and event-free (32.2% versus 42.5%; HR = 1.56, 95% CI: 1.18–2.05; P = 0.002) survivals were significantly reduced in the ECRF group. There were no significant differences in incidence or pattern of tumour recurrence. Comparing RIEC and NRIEC groups, there were no significant differences in short- or long-term outcomes before and after matching.ConclusionsECRF is associated with poorer long-term survival related to a reduced utilisation of neoadjuvant chemoradiotherapy and an increased incidence of tumour margin involvement at surgery. Outcomes appear to be dictated by the limitations related to previous radiotherapy administration more than the radiotherapy-induced carcinogenesis.     

Vimentin and tumor–stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer

Vimentin expression in tumor tissues and the tumor–stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients [three achieved pathological complete response (pCR), three did not]. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin [odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102–0.602, p = 0.002] and TSR (OR 4.971, 95% CI 1.933–15.431, p = 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-low/TSR-low or vimentin-high/TSR-high (OR 5.211, 95% CI 1.248–35.582, p = 0.042) and vimentin-low/TSR-high groups (OR 11.846, 95% CI 3.197–77.079, p = 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290–63.623, p = 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.     

Robot-assisted versus thoracolaparoscopic oesophagectomy for locally advanced oesophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy

IntroductionRobot-assisted oesophagectomy (RAE) and thoracolaparoscopic oesophagectomy (TLE) are surgical techniques for the treatment of oesophageal cancer. This study aimed to compare the perioperative and mid-term outcomes of RAE versus TLE for patients with locally advanced oesophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (nCRT).MethodsConsecutive patients receiving nCRT plus RAE or TLE were retrospectively included in this single-institution study from January 2016 to January 2021. Perioperative outcomes were compared and survival analysis was performed.ResultsThis study enrolled 251 patients, 80 (31.9%) in RAE and 171 (68.1%) in TLE. The conversion rate was equivalent in RAE versus TLE (3.8% vs 2.9%, P = 1). Median operative time in RAE was significantly shorter than that in TLE (254 vs 289 min, P < 0.001). Compared to TLE, RAE harvested more lymph nodes along the recurrent laryngeal nerve [4 (3–6) vs 3 (1–5), P < 0.001]. Overall complications were similar in RAE compared to TLE (38.8% vs 38.0%, P = 0.911). No statistically significant difference in disease-free survival (log-rank P = 0.721) or overall survival (log-rank P = 0.325) was found between groups.ConclusionsCompared to TLE, RAE could achieve shorter operative duration and better lymph nodes dissection along the bilateral RLN for locally advanced ESCC after nCRT, with comparable short-term outcomes. A long-term survival remains to be verified.     

Role of neoadjuvant chemoradiotherapy in clinical T2N0M0 esophageal cancer: A population-based cohort study

Background

The aim of this population-based cohort study was to determine whether the addition of neoadjuvant chemoradiotherapy (nCRT) to surgery is associated with improved pathologic outcomes and survival in patients with cT2N0M0 esophageal cancer.

Salvage surgery after failed chemoradiotherapy in squamous cell carcinoma of the esophagus

Aims

To investigate the survival benefit and preoperative risk factors for hospital mortality of salvage surgery in esophageal cancer patients who had locoregional residual/recurrent tumor after definitive chemoradiotherapy.

Methods

We retrospectively reviewed the esophageal cancer patients who presented at our hospital from 1997 to 2004. Forty-seven patients who had squamous cell cancer and developed locoregional recurrent/persistent disease after primary definitive chemoradiotherapy were elected. Twenty-seven of them received salvage esophagectomy (group 1) and the other 20 underwent non-operative treatment only (group 2). In order to assess the surgery-related mobility and mortality in group 1, 191 patients who received neoadjuvant chemoradiotherapy followed by operation during the same time period were also enrolled (group 3).

Results

The 5-year overall survival of group 1 patients was 25.4%. In contrast, all of the patients in the group 2 died within 16.7 months. The difference was statistically significant (p = 0.0029). In comparison with group 3, group 1 patients had significantly more surgery-related complications and hospital mortality. In univariate analysis for preoperative risk factors, a low albumin or hemoglobulin level was associated with high hospital mortality in group 1 (p = 0.004 and 0.003, respectively). After multivariate analysis, only the low albumin level remained borderline significance. As for disease specific survival after salvage surgery, R0 resection was the only independent prognosticator (p = 0.049).

Conclusion

Salvage surgery provides survival benefit in esophageal cancer patients with locoregional persistent or recurrent disease after primary definitive chemoradiotherapy. Preoperative albumin and hemoglobulin levels are associated with hospital mortality and may aid in selecting suitable patient for salvage surgery.     

Tumour-stroma ratio to predict pathological response to neo-adjuvant treatment in rectal cancer

IntroductionManagement of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker.MethodsTSR in pre-treatment biopsies was estimated according to the method described by van Pelt et al. The degree of pathological response was assessed on the tumour resection according to tumour regression grading (TRG) by Mandard. The primary endpoint of this study was the difference in pathological response to nCRT between TSR-high and TSR-low groups.ResultsWe found that 26.2% of patients with major response was classified as TSR-high, while 73.8% of patients were classified as TSR-low. A high TSR in pre-treatment biopsies was associated with a lower chance of major-response to nCRT (OR = 0.37, 95%CI; 0.19–0.73), p = 0.004), independent of tumour stage and time between nCRT and surgery.ConclusionIn rectal cancer, TSR in pre-treatment biopsies predicts pathologic response to nCRT, with a high TSR bringing twice the risk of poor to no response compared to low TSR. In future, assessment of TSR may fulfil a role in a therapeutic algorithm identifying patients who will or will not respond to nCRT prior to treatment initiation.     

Breast magnetic resonance imaging use in patients undergoing neoadjuvant chemotherapy is associated with less mastectomies in large ductal cancers but not in lobular cancers

BackgroundTo assess the impact of breast magnetic resonance imaging (MRI) use on surgical outcome per histological breast cancer subtype in patients treated with neoadjuvant chemotherapy.Patients and methodsAll patients aged 18–70 years who underwent neoadjuvant chemotherapy for stage I–III invasive breast cancer in the Netherlands in the years 2011–2013 were identified from the Netherlands Cancer Registry. Patients with cT4 tumours were excluded from the analysis. Use of breast MRI and impact on surgical treatment, resection margins and detection of contralateral breast cancer were analysed by multivariable analyses.ResultsBreast MRI was performed in 2879 (83.9%) out of 3433 patients treated with neoadjuvant chemotherapy. Younger age (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.17–1.71 for 18–50 years compared with 50–70 years), larger tumour stage (OR 1.46 [95% CI 1.15–1.86] for cT3, compared to cT1–2 tumours) and multifocality (OR 1.30; 95% CI 1.04–1.61, versus unifocality) were associated with increased breast MRI use. In ductal breast cancer, after stratification for cT-status, breast MRI use is associated with a significant lower OR for mastectomy as final surgery in cT3 tumours (OR 0.45, 95% CI 0.21–0.99). Resection margin involvement and detection of contralateral breast cancer were not associated with breast MRI use.ConclusionIn patients treated with neoadjuvant chemotherapy, the use of breast MRI was associated with a reduced mastectomy rate, particularly in patients with large invasive ductal breast tumours but not in patients with lobular breast cancer.     

Individualized conditional survival nomograms for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy and radical surgery

BackgroundConditional survival (CS) considers the time already survived after surgery when estimating the survival probability, which may provide further useful prognostic information.ObjectiveTo evaluate CS in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and to create CS nomograms predicting the conditional probability of survival after proctectomy.MethodsConsecutive patients with LARC who received nCRT followed by radical resection between 2011 and 2016 were identified. CS was defined as the probability of surviving y years after already surviving for x years. The formula used for CS was CS(x|y) = S(x + y)/S(x), where S(x) represents the survival at x years. Nomograms were constructed to predict the 5-year conditional overall survival (cOS) and conditional recurrence-free survival (cRFS).ResultsA total of 785 patients were included. The median follow-up time was 65.5 months. The probability of achieving 5-year survival after surgery for cancer increases with additional survival time. Maximum tumor diameter, distance from the anal verge, preoperative CA19-9 level, ypTNM stage and perineural invasion were independent predictors of OS, while maximum tumor diameter, distance from the anal verge, ypTNM stage and perineural invasion were independent risk factors for RFS. The nomograms predicted 5-year cOS and cRFS using these predictors and the time already survived. The online calculator can be accessed at http://www.rectalcancer.top/webcalculator.ConclusionThe proposed nomograms predict survival in patients after surgery, taking the time already survived into account.     

High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?

BackgroundAlthough commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy.Patients and MethodsThe prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence.ResultsSixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16–4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21–4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29–0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32–1.05; P = 0.07).ConclusionsAmong men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals.     

Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: An analysis of outcomes in a randomized trial

PURPOSE: To compare 5 x 5 Gy preoperative radiotherapy with immediate surgery vs. preoperative chemoradiotherapy (50.4 Gy, 5-fluorouracil, leucovorin) with delayed surgery in a randomized trial for cT3-T4 low-lying rectal cancer. Despite the downstaging effect of chemoradiotherapy, similar long-term outcomes were observed in both groups. METHODS: The Cox model was used to evaluate the prognostic value of ypTN ("yp" denotes that pathologic classification was performed after initial multimodality therapy) categories and the surgical margin status in 291 patients. RESULTS: Disease-free survival (DFS) (hazard ratio [HR] 1.05, 95% confidence interval [CI], 0.73-1.51), distant metastases (HR, 1.17; 95% CI, 0.77-1.78), and local control (HR, 1.45; 95% CI, 0.74-2.84) were similar in both arms. The ypN status was the only independent prognostic factor for DFS (p < 0.001). An interaction (p = 0.016) between N stage and the assigned treatment was demonstrated. For ypN-negative patients, DFS was similar in both arms (HR, 0.83, 95% CI, 0.47-1.48); however, for ypN-positive patients, DFS was worse in the chemoradiotherapy arm (HR, 1.73; 95% CI, 1.07-2.77). The 4-year (median follow-up) DFS rate in N-positive patients was 51% in the 5 x 5-Gy arm vs. 25% in the chemoradiotherapy arm. The corresponding 4-year rates for the incidence of local recurrence and distant metastases were 14% vs. 27% (HR, 1.95; 95% CI, 0.78-4.86) and 38% vs. 68% (HR, 2.05; 95% CI, 1.21-3.48). CONCLUSION: N-positive disease after chemoradiotherapy indicates radiochemoresistance. N-positive disease after 5 x 5 Gy RT includes both radiosensitive and radioresistant tumors, because the interval between radiotherapy and surgery was too short for radiosensitive cancer to undergo necrosis. Thus, the greater risk of distant metastases recorded in the chemoradiotherapy arm suggests that radiochemoresistance of nodal metastases from rectal cancer is associated with a high potential for developing distant metastases.     

Salvage radiotherapy in patients with recurrent or refractory primary or secondary central nervous system lymphoma after methotrexate-based chemotherapy

BackgroundTo assess the efficacy of salvage radiation therapy (RT) in patients with recurrent/refractory primary or secondary central nervous system lymphoma (CNSL) after initial methotrexate (MTX)-based chemotherapy and to identify factors associated with treatment outcome.Patients and methodsWe reviewed 36 patients with primary or secondary CNSL who relapsed after MTX therapy and received salvage RT. Primary end points were radiographic response and overall survival (OS).ResultsAfter salvage RT, 18 patients (50%) achieved a complete radiographic response and 6 (17%) achieved a partial response, for an overall response rate of 67% [95% confidence interval (CI) 49% to 81%]. The median OS from start of salvage RT was 11.7 months (range: 0.6–94.7). Patients treated with less than five cycles of MTX before failure had a significantly shorter OS than patients who received five or more cycles (9.2 months versus not reached, P = 0.04). Patients with CNSL limited to brain only had a significantly longer OS than patients with disease in the brain and other central nervous system locations (16.5 versus 4.5 months, P = 0.01).ConclusionSalvage RT is effective for patients with recurrent/refractory primary or secondary CNSL after initial MTX therapy. Having received five or more cycles of MTX before failure and CNSL limited to the brain at relapse are associated with longer OS.     

Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC—Update from PACIFIC

IntroductionIn the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42–65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53–0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study.MethodsPatients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method.ResultsAs of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55–0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses.ConclusionsUpdated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.     

Trimodality Therapy With or Without Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

BackgroundBladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown.Patients and MethodsWe identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan–Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias.ResultsWe identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation.ConclusionThese results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.     

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC—an Update From the PACIFIC Trial

IntroductionIn the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53–0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42–65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.MethodsPatients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan–Meier method.ResultsOverall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2–64.9), updated OS (HR = 0.71; 95% CI: 0.57–0.88) and PFS (HR = 0.55; 95% CI: 0.44–0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.ConclusionThese updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).