Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial.

BACKGROUND: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. PATIENTS AND METHODS: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. RESULTS: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. CONCLUSION: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

Impact of upfront randomization for postoperative treatment on quality of surgery in the CRITICS gastric cancer trial.

BACKGROUND: Preoperative randomization for postoperative treatment might affect quality of surgery. In the CRITICS trial (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach), patients were randomized before treatment to receive chemotherapy prior to a D1 + gastrectomy (removal of lymph node station (LNS) 1-9 + 11), followed by either chemotherapy (CT) or chemoradiotherapy (CRT). In this analysis, the influence of upfront randomization on the quality of surgery was evaluated. METHODS: Quality of surgery was analyzed in both study arms using surgicopathological compliance (removal of ≥ 15 lymph nodes), surgical compliance (removal of the indicated LNS), and surgical contamination (removal of LNS that should be left in situ). Furthermore, the 'Maruyama Index of Unresected disease' (MI) was evaluated in both study arms, and validated with overall survival. RESULTS: Between 2007 and 2015, 788 patients with gastric cancer were included in the CRITICS study of which 636 patients were operated with curative intent. No difference was observed between the CT and CRT group regarding surgicopathological compliance (74.8% vs 70.9%, P = 0.324), surgical compliance (43.2% vs 39.2%, P = 0.381), and surgical contamination (59.4% vs 59.9%, P = 0.567). Median MI was 1 in both groups (range CT 0-88 and CRT 0-136, P = 0.700). A MI below 5 was associated with better overall survival (CT: P = 0.009 and CRT: P = 0.013). CONCLUSION: Surgical quality parameters were similar in both study arms in the CRITICS gastric cancer trial, indicating that upfront randomization for postoperative treatment had no impact on the quality of surgery. A Maruyama Index below five was associated with better overall survival.

Association between hospital volume and quality of gastric cancer surgery in the CRITICS trial.

BACKGROUND: Studies investigating the association between hospital volume and quality of gastric cancer surgery are lacking. In the present study, the effect of hospital volume on quality of gastric cancer surgery was evaluated by analysing data from the CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. METHODS: Patients who underwent gastrectomy with curative intent in the Netherlands were selected from the CRITICS trial database. Annual hospital volume of participating centres was derived from the Netherlands Cancer Registry. Hospital volume was categorized into very low (1-10 gastrectomies per year per institution), low (11-20), medium (21-30) and high (31 or more), and linked to the CRITICS database. Quality of surgery was analysed by surgicopathological compliance (removal of at least 15 lymph nodes), surgical compliance (removal of indicated lymph node stations) and the Maruyama Index. Postoperative morbidity and mortality were also compared between hospital categories. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS study, of whom 494 were analysed. Surgicopathological compliance was higher (86·7 versus 50·4 per cent; P < 0·001), surgical compliance was greater (52·9 versus 19·8 per cent; P < 0·001) and median Maruyama Index was lower (0 versus 6; P = 0·006) in high-volume hospitals compared with very low-volume hospitals. There was no statistically significant difference in postoperative complications or mortality between the hospital volume categories. CONCLUSION: Surgery performed in high-volume hospitals was associated with better surgical quality than surgery carried out in lower-volume hospitals.

Adjuvant Chemoradiotherapy for Non-Pretreated Gastric Cancer.

BACKGROUND: While the curative approach to gastric cancer includes perioperative regimens in several countries, a substantial proportion of patients may not receive treatment prior to surgery. This study examines the adjuvant provision of chemoradiotherapy (CRT) for non-pretreated patients with cancer of the stomach including the gastric cardia. METHODS: All surgically treated patients with primary adenocarcinoma of the stomach and gastric cardia diagnosed between January 2004-December 2013 were selected from the Netherlands Cancer Registry. Patients who did not receive neoadjuvant treatment were included. Early gastric cancers (cT1), postoperative deaths within 90 days, patients with metastatic disease (M1), patients who received adjuvant chemotherapy and patients with macroscopic tumor after surgery (R2) were excluded. RESULTS: Some 3277 patients underwent surgery, and 99 patients (3%) received adjuvant CRT. Treatment was more often administered in patients with a younger age (<65 years) and a high socioeconomic status (SES), in case of non-cardia cancer, positive lymph nodes, and positive resection margins (R1). Median survival time was 28 months (95% CI 17-39), compared to 35 months (95% CI 33-38) in CRT-naïve patients. After adjustment for confounders, a small net benefit for adjuvant CRT was found (hazard ratio, HR: 0.75, 95% CI 0.58-0.96). In subgroup analyses, benefit was most pronounced for patients with seven or more lymph metastases. CONCLUSIONS: Marginal survival benefit was observed for adjuvant CRT in gastric cancer patients who did not receive neoadjuvant treatment. Treatment could be considered for patients with disease involving nodal invasion and those left with microscopic residual disease after surgery.

Technical feasibility and clinical evaluation of 4D-MRI guided liver SBRT on the MR-linac.

PURPOSE: Image-guided stereotactic body radiation therapy (SBRT) is an important local treatment for liver metastases. MRI-guidance enables direct tumor visualization, eliminating fiducial marker implantation. The purpose of this study was to test technical feasibility of our 4D-MRI guided liver SBRT workflow. Additionally, intra-fraction target motion and consequent target-coverage were studied. MATERIALS & METHODS: Patients with liver metastases were included in this sub-study of the prospective UMBRELLA-II clinical trial. Patients received mid-position (midP) SBRT. The daily adapt-to-position workflow included localization, verification and intra-fraction tumor midP monitoring using 4D-MRI. Technical feasibility was established based on persistence of the treatment protocol, treatment time ≤1 h, no geographical miss and no unexpected acute toxicity grade >3. All 4D-MRIs were registered to the planning midP-CT and tumor midP and amplitude were calculated. Additionally, delivered target dose was accumulated incorporating the 4D-MRI intra-fraction tumor motion and evaluated with Monte-Carlo error simulations. RESULTS: 20 patients with liver metastases were included and treated with 4D-MRI guided SBRT. Feasibility criteria were met in all-but-one patient. No grade ≥3 acute toxicity was observed. Group mean (M), systematic and random midP-drifts were 2.4 mm, 2.6 mm and 3.1 mm in CC-direction. 4D-MRI tumor CC-amplitudes were reduced compared to the simulation 4D-CT (M = -1.9 mm) and decreased during treatment (M = -1.4 mm). Dose accumulation showed adequate target-coverage on a population level. CONCLUSION: We successfully demonstrated technical feasibility of 4D-MRI guided SBRT in a cohort of 20 patients with liver metastases. However, substantial midposition drifts occurred which stress the need for intra-fraction motion management strategies to further increase the precision of treatment delivery.

Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy.

BACKGROUND: Postoperative chemoradiotherapy with concurrent 5-fluorouracil improves gastric cancer outcome. We previously demonstrated that chemoradiotherapy with a more intensified--and therefore potentially more effective--schedule with daily cisplatin and oral capecitabine is feasible. Because such an intensive schedule requires an extensive logistic infrastructure which is not available in every hospital, we additionally investigated the tolerability of this combined regimen with weekly instead of daily cisplatin in a dose-escalation study. PATIENTS AND METHODS: After R0 or R1 resection, treatment initiated with capecitabine 1000 mg/m(2) b.i.d. for 2 weeks and 1-week rest. Subsequently, patients received capecitabine (575-650 mg/m(2) orally b.i.d., 5 days/week) and cisplatin (20-25 mg/m(2) i.v., once weekly) according to a predefined dose-escalation schedule concurrent with radiation. Radiotherapy was given to a fixed total dose of 45 Gy in 25 fractions. RESULTS: Thirty-one patients were eligible and started treatment. During chemoradiotherapy, seven patients developed 10 items of grade III and one episode of grade IV (mainly hematological) toxicity (National Cancer Institute-Common Toxicity Criteria version 3.0). The maximum tolerable dose was determined to be for cisplatin 20 mg/m(2) i.v. weekly and for capecitabine 575 mg/m(2) b.i.d. orally. CONCLUSIONS: This phase I-II study demonstrated that postoperative chemoradiotherapy with weekly cisplatin and daily capecitabine is feasible in gastric cancer at the defined dose level. This schedule is currently being tested as the experimental arm in a phase III multicenter study (CRITICS: chemoradiotherapy after induction chemotherapy in cancer of the stomach; Clinicaltrials.gov NCT 00407186).

MRI-guided mid-position liver radiotherapy: Validation of image processing and registration steps.

BACKGROUND & PURPOSE: To propose a novel mid-position (midP) workflow for MRI-guided liver SBRT and provide a validation of the required midP-MRI generation and registration steps. MATERIALS & METHODS: The first step of the midP workflow is the generation of a simulation midP-MRI from a 4D-MRI scan using deformable image registration. Next, a planning midP-CT is warped to the midP-MRI to enable planning in the midP-MRI anatomy. For daily MRI-guidance, three different registration methods to the simulation midP-MRI are proposed; (1) 4D rigid registration of all phases of the daily 4D-MRI, (2) 3D rigid registration of the daily midP-MRI, and (3) 3D deformable registration of the daily midP-MRI. The midP-MRI image quality was assessed with respect to 4D-MRI acquisition time, which is related to over-sampling of the data acquisition (i.e. number of dynamics). The deformable registration precision for the midP-MRI generation was validated using the distance discordance metric (DDM). The deformable CT-MRI and daily MRI-MRI registration accuracies were quantified using the 'full circle method'. RESULTS: The DDM was 1.5 mm (median) within the liver, independent of the number of dynamics. The root-mean-squared difference between midP-MRIs based on 10 and 60 dynamics was only 5.2%. The full circle CT-MRI deformable registration error had a median 3D vector length of 1.8 mm in the liver. The daily MRI-MRI registration error was submillimeter for all three evaluated methods. CONCLUSION: The feasibility of an MRI-guided mid-position workflow for liver SBRT is supported by the demonstrated high precision of all image processing and registration steps.

Surgical morbidity and mortality after neoadjuvant chemotherapy in the CRITICS gastric cancer trial.

BACKGROUND: In order to determine the optimal combination of perioperative chemotherapy and chemoradiotherapy for Western patients with advanced resectable gastric cancer, the international multicentre CRITICS trial (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) was initiated. In this trial, patients with resectable gastric cancer were randomised before start of treatment between adjuvant chemotherapy or adjuvant chemoradiotherapy following neoadjuvant chemotherapy plus gastric cancer resection. The purpose of this study was to report on surgical morbidity and mortality in this trial, and to identify factors associated with surgical morbidity. METHODS: Patients who underwent a gastrectomy with curative intent were selected. Logistic regression analyses were used to assess risk factors for developing postoperative complications. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS trial, of whom 636 patients were eligible for current analyses. Complications occurred in 296 patients (47%). Postoperative mortality was 2.2% (n = 14). Complications due to anastomotic leakage was cause of death in 5 patients. Failure to complete preoperative chemotherapy (OR = 2.09, P = 0.004), splenectomy (OR = 2.82, P = 0.012), and male sex (OR = 1.55, P = 0.020) were associated with a greater risk for postoperative complications. Total gastrectomy and oesophago-cardia resection were associated with greater risk for morbidity compared with subtotal gastrectomy (OR = 1.88, P = 0.001 and OR = 1.89, P = 0.038). CONCLUSION: Compared to other Western studies, surgical morbidity in the CRITICS trial was slightly higher whereas mortality was low. Complications following anastomotic leakage was the most important factor for postoperative mortality. Important proxies for developing postoperative complications were failure to complete preoperative chemotherapy, splenectomy, male sex, total gastrectomy, and oesophago-cardia resection.

The essentials of locoregional control in the treatment of gastric cancer.

Gastric cancer is the fourth most frequent cancer in the world. For curative treatment and local control of gastric cancer, surgery is essential. The extent of the lymph node dissection is still under debate. Only one available trial showed significantly increased overall survival, whereas in all other randomised trials no significant difference could be found. As surgery alone often is not sufficient in the curative treatment in gastric cancer, different (neo)adjuvant treatment strategies have extensively been studied. The recently published MAGIC trial showed downstaging, downsizing and an improved overall survival for patients treated with perioperative chemotherapy, compared to surgery alone (difference 13%, p = 0.009). The INT 0116 trial on the other hand, demonstrated the benefit of postoperative chemoradiotherapy compared to surgery alone for patients with a curative resection of gastric cancer. However, the quality of resections in this trial was poor, illustrating the importance of standardisation by quality control. This could be done by the Maruyama index, which quantifies the likelihood of unresected disease. In the Netherlands, the CRITICS trial has recently been launched, which will be a quality controlled trial comparing postoperative chemoradiotherapy and chemotherapy on survival and/or locoregional control in patients who receive neoadjuvant chemotherapy followed by a D1+ gastric resection.

[New insights in the adjuvant treatment of gastric cancer]. / Nieuwe inzichten in de adjuvante behandeling van het maagcarcinoom.

The current standard treatment of patients with gastric cancer is partial or total stomach resection and dissection of the draining lymph nodes. This approach, however, results in a rather low survival rate, partly because the diagnosis is often established in an advanced stage. Various strategies, including adjuvant radiotherapy, chemotherapy or more extensive surgical procedures, have resulted mainly in increased morbidity without improving survival. In a recent randomised trial, concurrent postoperative radiotherapy and chemotherapy prolonged survival and reduced the chance of a local recurrence at an acceptable toxicity. Although several aspects of combined radiochemotherapy require further study, this new treatment concept appears to be a promising addition to the therapeutic arsenal for gastric cancer.

Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach?

AIM: To study the outcome of patients who were surgically treated for primary gastric cancer with specific attention to differences in treatment results for intestinal and diffuse type tumours. METHODS: All patients who underwent a potentially curative gastric resection between 1995 and 2011 in our institute were included. Patient, tumour and treatment characteristics were obtained retrospectively. Binary logistic and Cox regression models were used for multivariate analysis. RESULTS: A consecutive series of 132 patients was included. Median follow-up was 53 months. There were no significant differences between patients with intestinal (N = 62) versus diffuse type (N = 70) gastric cancer with regard to the proportion of patients who underwent (neo)adjuvant treatment. Postoperative mortality was 2%. Pathological T- and N-stage were significantly more advanced for patients with diffuse type tumours. There was a significant difference in the percentage of microscopically irradical resections (2% versus 24%, p < 0.001) and median overall survival (129 versus 17 months, p < 0.001) between patients with intestinal type tumours and those with diffuse type tumours. On multivariate analysis, diffuse type histology was the only factor significantly associated with an R1 resection. In a multivariate Cox regression model, diffuse type histology was a significant adverse prognostic factor for overall survival. CONCLUSIONS: Striking differences were found between patients with diffuse type tumours and those with intestinal type tumours. These differences call for a differentiated approach in the potentially curative treatment of these two tumour types.

Postoperative chemoradiotherapy in gastric cancer -- a Phase I/II dose-finding study of radiotherapy with dose escalation of cisplatin and capecitabine chemotherapy.

We hypothesised that gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy. This phase I/II study was performed to determine the maximal tolerated dose (MTD) and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabine. Patients were treated with capecitabine 1000 mg m(-2) twice a day (b.i.d.) for 2 weeks. Subsequently, patients received capecitabine (250-650 mg m(-2) orally b.i.d., 5 days week(-1)) and cisplatin (3-6 mg m(-2) i.v., 5 days week(-1)) according to an alternating dose-escalation schedule. Radiotherapy was given to a total dose of 45 Gy in 25 fractions. Thirty-one patients completed treatment. During chemoradiotherapy, eight patients developed nine items of grade III and one episode of grade IV (mainly haematological) toxicity. The MTD was determined to be cisplatin 5 mg m(-2) i.v. and capecitabine 650 mg m(-2) b.i.d. orally. This phase I/II study demonstrated that chemoradiotherapy with daily cisplatin and capecitabine is feasible in postoperative gastric cancer at the defined dose level and is currently being tested in a phase III multicenter study.