E.P.M. Jansen

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).

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.

IMRT limits nephrotoxicity after chemoradiotherapy for gastric cancer

OBJECTIVE This observational study compares the effect of different radiotherapy techniques on late nephrotoxicity after postoperative chemoradiotherapy for gastric cancer. PATIENTS AND METHODS Dosimetric parameters were compared between AP-PA, 3D-conformal and IMRT techniques. Renal function was measured by (99m)Tc-MAG-3 renography, glomerular filtration rate (GFR) and the development of hypertension. Mixed effects models were used to compare renal function over time. RESULTS Eighty-seven patients treated between 2002 and 2010 were included, AP-PA (n=31), 3D-conformal (n=25) and IMRT (n=31), all 45 Gy in 25 fractions. Concurrent chemotherapy: 5FU/leucovorin (n=4), capecitabine (n=37), and capecitabine/cisplatin (n=46). Median follow-up time was 4.7 years (range 0.2-8). With IMRT, the mean dose to the left kidney was significantly lower. Left kidney function decreased progressively in the total study population, however with IMRT this occurred at a lower rate. A dose-effect relationship was present between mean dose to the left kidney and the left kidney function. GFR decreased only moderately in time, which was not different between techniques. Six patients developed hypertension, of whom none in the IMRT group. CONCLUSIONS This study confirms progressive late nephrotoxicity in patients treated with postoperative chemoradiotherapy by different techniques for gastric cancer. Nephrotoxicity was less severe with IMRT and should be considered the preferred technique.

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.

Radiation-induced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer.

BACKGROUND AND PURPOSE Abdominal (chemo-)radiotherapy is associated with dose-limiting toxicity of various normal structures. The purpose of this retrospective study was to investigate radiation-induced changes of the spleen and their clinical consequences. PATIENTS AND METHODS In gastric cancer patients treated with postoperative chemoradiotherapy, the spleen size and its functions were assessed at follow-up by spleen volume on CT-scan, serum leucocytes/thrombocytes, and the occurrence of infectious events consisting of pneumonia and fatal sepsis. To evaluate the effect of radiation dose, mixed effects and Cox regression models were used. RESULTS Forty-six out of 90 consecutive patients treated from 2006 to 2011 were evaluable. All patients received 45 Gy in 25 fractions with concurrent capecitabine (n=8), and capecitabine/cisplatin (n=38). Median Dmean to the spleen was 40 Gy (range 32-46). Mean relative spleen volume reduced to 37% (95% CI 32-42%) at 4-year follow-up, which was most strongly associated to the V44 (p<0.001). Median follow-up time was 67 (95% CI 57-78) months. Eleven patients had 13 pneumonias and 3 fatal sepsis. No association with dosimetric parameters was observed. CONCLUSIONS In postoperative chemoradiotherapy for gastric cancer, the spleen received a high radiation dose. This resulted in a progressive, radiation dose-dependent reduction of spleen volume. Pneumonia and fatal sepsis occurred frequently, possibly as a result of functional hyposplenia.

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

BackgroundPreoperative 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.MethodsQuality 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.ResultsBetween 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).ConclusionSurgical 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

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.