Cornelis Verhoef

Body composition and outcome in patients undergoing resection of colorectal liver metastases.

Recent evidence suggests that depletion of skeletal muscle mass (sarcopenia) and an increased amount of intra‐abdominal fat (central obesity) influence cancer statistics. This study investigated the impact of sarcopenia and central obesity on survival in patients undergoing liver resection for colorectal liver metastases (CLM).

Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes.

Summary Background Data:The more intensive sentinel node (SN) pathologic workup, the higher the SN-positivity rate. This is characterized by an increased detection of cases with minimal tumor burden (SUB-micrometastasis <0.1 mm), which represents different biology. Methods:The slides of positive SN from 3 major centers within the European Organization of Research and Treatment of Cancer (EORTC) Melanoma Group were reviewed and classified according to the Rotterdam Classification of SN Tumor Burden (<0.1 mm; 0.1–1 mm; >1 mm) maximum diameter of the largest metastasis. The predictive value for additional nodal metastases in the completion lymph node dissection (CLND) and disease outcome as disease-free survival (DFS) and overall survival (OS) was calculated. Results:In 388 SN positive patients, with primary melanoma, median Breslow thickness was 4.00 mm; ulceration was present in 56%. Forty patients (10%) had metastases <0.1 mm. Additional nodal positivity was found in only 1 of 40 patients (3%). At a mean follow-up of 41 months, estimated OS at 5 years was 91% for metastasis <0.1 mm, 61% for 0.1 to 1.0 mm, and 51% for >1.0 mm (P < 0.001). SN tumor burden increased significantly with tumor thickness. When the cut-off value for SUB-micrometastases was taken at <0.2 mm (such as in breast cancer), the survival was 89%, and 10% had additional non-SN nodal positivity. Conclusion:This large multicenter dataset establishes that patients with SUB-micrometastases <0.1 mm have the same prognosis as SN negative patients and can be spared a CLND. A <0.2 mm cut-off for SUB-micrometastases does not seem correct for melanoma, as 10% additional nodal positivity is found.

Prognosis in Patients With Sentinel Node–Positive Melanoma Is Accurately Defined by the Combined Rotterdam Tumor Load and Dewar Topography Criteria

PURPOSE Prognosis in patients with sentinel node (SN)-positive melanoma correlates with several characteristics of the metastases in the SN such as size and site. These factors reflect biologic behavior and may separate out patients who may or may not need additional locoregional and/or systemic therapy. PATIENTS AND METHODS Between 1993 and 2008, 1,080 patients (509 women and 571 men) were diagnosed with tumor burden in the SN in nine European Organisation for Research and Treatment of Cancer (EORTC) melanoma group centers. In total, 1,009 patients (93%) underwent completion lymph node dissection (CLND). Median Breslow thickness was 3.00 mm. The median follow-up time was 37 months. Tumor load and tumor site were reclassified in all nodes by the Rotterdam criteria for size and in 88% by the Dewar criteria for topography. RESULTS Patients with submicrometastases (< 0.1 mm in diameter) were shown to have an estimated 5-year overall survival rate of 91% and a low nonsentinel node (NSN) positivity rate of 9%. This is comparable to the rate in SN-negative patients. The strongest predictive parameter for NSN positivity and prognostic parameter for survival was the Rotterdam-Dewar Combined (RDC) criteria. Patients with submicrometastases that were present in the subcapsular area only, had an NSN positivity rate of 2% and an estimated 5- and 10-year melanoma-specific survival (MSS) of 95%. CONCLUSION Patients with metastases < 0.1 mm, especially when present in the subcapsular area only, may be overtreated by a routine CLND and have an MSS that is indistinguishable from that of SN-negative patients. Thus the RDC criteria provide a rational basis for decision making in the absence of conclusions provided by randomized controlled trials.

Stereotactic body radiation therapy for colorectal liver metastases

Stereotactic body radiation therapy (SBRT) is a treatment option for colorectal liver metastases. Local control, patient survival and toxicity were assessed in an experience of SBRT for colorectal liver metastases.

KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue

Although anti‐EGFR therapy has established efficacy in metastatic colorectal cancer, only 10‐20% of unselected patients respond. This is partly due to KRAS and BRAF mutations, which are currently assessed in the primary tumor. To improve patient selection, assessing mutation status in circulating tumor cells (CTCs), which possibly better represent metastases than the primary tumor, could be advantageous. We investigated the feasibility of KRAS and BRAF mutation detection in colorectal CTCs by comparing three sensitive methods and compared mutation status in matching primary tumor, liver metastasis and CTCs. CTCs were isolated from blood drawn from 49 patients before liver resection using CellSearch™. DNA and RNA was isolated from primary tumors, metastases and CTCs. Mutations were assessed by co‐amplification at lower denaturation temperature‐PCR (Transgenomic™), real‐time PCR (EntroGen™) and nested Allele‐Specific Blocker (ASB‐)PCR and confirmed by Sanger sequencing. In 43 of the 49 patients, tissue RNA and DNA was of sufficient quantity and quality. In these 43 patients, discordance between primary and metastatic tumor was 23% for KRAS and 7% for BRAF mutations. RNA and DNA from CTCs was available from 42 of the 43 patients, in which ASB‐PCR was able to detect the most mutations. Inconclusive results in patients with low CTC counts limited the interpretation of discrepancies between tissue and CTCs. Determination of KRAS and BRAF mutations in CTCs is challenging but feasible. Of the tested methods, nested ASB‐PCR, enabling detection of KRAS and BRAF mutations in patients with as little as two CTCs, seems to be superior.

Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study)

This prospective multicentre study was performed to quantify the number of patients with minimal residual disease (ypT0–1) after neoadjuvant chemoradiotherapy and transanal endoscopic microsurgery (TEM) for rectal cancer.

Activated tumor‐infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer

The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor‐infiltrating regulatory T cells on tumor‐specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM‐CRC). Here we report that in both HCC and LM‐CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor‐specific T cell responses. Especially in LM‐CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up‐regulate the expression of glucocorticoid‐induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor‐free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor‐infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25− T cells. Conclusion: Our results show that tumor‐associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease. (HEPATOLOGY 2013)

Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population‐based series

Aim  The incidence, patterns of care and survival were determined in patients with stage IV colorectal cancer (CRC) in a population‐based series.

Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors.

PURPOSE To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. METHODS Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). RESULTS Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED ≤ 100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1-2 esophagitis was observed in 11% of patients. CONCLUSION SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions.

Optimizing the outcome of surgery in patients with rectal cancer and synchronous liver metastases

This study evaluated the outcome of patients treated for rectal cancer and synchronous hepatic metastases in the era of effective induction radiotherapy and chemotherapy.