Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial.

PURPOSE: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Effect of Neoadjuvant Chemoradiotherapy on Health-Related Quality of Life in Esophageal or Junctional Cancer: Results From the Randomized CROSS Trial.

Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and -Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen's d: -0.93, P < .001; 0.47, P < .001; -0.84, P < .001; 1.45, P < .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen's d: -1.00, 0.33, -0.47, -0.34, and 0.33, respectively; all P < .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen's d: 0.52 and -0.53, respectively; both P < .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study-regimen can be regarded as a standard of care.

Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.

BACKGROUND: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. METHODS: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. FINDINGS: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1-116·8, IQR 70·7-96·6), median overall survival was 48·6 months (95% CI 32·1-65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2-33·7) in the surgery alone group (HR 0·68 [95% CI 0·53-0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2-116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4-26·7) in the surgery alone group (HR 0·48 [95% CI 0·28-0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9-61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0-41·2) in the surgery alone group (HR 0·73 [95% CI 0·55-0·98]; log-rank p=0·038). INTERPRETATION: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

OBJECTIVES: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. BACKGROUND: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. METHODS: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. RESULTS: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). CONCLUSIONS: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials.

PURPOSE: To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS: Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS: Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION: Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Brachytherapy versus cystectomy in solitary bladder cancer: a case control, multicentre, East-Netherlands study.

PURPOSE: Comparing the outcome of surgery and brachytherapy-based radiotherapy in patients with solitary T1G3/T2 bladder tumour in, a retrospective case-control study, because efforts for a randomised clinical trial comparing these modalities have failed. MATERIALS AND METHODS: Cystectomy group. Patients were selected using the pathological registration system (PALGA). 289 cases of TURT followed by cystectomy, indicated by a muscle--invading bladder tumour were performed in three East-Netherlands medical centres between 1991 and 2001. Out of this group 179 patients with clinical T2N0M0 bladder tumour were selected. All the consecutive files were analysed by a urologist and a radiation oncologist and 65 of those patients (mean age 63.7 years) would have been eligible for brachytherapy, based on an initial analysis: cystoscopy estimated tumour size, post-TURT pathological report, completed by CT-scan and/or, MRI-scan. A final pathological report after radical cystectomy was not considered for patients' selection. Brachytherapy group. Patients were selected using a prospective registration study aiming at determination of our treatment results. 89 Patients (mean age 68.4 years) underwent TURT followed by a course of external beam irradiation and interstitial brachytherapy from 1983 till 2005 in the Arnhem Radiotherapy Institute. RESULTS: The median follow-up for the brachytherapy group was 5.7 years (range 0.2-21.4 years), for the cystectomy group was 5.05 years (range: 0.04-16.8 years). No difference in disease-specific survival (DSS) could be detected with a 5- and 10-year DSS of 71% and 66% in the brachytherapy group and 60% and 57% in the cystectomy group, respectively. Five-year overall survival (OS) was 57% in the brachytherapy group and 52% in the cystectomy group, however, the 10-year OS was better in the cystectomy than in the brachytherapy group (42% and 33%, respectively). This is caused by the significant age difference in favour of the cystectomy group. Cystectomy-free survival in the brachytherapy group was 70%. CONCLUSION: Radical cystectomy is the treatment of choice for patients with muscle-invasive bladder carcinoma. However, in a selected patient population a bladder sparing treatment, i.e. a combination of transurethral tumour resection (TURT), external beam irradiation and interstitial brachytherapy, can be applied successfully. This concerns a solitary, T1G3 or T2 bladder tumour, with a diameter<5 cm.

Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial.

BACKGROUND: Both single-dose brachytherapy and self-expanding metal stent placement are commonly used for palliation of oesophageal obstruction due to inoperable cancer, but their relative merits are unknown. We undertook a randomised trial to compare the outcomes of brachytherapy and stent placement in patients with oesophageal cancer. METHODS: Nine hospitals in the Netherlands participated in our study. Between December, 1999, and June, 2002, 209 patients with dysphagia from inoperable carcinoma of the oesophagus or oesophagogastric junction were randomly assigned to stent placement (n=108) or single-dose (12 Gy) brachytherapy (n=101), and were followed up after treatment. Primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, health-related quality of life, and costs. Analysis was by intention to treat. FINDINGS: Nine patients (six [brachytherapy] vs three [stent placement]) did not receive their allocated treatments. None was lost to follow-up. Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (36 [33%] of 108 vs 21 [21%] of 101; p=0.02), which was mainly due to an increased incidence of late haemorrhage (14 [13%] of 108 vs five [5%] of 101; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Quality-of-life scores were in favour of brachytherapy compared with stent placement. Total medical costs were also much the same for stent placement (8215) and brachytherapy (8135). INTERPRETATION: Despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, we recommend it as the primary treatment for palliation of dysphagia from oesophageal cancer.

Saving bladders with brachytherapy: implantation technique and results.

PURPOSE: To analyze and report the treatment results of brachytherapy for solitary bladder cancer in the Arnhem Radiotherapy Institute. METHODS AND MATERIALS: Between January 1983 and October 1998, 63 patients with a solitary bladder tumor were treated with a combination of transurethral resection, external beam radiotherapy (EBRT), and interstitial radiotherapy. The indications for bladder-conserving treatment were tumor < or =5 cm, T1G3 (n = 14), T2G2 (n = 8), T2G3 (n = 37), and T3a (n = 4). The prescribed implant dose was either 55 Gy (range 50-65 Gy) in combination with small pelvis external beam RT, 3-4 fractions of 3.5 Gy (n = 58), or 30 Gy in combination with 20 fractions of 2 Gy external beam radiotherapy (n = 5). Brachytherapy was performed with 2-8 137Cs needles until 1995 (n = 48) and 2-5 afterloading catheters (192Ir) since 1996 (n = 15). Follow-up cystoscopies were performed at 3-month intervals during the first 2 years, then every 6 months for 3 years, and annually after the fifth year. The median follow-up was 4.9 years. RESULTS: Twenty patients developed local recurrences, of which 6 were "true in-implant recurrences," 12 were in second bladder locations, and 2 were urethral recurrences. All recurrences developed within 2.5 years after treatment. Of these 20 patients, 13 underwent cystectomy: 6 stayed disease-free, 1 died of postoperative complications, 2 developed regional metastases, and 4 developed distant metastases. The 5-year disease-specific survival rate was 80% for patients with Stage T1 and 60% for those with Stage T2 disease. The local control rate was 70% in the whole patient population and 80% after salvage cystectomy. Forty-four bladders were saved. Acute complications were seen in 14 patients, and no significant late complications occurred. CONCLUSION: Using this treatment technique, a high cure rate with conservation of the bladder and only minor toxicity can be obtained in a selected patient population having a solitary tumor < or =5 cm.