Longitudinal associations of light-intensity physical activity with quality of life, functioning and fatigue after colorectal cancer.

PURPOSE: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. METHODS: Data were used of a prospective cohort study among 325 stage I-III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. RESULTS: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (ß = 1.67, 95% CI 0.71; 2.63; total range scale: 0-100) and less fatigue (ß = - 1.22, 95% CI - 2.37; - 0.07; scale: 20-140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. CONCLUSION: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

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.

Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson's disease model.

Current conventional treatments for Parkinson's disease (PD) are aimed at symptom management, as there is currently no known cure or treatment that can slow down its progression. Ayurveda, the ancient medical system of India, uses a combination of herbs to combat the disease. Herbs commonly used for this purpose are Zandopa (containing Mucuna pruriens), Withania somnifera, Centella asiatica, Sida cordifolia and Bacopa monnieri. In this study, these herbs were tested for their potential ability to improve climbing ability of a fruit fly (Drosophila melanogaster) PD model based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1). Fruit flies were cultured on food containing individual herbs or herbal formulations, a combination of all five herbs, levodopa (positive control) or no treatment (negative control). Tests were performed in both PINK1 mutant flies and healthy wild-type (WT) flies. A significant improvement in climbing ability was observed in flies treated with B. monnieri compared with untreated PINK1 mutant flies. However, a significant decrease in climbing ability was observed in WT flies for the same herb. Centella asiatica also significantly decreased climbing ability in WT flies. No significant effects were observed with any of the other herbs in either PINK1 or WT flies compared with untreated flies.

[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.).

Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response.

PURPOSE: To analyze the putative relationship between immunotherapy-associated dysthyroidism and the probability of a tumor response. PATIENTS AND METHODS: A total of 89 consecutive patients with advanced cancer were treated with interleukin-2 (IL2)-based immunotherapy in a prospective study. RESULTS: Twenty patients developed thyroid dysfunction. Repeatedly positive tests for thyroid antibodies developed in 28% of the patients. Twenty-two patients achieved a response. There was no relationship between the formation of antibodies and the probability of response. There appeared to be a trend toward a relationship between thyroid dysfunction and response (P = .23). A strong relationship was found between response on the one hand and cumulative dose of IL2 (P = .01) and treatment duration with IL2 (P = .025) on the other. The frequency of thyroid dysfunction was also significantly correlated with treatment duration (P = .001). After adjustment for cumulative dose of IL2 and treatment duration, no relationship between thyroid dysfunction and response remained (P = .99). CONCLUSION: There is no relationship between thyroid dysfunction and the probability of tumor response. Thyroid dysfunction is merely a function of treatment duration and cumulative dose of IL2.

Interleukin-2 and interferon-alpha in the treatment of patients with advanced non-small-cell lung cancer.

The role of combination chemotherapy in the treatment of advanced non-small-cell lung cancer is controversial. At best, a small survival benefit can be achieved. Therefore, other treatment modalities are needed. On the basis of the promising treatment results with interleukin-2 (IL-2) -containing immunotherapy in renal cell cancer and melanoma, we performed a phase I-II study with IL-2 and interferon alpha (IFN-alpha). Eligible patients were treated with IL-2 18 x 10(6) IU/m2/day by continuous intravenous infusion (c.i.v.) for 3 days. On the same days, 5 x 10(6) U/m2/day IFN-alpha was given intramuscularly. After a rest period of 4 days, patients at the first dose level received IL-2 2.4 x 10(6) IU/m2/day c.i.v. for a period of 28 days, followed by 14 days' rest, 14 days' treatment, 7 days' rest, and a final treatment for 14 days. Patients at the second dose level were treated according to the same schedule, in which the dose of IL-2 was increased to 3.6 x 10(6) IU/m2/day. During low-dose IL-2 treatment, patients received IFN-alpha 5 x 10(6) U/m2/day on days 1 and 4 of each week. Eleven patients were admitted to the study, six at the first and five at the second dose level. Median age was 54 years; all patients had a performance status of 0 or 1. The most important adverse effects included anorexia, fatigue, nausea, and headache, which were not dose limiting. In the 11 patients treated, no responses were seen. Nine patients developed progressive disease during the first 5 weeks of treatment. We concluded that this regimen of IL-2 and IFN-alpha is ineffective.

Repetitive weekly cycles of 4-day continuous infusion of recombinant interleukin-2: a phase I study.

A phase I trial was performed with a new interleukin-2 (IL-2) given as a continuous intravenous infusion in patients with solid tumors. The objectives of the study were to examine the feasibility of administering IL-2 in 4-day cycles for 4 consecutive weeks, and to investigate the response pattern of peripheral blood lymphocytes. Tumor necrosis factor (TNF) and IL-2 serum concentrations were also measured. Prior to this study, IL-2 had been tested at increasing dosages during one 4-day cycle, and it appeared that a dose of 1300 mcg/m2/day was tolerated. However, when this treatment schedule was maintained for 4 consecutive weeks, the maximum tolerated dose was 430 mcg/m2/day. In this schedule, a dose-dependent progressive increase in rebound lymphocyte count occurred after each weekly cycle, resulting in a 5-70-fold increase after the 4th cycle. Serum TNF peak concentrations also showed a tendency to increase during each subsequent cycle, while serum IL-2 peak concentrations showed a paradoxical decrease. Clinical toxicity comprised several events, which, possibly, could be ascribed to autoimmune phenomena. Myocardial infarction as a late toxicity of IL-2 is suggested. One complete response (renal carcinoma) and two partial responses (renal and breast carcinoma) were documented, one of these occurring in a patient who previously had shown a transient response on interferon therapy.

Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin.

BACKGROUND: The autoinducible metabolic transformation of the anticancer agent ifosfamide involves activation through 4-hydroxyifosfamide to the ultimate cytotoxic ifosforamide mustard and deactivation to 2- and 3-dechloroethylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde. Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by CYP3A4 and CYP2B6. The aim of this study was to investigate modulation of the CYP-mediated metabolism of ifosfamide with ketoconazole, a potent inhibitor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. METHODS: In a double-randomized, 2-way crossover study a total of 16 patients received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatment and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethylifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data analysis was performed with a population pharmacokinetic model with a description of autoinduction of ifosfamide. RESULTS: Rifampin increased the clearance of ifosfamide at the start of therapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, whereas exposure to the metabolites was decreased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketoconazole did not affect the fraction metabolized or the exposure to the dechloroethylated metabolites, whereas both parameters were reduced with 4-hydroxyifosfamide. CONCLUSIONS: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.

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.

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery. EORTC Genitourinary Tract Cancer Cooperative Group (EORTC GU Group)

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

Phase II study on cisplatin and ifosfamide in recurrent high grade gliomas.

27 patients with recurrent high grade glioma following surgery and radiation therapy were treated with 100 mg/m2 cisplatin and 6 g/m2 ifosfamide per cycle, administered on days 1-3 in 4 week cycles, for a maximum of six cycles. Toxicity was assessed after every cycle. Response was assessed following every second cycle, and a 50% decrease of the largest cross-sectional tumour area on contrast enhanced magnetic resonance imaging or computed tomography scan was considered a partial response (PR). A total of 95 cycles was administered; 26 patients were evaluable for response. In 5 patients (19%), a PR was obtained (median time to progression (TTP): 34 weeks). Stable disease was observed in 6 patients (23%, median TTP: 22 weeks). The most frequent toxicity was haematological: 37% of cycles were complicated by a grade 3 or 4 leucopenia. 1 patients died, probably as a consequence of increased cerebral oedema induced by the cisplatin hydration schedule. Determination of the cisplatin concentration in this patient showed a 10-fold increase in the tumour concentration as compared with that in normal brain tissue, demonstrating the absence of a blood-brain barrier in the tumour. In conclusion, generally this schedule was well tolerated, but it is of moderate activity for recurrent glioma.

Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

High-dose chemotherapy with autologous bone marrow support as consolidation after standard-dose adjuvant therapy in primary breast cancer patients with seven or more involved axillary lymph nodes.

Despite adjuvant chemotherapy the prognosis of patients with breast cancer and a high number of involved axillary lymph nodes is very poor. The aim of the present study was to evaluate the efficacy of high-dose chemotherapy with autologous bone marrow support in patients with seven or more involved axillary lymph nodes. Nineteen patients underwent four courses of standard adjuvant chemotherapy, followed by high-dose busulphan/cyclophosphamide chemotherapy with autologous bone marrow support. The median age was 41.4 years and the median number of involved lymph nodes 11. Mucositis WHO grade > or = 3 was observed in 15 patients and 18 patients suffered febrile neutropenia. Transplant-related mortality was encountered in two patients, due to hepatic veno-occlusive disease and sepsis complicated by multi-organ failure, respectively. After a median follow-up period of 1490 days (range 582-2024 days) from diagnosis, nine patients have relapsed and the overall event-free survival (EFS) is 42% (95% CI 19-65%). The median EFS is 487 days. High-dose treatment with BuCy2 in high-risk breast cancer patients is a toxic regimen and does not seem to improve disease-free survival.

Relevance of the expression of bcl-2 in combination with p53 as a prognostic factor in breast cancer.

BACKGROUND: Both the proto-oncogene bcl-2 and the tumour suppressor gene p53 are involved in the regulation of apoptosis. PATIENTS AND METHODS: We have investigated the prognostic value of the immunohistochemical expression of p53 and bcl-2 separately and in combination in a group of 345 breast cancer patients from one hospital with a long median follow-up of more than 10 years. RESULTS: Bcl-2 expression was not a prognostic factor. p53 was an independent prognostic factor for overall survival (p = 0.005) and for post-relapse survival (p = 0.006). Looking at bcl-2/p53 subgroups in the bcl-2 positive subgroup there was a large difference in both disease-free and overall survival between p53 negative and p53 positive patients. In the bcl-2 negative subgroup the p53 status was not a prognostic factor at all. CONCLUSIONS: p53 is an independent prognostic factor for overall survival and post-relapse survival. However, p53 status is only important in the bcl-2 positive subgroup.

pS2 is an independent prognostic factor for post-relapse survival in primary breast cancer.

BACKGROUND: The pS2 protein is involved in the maintenance of the integrity of the gastrointestinal tract. In breast cancer pS2 can be demonstrated in at least half of the tumors and probably reflects the functional status of ER. Several features make it likely that pS2 is involved in growth regulation. PATIENTS AND METHODS: We have investigated the value of immunohistochemical pS2 determination as a prognostic factor in 339 breast cancer patients with long follow-up from one hospital. RESULTS: A prognostic role for pS2 could not be demonstrated considering disease-free and overall survival, although in pS2-negative tumors a trend for less locoregional relapse was found. However, in multivariate analysis pS2 showed independent prognostic value for post-relapse survival. CONCLUSIONS: PS2 is an independent prognostic factor for post-relapse survival, most likely because it is a predictive factor for response to systemic therapy.

Anti-apoptotic phenotype is associated with decreased locoregional recurrence rate in breast cancer.

PURPOSE: Tumor stage and nodal status are the most important factors predicting locoregional recurrence in breast cancer. We wanted to investigate the prognostic value of some newer molecular genetic markers for the occurrence of a locoregional recurrence, in order to improve the selection of patients for locoregional adjuvant therapy. METHODS: Bcl-2, p53, MIB-1, pS2 and CD44v6 were determined immunohistochemically on formalin-fixed and paraffin embedded tumour tissues of 163 patients treated by modified radical mastectomy between 1982 and 1987. Postoperative irradiation was given to 35 patients to the intermammary chain only and to only 13 (8%) patients to the chest wall with or without the regional lymph nodes. Node-positive patients were treated with CAF adjuvant chemotherapy and were randomized for whether or no additional Medroxyprogesteroneacetate (MPA). A multivariate analysis was performed on a number of potential prognostic factors. The risk for locoregional recurrence was estimated using the competing risk approach. RESULTS: After a median period of 7.5 years 28 patients developed a locoregional recurrence. The cumulative incidence of loco-regional recurrence at 10 years was 17%. Bcl-2 and p53 were found to be independent factors predicting locoregional recurrence, whereas a trend was found for MIB-1. Increased Bcl-2 as well as p53 expression were associated with a decreased risk, whereas the increased presence of MIB-1 was associated with an increased risk. CONCLUSION: Results indicate that molecular markers of apoptosis as well as proliferation provide additional information for the risk of locoregional recurrence after modified radical mastectomy. If confirmed, these markers may play a role in the selection of appropriate locoregional adjuvant treatment after primary surgery.

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.