Short-Course Radiotherapy Followed by Neoadjuvant Bevacizumab, Capecitabine, and Oxaliplatin and Subsequent Radical Treatment in Primary Stage IV Rectal Cancer: Long-Term Results of a Phase II Study.

BACKGROUND: In a Dutch phase II trial conducted between 2006 and 2010, short-course radiotherapy followed by systemic therapy with capecitabine, oxaliplatin, and bevacizumab as neoadjuvant treatment and subsequent radical surgical treatment of primary tumor and metastatic sites was evaluated. In this study, we report the long-term results after a minimum follow-up of 6 years. METHODS: Patients with histologically confirmed rectal adenocarcinoma with potentially resectable or ablatable metastases in liver or lungs were eligible. Follow-up data were collected for all patients enrolled in the trial. Overall and recurrence-free survival were calculated using the Kaplan-Meier method. RESULTS: Follow-up data were available for all 50 patients. After a median follow-up time of 8.1 years (range 6.0-9.8), 16 patients (32.0%) were still alive and 14 (28%) were disease-free. The median overall survival was 3.8 years (range 0.5-9.4). From the 36 patients who received radical treatment, two (5.6%) had a local recurrence and 29 (80.6%) had a distant recurrence. CONCLUSIONS: Long-term survival can be achieved in patients with primary metastatic rectal cancer after neoadjuvant radio- and chemotherapy. Despite a high number of recurrences, 32% of patients were alive after a median follow-up time of 8.1 years.

Modern multidisciplinary treatment of rectal cancer based on staging with magnetic resonance imaging leads to excellent local control, but distant control remains a challenge.

AIM: The purpose of this multicenter cohort study was to evaluate whether a differentiated treatment of primary rectal cancer based on magnetic resonance imaging (MRI) can reduce the number of incomplete resections and local recurrences and improve recurrence-free and overall survival. METHODS: From February 2003 until January 2008, 296 patients with rectal cancer underwent preoperative MRI using a lymph node specific contrast agent to predict circumferential resection margin (CRM), T- and N-stage. Based on expert reading of the MRI, patients were stratified in: (a) low risk for local recurrence (CRM>2mm and N0 status), (b) intermediate risk and (c) high risk (close/involved CRM, N2 status or distal tumours). Mainly based on this MRI risk assessment patients were treated with (a) surgery only (TME or local excision), (b) preoperative 5 × 5 Gy+TME and (c) a long course of chemoradiation therapy followed by surgery after a 6-8 week interval. RESULTS: Overall 228 patients underwent treatment with curative intent: 49 with surgery only, 86 with 5 × 5 Gy and surgery and 93 with chemoradiation and surgery. The number of complete resections (margin>1mm) was 218 (95.6%). At a median follow-up of 41 months the three-year local recurrence rate, disease-free survival rate and overall survival rate is 2.2%, 80% and 84.5%, respectively. CONCLUSION: With a differentiated multimodality treatment based on dedicated preoperative MR imaging, local recurrence is no longer the main problem in rectal cancer treatment. The new challenges are early diagnosis and treatment, reducing morbidity of treatment and preferably prevention of metastatic disease.

HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer.

Fifteen patients with chemosensitive metastatic breast cancer (MBC) underwent reduced intensity (RIST) allo-SCT between 1999 and 2006. The purpose of this single-center study was to evaluate the feasibility, safety and efficacy of this therapeutic approach. The pretransplant conditioning regimen consisted of fludarabine (25 mg/m(2) at days -5 to -1) and CY (60 mg/kg at days -2, -1). Stem cells were from HLA-matched sibling donors. The treatment-related mortality was 2/15 (13%). Median PFS and OS were 144 days (43-509 days) and 303 days (122-1376 days), respectively. The 1-year PFS was 20%, and the 1-year and 2-year OS was 40 and 20%, respectively. No objective tumor responses were observed, but the relatively long PFS does suggest a graft-vs-tumor effect. Although RIST using this CY/fludarabine regimen is feasible, the efficacy in this set of patients was limited. Future clinical trials should be performed to improve the knowledge of mechanisms of antitumor effects in breast cancer.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Primary monophasic mediastinal, cardiac and pericardial synovial sarcoma: a young man in distress.

A 19-year-old male was admitted because of exertional dyspnoea. The imaging studies revealed epicardial, pericardial and mediastinal masses. The tumours could not be resected through a minor thoracotomy, only biopsies could be taken. Analyses led to the final diagnosis of a monophasic synovial sarcoma. The patient preferred a conservative and palliative approach. Three months later he died at home. Autopsy demonstrated dramatic extension of the tumour masses. We conclude this report with a discussion on primary cardiac tumours. (Neth Heart J 2007;15:226-8.).

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

The unknown biology of the unknown primary tumour: a literature review.

The unknown primary tumour (UPT) is an intriguing clinical phenomenon found in approximately 5% of all newly diagnosed patients with cancer. It is unclear whether UPT forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is merely a clinical presentation of metastases in patients in whom the primary tumour cannot be detected and does not result in any visible clinical signs. Understanding the basic biology of UPT may shed light on this issue and, moreover, may have a direct impact on clinical care. A review of the literature revealed only a limited number of publications describing the genetic and phenotypic features of UPT, most of which focus only on the potential of these markers to predict prognosis. The question as to whether the biology of UPT is different from tumours of known primaries therefore remains unanswered. Further insight into the molecular mechanisms underlying the oncogenesis of UPT, e.g. by applying newly available DNA and gene profiling microarray techniques, will be necessary to understand its specific biology and to develop more effective treatments.

Clinical relevance of apoptotic markers in breast cancer not yet clear.

Currently, the mainly used characteristics to predict outcome or treatment response in patients with breast cancer are tumor size, N-status, histological grade and receptor status (ER/PgR). However, these conventional clinico-pathological characteristics are of limited value. More accurate determinators are needed to select patients who are most likely to benefit from treatment in terms of prognosis as well as treatment response. Proliferation and apoptosis are assumed to play a key role in tumor progression as well as response to treatment. Currently, an increasing number of molecular factors controlling apoptosis as well as proliferation is known. The clinical relevance of apoptotic tumor markers in the treatment strategy of patients with breast cancer is the subject of this review. In addition, potential future developments are discussed.