Preoperative chemoradiation combined with regional hyperthermia for patients with resectable esophageal cancer.

PURPOSE: To analyse the treatment results of neo-adjuvant chemoradiation combined with regional hyperthermia in patients with resectable esophageal cancer. PATIENTS AND METHODS: Between August 2003 and December 2004, 28 patients entered a phase II study combining chemoradiation over a 4.5-week period with five sessions of regional hyperthermia. Chemotherapy consisted of carboplatin (AUC = 2) and paclitaxel (50 mg/m(2)) and radiotherapy of 41.4 Gy in 1.8 Gy daily fractions. Locoregional hyperthermia was applied using the AMC phased array of four 70 MHz antennas, aiming at a stable tumor temperature of 41 degrees C for one hour. Carboplatin was infused during the hyperthermia session. Esophageal resection was planned at 6-8 weeks after the end of radiotherapy. The majority of the patients had a T3 tumor (86%) and were cN+ (64%). Median follow-up for survivors was 37 months (range 31-46). RESULTS: Twenty-five patients (89%) completed the planned neo-adjuvant treatment and acute toxicity was generally mild. Twenty-six patients were operated on. A pathologically CR, PRmic, PR and SD were seen in 19%, 27%, 31% and 23% respectively. All patients had a R0 resection. In-field locoregional control during follow up for the operated patients was 100%. Quality of life was good for patients without disease progression. Survival rates at one, two and three years were 79%, 57% and 54% respectively. CONCLUSION: Neo-adjuvant chemoradiation combined with regional hyperthermia followed by esophageal resection for patients with esophageal cancer resulted in good locoregional control and overall survival.

[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'.

Mechanisms of heparin induced anti-cancer activity in experimental cancer models.

BACKGROUND: Retrospective analyses of clinical trials and prospective clinical studies have suggested that heparins may have an effect on cancer survival. This putative anti-cancer activity of heparins is supported by data from studies in animal tumour models. OBJECTIVE: To clarify the various potential mechanisms of heparin anti-cancer activity we evaluated the data from pre-clinical studies in which heparins have been tested as anti-cancer therapy. METHODS: Pre-clinical studies, published between 1960 and 2005 were assessed. Data were collected on the type and dose of heparin used, duration of exposure to heparin, interval between heparin administration and cancer cell inoculation, and the animal tumour model used. In addition, a distinction was made in the analysis between heparin effects on the primary tumour or on established metastases and effects on the metastatic potential of infused cells. RESULTS: Heparins seemed to affect the formation of metastasis rather than the growth of primary tumours. Chemically modified heparins with no or limited anticoagulant activity also showed anti-metastatic properties. Possible mechanisms to explain the effects on the process of metastases include inhibition of blood coagulation, inhibition of cancer cell-platelet and -endothelial interactions by selectin inhibition and inhibition of cell invasion and angiogenesis. CONCLUSION: The anti-cancer activity of heparins depends more on inhibition of metastasis formation than on the effects on primary tumour growth. These effects are probably related to both coagulation and non-coagulation dependent factors. For a definitive proof of the anti-cancer activity of heparins in the clinic, prospective randomized trials especially in patients with early metastatic disease or in the adjuvant setting are urgently needed.

[Guideline 'Diagnosis and treatment of oesophageal carcinoma']. / Richtlijn 'Diagnostiek en behandeling oesofaguscarcinoom'.

An evidence-based guideline for the diagnosis and treatment of oesophageal carcinoma was developed on the initiative of the Netherlands Society of Gastroenterohepatology in cooperation with the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Association of Comprehensive Cancer Centres. If a patient with oesophageal carcinoma is eligible for treatment with curative intent, they should undergo thoracic and abdominal CT, ultrasound investigation of the supraclavicular region and endoscopic ultrasonography for staging purposes. Endoscopic therapy is the preferred treatment for high-grade dysplasia or early cancer in Barrett's oesophagus confined to the mucosa. Surgical resection is indicated if the tumour invades the submucosa. If resection of the oesophageal carcinoma is performed with curative intent, one should aim for radical resection. The type and extent of the resection depends on the location of the tumour. There is evidence that the mortality rate following surgery can be reduced by performing it in centres with ample experience with oesophageal cancer surgery. Preoperative chemotherapy and radiotherapy may improve survival in patients with oesophageal carcinoma. Palliative treatment for oesophageal carcinoma should be considered in cases of local invasion of surrounding organs, metastases, poor physical condition of the patient or recurrent disease after previous curative treatment. Psychosocial support is an important element in the follow-up of patients with oesophageal carcinoma.

Limited regression of central giant cell granuloma by interferon alpha after failed calcitonin therapy: a report of 2 cases.

Central giant cell granuloma (CGCG) is a benign lesion of the jaws with a sometimes locally aggressive behaviour. The most common therapy is surgical curettage which has a high recurrence rate, especially in lesions with aggressive signs and symptoms (i.e. pain, paresthesia, root-resorption and rapid growth). Alternative therapies such as interferon alpha (INFalpha) or calcitonin are described in the literature. In this study 2 patients with an aggressive CGCG are presented who were treated with INF mono-therapy. INF mono-therapy was capable of terminating the rapid growth of the lesion in both patients and induced a partial reduction. Total resolution, however, was not obtained and alternative treatment is still necessary.

COX-2 inhibition as a tool to treat and prevent colorectal cancer.

The cyclooxygenase-2 (COX-2) enzyme has a fundamental role in the carcinogenesis of colorectal cancer. The anticarcinogenic mechanisms of NSAIDs are not completely understood and appear to be only partially dependent on inhibition tumoral COX-2. Moreover, the mechanisms of NSAIDs depend on the concentration. In experimental setting, at low levels NSAIDs downregulate the COX-2 gene in colorectal cancer cells, whereas at clinical relevant concentrations the production of prostaglandin E2 by enzymatic activity of COX-2 is diminished resulting in inhibition of the tumor angiogenesis. At higher levels NSAIDs and especially some selective COX-2 inhibitors are capable of COX-2 independent effects, such as apoptosis induction of tumor cells. In animal models, NSAIDs administration results in inhibition of angiogenesis and proliferation, induction apoptosis and prevention of metastasis. In clinical setting, NSAIDs and selective COX-2 inhibitors have the capacity to prevent the development of colorectal adenomas. We have summarized data regarding the role of COX-2 in CRC and discuss the multiple targets of NSAIDs in their anticarcinogenic action. However, the translation of these anticarcinogenic effects of NSAIDs to its clinical application as adjuvant therapy in CRC is hampered by a lack of randomized clinical trials with long-term follow-up.

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.

This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia.

Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement.

BACKGROUND: Uncontrolled studies suggest that high-dose chemotherapy is beneficial in patients with breast cancer and multiple metastases to the axillary lymph nodes. Many physicians accept this treatment as standard care. We aimed to assess adjuvant high-dose chemotherapy in breast cancer in a phase II randomised trial. METHODS: 97 women aged younger than 60 years, who had breast cancer with extensive axillary-node metastases (confirmed by a tumour-positive infraclavicular lymph-node biopsy), received three courses of up-front chemotherapy (FE120C). This regimen consisted of cyclophosphamide 500 mg/m2, epirubicin 120 mg/m2, and 5-fluorouracil 500 mg/m2 once weekly for 3 weeks. After surgery, stable patients or those who responded to chemotherapy were randomly assigned conventional therapy (fourth course of FE120C, followed by radiation therapy and 2 years of tamoxifen [40 patients]) or high-dose therapy (identical treatment but an additional high-dose regimen and peripheral-blood progenitor-cell [PBPC] support after the fourth FE120C course [41 patients]). This high-dose regimen comprised cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2. The primary endpoint was overall and disease-free survival. All analyses were by intention to treat. FINDINGS: No patients died from toxic effects of chemotherapy. With a median follow-up of 49 (range 21-76) months, the 4-year overall and relapse-free survivals for all 97 patients were 75% and 54%, respectively. There was no significant difference in survival between the patients on conventional therapy and those on high-dose therapy. INTERPRETATION: High-dose therapy is associated with substantial cost and acute toxic effects, but also has potentially irreversible long-term effects. Until the benefit of this therapy is substantiated by large-scale phase III trials, high-dose chemotherapy should not be used in the adjuvant treatment of breast cancer, apart from in randomised studies.