[Show abstract][Hide abstract] ABSTRACT: For gastric cancer patients, surgical resection with en-bloc lymphadenectomy is the cornerstone of curative treatment. Open gastrectomy has long been the preferred surgical approach worldwide. However, this procedure is associated with considerable morbidity. Several meta-analyses have shown an advantage in short-term outcomes of laparoscopic gastrectomy compared to open procedures, with similar oncologic outcomes. However, it remains unclear whether the results of these Asian studies can be extrapolated to the Western population. In this trial from the Netherlands, patients with resectable gastric cancer will be randomized to laparoscopic or open gastrectomy.
The study is a non-blinded, multicenter, prospectively randomized controlled superiority trial. Patients (≥18 years) with histologically proven, surgically resectable (cT1-4a, N0-3b, M0) gastric adenocarcinoma and European Clinical Oncology Group performance status 0, 1 or 2 are eligible to participate in the study after obtaining informed consent. Patients (n = 210) will be included in one of the ten participating Dutch centers and are randomized to either laparoscopic or open gastrectomy. The primary outcome is postoperative hospital stay (days). Secondary outcome parameters include postoperative morbidity and mortality, oncologic outcomes, readmissions, quality of life and cost-effectiveness.
In this randomized controlled trial laparoscopic and open gastrectomy are compared in patients with resectable gastric cancer. It is expected that laparoscopic gastrectomy will result in a faster recovery of the patient and a shorter hospital stay. Secondly, it is expected that laparoscopic gastrectomy will be associated with a lower postoperative morbidity, less readmissions, higher cost-effectiveness, better postoperative quality of life, but with similar mortality and oncologic outcomes, compared to open gastrectomy. The study started on 1 December 2014. Inclusion and follow-up will take 3 and 5 years respectively. Short-term results will be analyzed and published after discharge of the last randomized patient.
BMC Cancer 12/2015; 15(1):556. DOI:10.1186/s12885-015-1551-z · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Current guidelines indicate that D2 resection is the standard of care for patients with locally advanced gastric cancer. To assess the impact of quality assurance of lymph node removal, non-compliance and contamination in the D1 and D2 study arms of the Dutch Gastric Cancer Trial were investigated with respect to recurrence and survival.
The location and numbers of lymph nodes detected at pathological investigation in the Dutch Gastric Cancer Trial were compared according to the guidelines of the Japanese Research Society for the study of Gastric Cancer. Non-compliance was defined as inadequate removal of lymph node stations. Contamination was defined as lymph nodes removed outside the intended level of resection. The dissection groups D1 and D2 were divided into non-compliance, compliance and contamination categories. Long-term overall survival was calculated for minor (2 or fewer lymph nodes) and major (more than 2 lymph nodes) non-compliance and contamination in the D1 and D2 group, using Kaplan-Meier plots.
Some 1078 patients were included, of whom 711 with potentially curative surgical resections were evaluated. Overall non-compliance was 80·5 per cent in the D1 and 81·6 per cent in the D2 group. Major non-compliance occurred in 15·3 per cent of the D1 and 26·0 per cent of the D2 group. Major contamination hardly occurred. Overall 15-year survival rates in the randomized groups were 21·2 per cent (D1) and 29·0 per cent (D2) (P = 0·351). After exclusion of patients with major non-compliance and/or major contamination, survival rates were 23·2 per cent (319 patients) and 32·6 per cent (245) respectively (P = 0·261). Where there was major non-compliance, survival rates in the D1 (58 patients) and D2 (86) groups were 10 and 17 per cent respectively (P = 0·302). Survival in the D2 compliant + contaminated group (139 patients) was significantly better than that in the D1 group without contamination (282): 35·7 versus 19·9 per cent (P = 0·041). In the D2 group, there was a significant difference in survival between contaminated (95 patients) and non-contaminated (236) groups: 39 versus 25·1 per cent (P = 0·041).
Non-compliance in the D2 dissection group may have obscured a significant difference in survival between the randomized groups. A D2 dissection with contamination was associated with the best survival, suggesting that extended D2 lymph node dissections improve survival.
British Journal of Surgery 08/2015; 102(11). DOI:10.1002/bjs.9891 · 5.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting.
Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II).
A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases.
Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.
[Show abstract][Hide abstract] ABSTRACT: After surgical treatment of high-grade soft tissue sarcomas, local recurrences, metastases and survival remain a great concern. Further knowledge on factors with a possible impact on these endpoints, specifically resection margins, is relevant for decision-making regarding the aggressiveness of local treatment. The aim of this study is to investigate the impact of prognostic factors on local recurrence and overall survival for patients with high-grade soft tissue sarcomas of the extremities.
In a retrospective cohort study of 127 patients (mean age 48 years, range five to 91; median follow-up 71 months) the prognostic effect of margin status and other clinicopathologic characteristics on local recurrence and overall survival were analysed by employing a multivariate Cox regression.
Five-year cumulative incidence of local recurrence and distant metastases was 26 % and 40 %, respectively. The estimated five-year overall survival was 59 %. Tumour size proved a consistent adverse prognostic factor for local recurrence (hazard ratio (HR) 3.9), distant metastasis (HR 4.9) and overall survival (HR 2.4). The significant association of resection margins with local recurrence (HR 10.2) was confirmed. Margins were however not significantly associated with the occurrence of distant metastasis or overall survival. The occurrence of local recurrence had a significant impact on overall survival (HR 2.0).
The results of this study confirm the critical role of tumour size on survival and margins on local recurrence, and stress the need for further investigation concerning the association between margins, local recurrence and survival.
International Orthopaedics 03/2015; 39(5). DOI:10.1007/s00264-015-2694-x · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pathologic staging of oncologic specimens includes the identification of the accurate lymph node status. Retrieving more lymph nodes leads to a more reliable N0 status in the TNM classification. The aim of this prospective study was to evaluate whether more lymph nodes can be retrieved from oncologic resection specimens when more time is invested in the search and if this contributes to a more reliable N-status in the individual patient. A total of 67 gastrointestinal oncologic specimens were reexamined for additional lymph nodes. The mean number of lymph nodes collected in the prospective group was compared against two retrospective groups, one before minima for lymph node counts were set (retrospective group 1) and one after (retrospective group 2). More lymph nodes were dissected per specimen in the prospective group (24.1 lymph nodes), compared to the retrospective group (14.3 lymph nodes, P = <0.001). During the study period, more patients were diagnosed as pN+ compared to the two retrospective groups (62.7 vs. 47.8 % respectively, P = 0.082). Significantly more lymph nodes can be found in oncologic specimens when more time is invested in the search. This will result in more accurate staging of the tumor.
Journal of Gastrointestinal Surgery 02/2015; 19(5). DOI:10.1007/s11605-015-2764-9 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Japanese Research Society for Gastric Cancer has defined 16 lymph node stations surrounding the stomach, and developed different types of lymphadenectomy. In several randomized studies, the extent of lymph node dissection in gastric cancer has been studied, and based on these trials both Asian and Western guidelines now recommend a D2 lymph node dissection for advanced gastric cancer. In the majority of these studies, distal pancreatectomy and splenectomy were associated with increased morbidity and mortality, and therefore these procedures are not recommended to perform routinely. As outcomes after gastrectomy are strongly dependent on surgical quality, both centralization of surgery and auditing programs are used to improve outcomes on a national level.
[Show abstract][Hide abstract] ABSTRACT: Women at hereditary increased risk of breast cancer are subjected to frequent clinical breast examination (CBE) and radiological evaluation of the breasts. This review appraises the additional cancer yield by CBE in screening of women at increased risk of breast cancer who are also subjected to frequent radiological evaluation. A literature search was conducted to identify all prospective studies on the additional value of CBE in screening of women at increased risk of breast cancer. Quality appraisal of included studies was performed using the QUADAS-2 tool. A total of 514 citations were identified. Relevant literature was scarce and highly heterogeneous. Seven prospective studies were included for review of which two studies reported additional cancer yield of CBE (3 and 5 % of total cancer cases). These two studies reported lower screen detection (77 and 80 %) compared to the studies in which no additional cases were detected by CBE (screen detection ≥94 %). Current literature on CBE in screening of women at increased risk of breast cancer is insufficient. However, it suggests that the additional cancer yield by performing CBE is minimal or absent. Reconsideration of the role of CBE in intensified screening might be warranted.
Breast Cancer Research and Treatment 08/2014; 147(1). DOI:10.1007/s10549-014-3074-8 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim
To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose.
Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival.
Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150mg oxaliplatin. The areas under the concentration-time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100mg oxaliplatin ranged from 11.9 mg/L x h to 16.5 mg/L x h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP.
In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.
European Journal of Surgical Oncology 07/2014; 40(11). DOI:10.1016/j.ejso.2014.06.010 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The extent of surgery for gastric cancer has been debated since Billroth performed his first gastrectomy in 1881. This review gives an overview of the available literature on the extent of gastrectomy and lymphadenectomy for advanced resectable gastric cancer. Subtotal gastrectomy is associated with lower morbidity and mortality compared with total gastrectomy, without compromising long-term survival. However, a positive resection margin decreases the chance of curation. Frozen section examination may prevent this. For poorly differentiated singlet ring cell tumors, there may be an argument to perform a total gastrectomy in all cases. In 1981, the Japanese Research Society for the Study of Gastric Cancer provided guidelines for the standardization of surgical treatment and pathological evaluation of gastric cancer. Since then, D2 lymph node dissections have become the standard of care in Japan. Because of the superior stage-specific survival rates in Japan, a D2 dissection was evaluated in several Western randomized controlled trials, but no survival benefit was found for a D2 over a D1 dissection. This might be explained by the increased mortality in the D2 dissection groups which might be the result of a standard pancreaticosplenectomy and low experience with D2 dissections. Adding the removal of the para-aortic nodes to a D2 dissection does not further improve survival. The removal of lymph node stations 10 and 11 by splenectomy showed an increased morbidity, no survival benefit, and a very poor prognosis if lymph nodes were affected. Therefore, pancreaticosplenectomy should only be performed in cases of tumor invasion into these organs. A D2 dissection without routine splenectomy and pancreatic tail resection in experienced hands should be considered standard of care for advanced resectable gastric cancer, both in Asian and in Western patients. Centralization and auditing may further improve outcomes after gastrectomy.
Digestive surgery 07/2013; 30(2):96-103. DOI:10.1159/000350873 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In May 2009, a new clinical practice guideline for gastric cancer was released in the Netherlands. To determine the impact of this guideline, we evaluated trends in patterns of care, thereby focusing on the use of perioperative chemotherapy, the adequacy of lymphadenectomy and the proportion of non-curative resections. For our evaluation, we retrospectively collected information from the Netherlands Cancer Registry on 2,511 patients diagnosed with primary adenocarcinoma of the stomach during the period July 2008-June 2010, excluding tumors of the cardia. After comparing clinical management for patients diagnosed from July 2008 to June 2009 with that for patients diagnosed from July 2009 to June 2010, we conclude that our indicators for guideline adherence did not show major change, except for the proportion of patients that received an adequate lymphadenectomy (examination of ≥10 lymph nodes), which increased from 49% to 58% (p = 0.005), this increase being more pronounced for high-volume hospitals (p = 0.006). Preoperative chemotherapy was given in 45% of patients and 25% of resections was non-curative. For the total study population, the resection rate was 41% and 30-day mortality was 5.7%. However, this measure may underestimate the real operative risk for gastric cancer patients given supplementary information on postdischarge death and prolonged hospital stay.
International Journal of Cancer 03/2013; 132(5). DOI:10.1002/ijc.27718 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS: Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas. METHODS: Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression-free and overall survival. RESULTS: The patients underwent surgery after a median of 8 (range 1-55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2-30) cm and reduced to 6.2 (range 1-20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease. CONCLUSIONS: Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 10/2012; 39(2). DOI:10.1016/j.ejso.2012.09.004 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To evaluate long-term local control, survival, radiation side effects and functional outcome after limb-sparing surgery followed by postoperative radiotherapy (RT) for soft tissue sarcoma (STS).
Material and methods:
Between 1995 and 2010, 118 patients with STS of an extremity were treated with limb-sparing surgery and postoperative RT. Follow-up was complete for all patients. Acute and late radiation related toxicities were scored using CTCAE v4.0.
Median follow-up was 93 months. RT dose was 60 Gy in 92.4% of the patients; 5.1% received 66 Gy; 2.5% 50-56 Gy. Actuarial local recurrence rates at five and 10 years were 9% and 12%. Five- and 10-year overall survival rates were 69% and 51%. Acute radiation toxicities occurred in 91% of the patients; 19% were grade 3, 2% grade 4. Late radiation toxicities were reported in 71% of the patients: 50% grade 1, 18% grade 2, and 3% grade 3. Limb and joint function after treatment were good, 19% having mild limitation of motion, 1.5% moderate, and 2.5% severe limitations.
Limb-sparing surgery with 60 Gy postoperative radiotherapy for patients with STS provides excellent local control and high survival rates with acceptable toxicity and functional outcomes.
[Show abstract][Hide abstract] ABSTRACT: Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy with imatinib. Surgery is performed to remove metastatic lesions to induce long-term remission or even curation. In other patients, surgery is performed to remove (focal) progressive or symptomatic lesions. The impact and long-term results of surgery after systemic therapy have not been clearly defined.
Between September 2001 and May 2010, all patients with metastatic GIST who underwent surgery for metastatic GIST after systemic therapy (that is, imatinib and sunitinib) at four Dutch specialized institutions were included. Primary end-points were progression-free survival (PFS) and overall survival (OS).
All 55 patients underwent surgery after treatment with systemic therapy. At the last follow-up, tumor recurrence or progression was noted after surgery in 48% of the patients who responded on systemic therapy, and in 85% of the patients who were treated while having progressive disease. Median PFS and OS were not reached in the group of responders. In the non-responders group PFS and OS were median 4 and 25 months, respectively. Response on systemic therapy and a surgical complete resection were significantly correlated to PFS and OS.
Surgery may play a role in responding patients. In patients with progressive disease, the role of surgery is more difficult to distinguish in this retrospective analysis since PFS is short. Which patients benefit and whether this improves long-term outcome should be established in a multicentric randomized trial.
World Journal of Surgical Oncology 06/2012; 10(1):111. DOI:10.1186/1477-7819-10-111 · 1.41 Impact Factor