Johannes H. W. de Wilt

Predicting lymph node metastasis in pT1 colorectal cancer: a systematic review of risk factors providing rationale for therapy decisions

BACKGROUND AND STUDY AIMnPopulation screening for colorectal cancer (CRC) is expected to increase the number of pT1 CRCs. Local excision is an attractive treatment option, but is only oncologically safe in the absence of lymph node metastasis (LNM). A systematic review of the predictive value of pathological risk factors for LNM in pT1 CRC was conducted to provide data for an evidence-based decision regarding follow-up or radical surgery after local excision.nnnMETHODSnPubMed was searched for reports on predictors of LNM in pT1 CRC. Published papers written in English and containing at least 50 patients were included. Meta-analyses were performed using Review Manager 5.1.nnnRESULTSnA total of 17 studies were included involving a total of 3621 patients with available nodal status. The strongest independent predictors of LNM were lymphatic invasion (relative risk [RR] 5.2, 95 % confidence interval [CI] 4.0 - 6.8), submucosal invasion ≥ 1 mm (RR 5.2, 95 %CI 1.8 - 15.4), budding (RR 5.1, 95 %CI 3.6 - 7.3), and poor histological differentiation (RR 4.8, 95 %CI 3.3 - 6.9). Limitations of the study were: results could not be stratified according to location in the colon or rectum; very early tumors removed by polypectomy without surgical resection were not included in the meta-analysis; and included studies were primarily from Asian countries and results therefore need to be verified in Western populations.nnnCONCLUSIONnThe absence of lymphatic invasion, budding, submucosal invasion ≥ 1 mm, and poor histological differentiation were each associated with low risk of LNM. Risk stratification models integrating these factors need to be investigated further.

Cytoreduction and HIPEC in The Netherlands : Nationwide Long-term Outcome Following the Dutch Protocol

PurposeThis nationwide study evaluated results of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis of colorectal origin in the Netherlands following a national protocol.MethodsIn a multi-institutional study prospective databases of patients with peritoneal carcinomatosis (PC) from colorectal cancer and pseudomyxoma peritonei (PMP) treated according to the Dutch HIPEC protocol, a uniform approach for the CRS and HIPEC treatment, were reviewed. Primary end point was overall survival and secondary end points were surgical outcome and progression-free survival. ResultsNine-hundred sixty patients were included; 660 patients (69xa0%) were affected by PC of colorectal carcinoma and the remaining suffered from PMP (31xa0%). In 767 procedures (80xa0%), macroscopic complete cytoreduction was achieved. Three-hundred and thirty one patients had grade III–V complications (34xa0%). Thirty-two patients died perioperatively (3xa0%). Median length of hospital stay was 16xa0days (range 0–166xa0days). Median follow-up period was 41xa0months (95xa0% confidence interval (CI), 36–46xa0months). Median progression-free survival was 15xa0months (95xa0% CI 13–17xa0months) for CRC patients and 53xa0months (95xa0% CI 40–66xa0months) for PMP patients. Overall median survival was 33 (95xa0% CI 28–38xa0months) months for CRC patients and 130xa0months (95xa0% CI 98–162xa0months) for PMP patients. Three- and five-year survival rates were 46 and 31xa0% respectively in case of CRC patients and 77 and 65xa0% respectively in case of PMP patients.ConclusionsThe results underline the safety and efficacy of cytoreduction and HIPEC for PC from CRC and PMP. It is assumed the uniform Dutch HIPEC protocol was beneficial.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience

BackgroundPreoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure.MethodsWe have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46xa0months.ResultsThe primary tumor was located in the stomach (55xa0%), followed by rectum (20xa0%), duodenum (10xa0%), ileum/jejunum/other (11xa0%), and esophagus (3xa0%). The tumor resection after preoperative imatinib (median time on therapy, 40xa0weeks) was R0 in 83xa0%. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65xa0%, respectively, median OS was 104xa0months, and median DFS was not reached. There were 56xa0% of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65xa0%). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib.ConclusionsOur analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases

Abstract The aim of this study was to determine trends in incidence, treatment and survival of colorectal cancer (CRC) patients with synchronous metastases (Stage IV) in the Netherlands. This nationwide population-based study included 160,278 patients diagnosed with CRC between 1996 and 2011. We evaluated changes in stage distribution, location of synchronous metastases and treatment in four consecutive periods, using Chi square tests for trend. Median survival in months was determined, using Kaplan–Meier analysis. The proportion of Stage IV CRC patients (nxa0=xa033,421) increased from 19xa0% (1996–1999) to 23xa0% (2008–2011, pxa0<xa00.001). This was predominantly due to a major increase in the incidence of lung metastases (1.7–5.0xa0% of all CRC patients). During the study period, the primary tumor was resected less often in Stage IV patients (65–46xa0%) and the use of systemic treatment has increased (29–60xa0%). Also an increase in metastasectomy was found in patients with one metastatic site, especially in patients with liver-only disease (5–18xa0%, pxa0<xa00.001). Median survival of all Stage IV CRC patients increased from 7 to 12xa0months. Especially in patients with metastases confined to the liver or lungs this improvement in survival was apparent (9–16 and 12–24xa0months respectively, both pxa0<xa00.001). In the last two decades, more lung metastases were detected and an increasing proportion of Stage IV CRC patients was treated with systemic therapy and/or metastasectomy. Survival of patients has significantly improved. However, the prognosis of Stage IV patients becomes increasingly diverse.

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BackgroundThe peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate.These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay.Methods/DesignThe aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30xa0min at 42-43xa0°C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18xa0months. Diagnostic laparoscopy will be performed routinely after 18xa0months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA.DiscussionAdjuvant HIPEC is assumed to reduce the expected 25xa0% absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10xa0%. This reduction is likely to translate into a prolonged overall survival.Trial registration numberNCT02231086 (Clinicaltrials.gov)

Prevalence and prognosis of synchronous colorectal cancer: A Dutch population-based study

BACKGROUNDnA noticeable proportion of colorectal cancer (CRC) patients are diagnosed with synchronous CRC. Large population-based studies on the incidence, risk factors and prognosis of synchronous CRC are, however, scarce, and are needed for better determination of risks of synchronous CRC in patients diagnosed with colonic neoplasia.nnnMETHODSnAll newly diagnosed CRC between 1995 and 2006 were obtained from the Rotterdam Cancer Registry in The Netherlands, and studied for synchronous CRC.nnnRESULTSnOf the 13,683 patients diagnosed with CRC, 534 patients (3.9%) were diagnosed with synchronous CRC. The risk of having synchronous CRC was significantly higher in men (OR 1.54, 95% CI 1.29-1.84) and in patients aged >70 years (OR 1.83, 95% CI 1.39-2.40). Synchronous CRC patients had a significantly higher risk of distant metastases (OR 1.69, 95% CI 1.27-2.26). In 34% (184/534) the two tumours were located in different surgical segments. Five-year relative survival of synchronous CRC was similar to patients with solitary CRC after multivariate adjustment for the presence of distant metastases.nnnCONCLUSIONnOne out of 25 patients diagnosed with CRC presents with synchronous CRC. In the multivariate analysis, survival of patients with synchronous CRC was similar to patients with solitary CRC, when corrected for the presence of distant metastases at first presentation. One third of the synchronous CRC were located in different surgical segments, which stresses the importance of performing total colon examination preferably prior to surgery.

Surgeons' opinions on lymphadenectomy in melanoma patients with positive sentinel nodes: a worldwide web-based survey

PurposeA worldwide web-based survey was conducted among melanoma surgeons to investigate opinions about completion lymph node dissection (CLND) in patients with positive sentinel nodes (SN).MethodsA questionnaire was designed following input from a group of melanoma surgeons. Cognitive interviews and pilot testing were performed. Surgeons identified through a systematic-review of the SN and CLND literature were invited by email.ResultsOf 337 surgeons, 193 (57.2xa0%) from 25 countries responded (January–July 2011). Most respondents work in melanoma (30.1xa0%) and surgical oncology (44.6xa0%) units. In patients with a positive SN, 169 (91.8xa0%) recommend CLND; the strength of the recommendation is mostly influenced by patient comorbidities (64.7xa0%) and SN tumor burden (59.2xa0%). Seventy-one responders enroll patients in the second Multicenter Selective-Lymphadenectomy Trial (MSLT-2), and 64 of them (76xa0%) suggest entering the trial to majority of patients. In cases requiring neck CLND, level 1–5 dissection is recommended by 35xa0% of responders, whereas 62xa0% base the extent of dissection on primary site and lymphatic mapping patterns. Only inguinal dissection or ilioinguinal dissection is performed by 36 and 30xa0% of surgeons, respectively. The remaining 34xa0% select either procedure according to number of positive SNs, node of Cloquet status, and lymphatic drainage patterns. Most surgeons (81xa0%) perform full axillary dissections in positive SN cases.ConclusionsThe majority of melanoma surgeons recommend CLND in SN-positive patients. Surgeons participating in the MSLT-2 suggest entering the trial to the majority of patients. More evidence is needed to standardize the extent of neck and groin CLND surgeries.

The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG)

BackgroundThere is no consensus regarding resection of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastatic colorectal cancer (CRC). A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour in later stages of the disease. We here propose a randomized trial in order to demonstrate that resection of the primary tumour improves overall survival.Methods/designThe CAIRO4 study is a multicentre, randomized, phase III study of the Dutch Colorectal Cancer Group (DCCG). Patients with synchronous unresectable metastases of CRC and few or absent symptoms of the primary tumour are randomized 1:1 between systemic therapy only, and resection of the primary tumour followed by systemic therapy. Systemic therapy will consist of fluoropyrimidine-based chemotherapy in combination with bevacizumab. The primary objective of this study is to determine the clinical benefit in terms of overall survival of initial resection of the primary tumour. Secondary endpoints include progression free survival, surgical morbidity, quality of life and the number of patients requiring resection of the primary tumour in the control arm.DiscussionThe CAIRO4 study is a multicentre, randomized, phase III study that will assess the benefit of resection of the primary tumour in patients with synchronous metastatic CRC.Trial registrationThe CAIRO4 study is registered at clinicaltrials.gov (NCT01606098)

Outcome After Therapeutic Lymph Node Dissection in Patients with Unknown Primary Melanoma Site

PurposeThe aim of this study was to evaluate the incidence and outcome of melanoma of unknown primary site (MUP) after therapeutic lymph node dissection (TLND) of palpable nodal melanoma metastases. Disease-free (DFS) and overall survival (OS) time of MUP patients were analyzed and compared to patients undergoing a TLND for known primary melanomas (MKP).MethodsThis single institution retrospective study analyzed 342 consecutive patients who were treated with 415 TLNDs for palpable nodal disease from 1982 to 2009. Univariate and multivariate analyses included: MUP versus MKP, gender, Breslow thickness, ulceration of primary tumor, site of primary tumor, site of dissection, extracapsular extension, number of collected nodes, number of positive nodes and the node positive ratio.ResultsA total of 47 MUP were identified in 342 patients (13.7%). In univariate analysis, a trend was seen toward better survival for MUP patients compared to MKP patients having 5-year OS rates of 40% and 27%, respectively (Pxa0=xa00.06). Multivariate analysis for OS showed two highly significant factors associated with worse prognosis: extracapsular extension and N3 status (both Pxa0<xa00.001). Two factors were associated with a significant better prognosis: MUP (Pxa0=xa00.03) and a neck dissection (Pxa0=xa00.04).ConclusionsPatients with MUP showed a statistically significant better OS compared to patients with melanoma metastases from known primary tumors. Presence of extracapsular extension and an increased number of positive nodes are statistically significantly negative prognostic factors for OS. The absence of a primary melanoma in stage III melanoma patients does not preclude surgery.

The Prognostic Value of Lymph Node Ratio in Node-Positive Breast Cancer: A Dutch Nationwide Population-Based Study

The absolute number of involved axillary lymph nodes (LNs) is considered the most important prognostic factor in breast cancer. Over the last decade, several studies indicated that the lymph node ratio (LNR) might predict outcome better than the number of positive LNs. In this study we test the applicability of earlier published LNR cutoff values and study the prognostic value of the LNR on a nationwide level. A nationwide population-based study was performed, using data from the Netherlands Cancer Registry, including all women diagnosed with node-positive breast cancer between 1999 and 2005 (Nxa0=xa025,315). Patients were divided into 3 LNR risk groups (low, ≤0.20; intermediate, 0.21–0.65; and high, >0.65). Kaplan–Meier survival analysis was performed. In order to evaluate whether LNR was associated with overall survival (OS), Cox proportional hazards modeling was used. For the entire cohort, 5- and 10-year OS rates were 78xa0% and 62xa0%, respectively. The number of positive LNs correlated with OS (5-year OS 84xa0%, 72xa0%, and 55xa0% for patients with 1–3, 4–9, and 10 or more positive LNs, respectively, Pxa0<xa0.001). LNR also correlated with OS (5-year OS 86xa0%, 75xa0%, and 54xa0% for low-, intermediate-, and high-risk groups, respectively, Pxa0<xa0.001). In the multivariable analysis, the risk of death increased with increasing LNR (Pxa0<xa0.001). The LNR has an important prognostic value in node-positive patients, independent of traditional clinicopathological factors. LNR should be added as an independent prognostic variable to the current staging system.BackgroundThe absolute number of involved axillary lymph nodes (LNs) is considered the most important prognostic factor in breast cancer. Over the last decade, several studies indicated that the lymph node ratio (LNR) might predict outcome better than the number of positive LNs. In this study we test the applicability of earlier published LNR cutoff values and study the prognostic value of the LNR on a nationwide level.MethodsA nationwide population-based study was performed, using data from the Netherlands Cancer Registry, including all women diagnosed with node-positive breast cancer between 1999 and 2005 (Nxa0=xa025,315). Patients were divided into 3 LNR risk groups (low, ≤0.20; intermediate, 0.21–0.65; and high, >0.65). Kaplan–Meier survival analysis was performed. In order to evaluate whether LNR was associated with overall survival (OS), Cox proportional hazards modeling was used.ResultsFor the entire cohort, 5- and 10-year OS rates were 78xa0% and 62xa0%, respectively. The number of positive LNs correlated with OS (5-year OS 84xa0%, 72xa0%, and 55xa0% for patients with 1–3, 4–9, and 10 or more positive LNs, respectively, Pxa0<xa0.001). LNR also correlated with OS (5-year OS 86xa0%, 75xa0%, and 54xa0% for low-, intermediate-, and high-risk groups, respectively, Pxa0<xa0.001). In the multivariable analysis, the risk of death increased with increasing LNR (Pxa0<xa0.001).ConclusionsThe LNR has an important prognostic value in node-positive patients, independent of traditional clinicopathological factors. LNR should be added as an independent prognostic variable to the current staging system.