Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

<p>Abstract</p> <p>Background</p> <p>In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.</p> <p>Findings</p> <p>Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.</p> <p>Conclusions</p> <p>When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00455351">NCT00455351</a></p

Serum-borne factors in cancer patients with advanced cachexia: influence on adipose cells

Background: The clinical syndrome cancer cachexia is recognized by a considerable weight loss being out of proportion to any reduction in energy intake. The underlying mechanisms are not completely known, but the marked weight loss is attributable to depletion of adipose tissue as well as skeletal muscle mass. Enhanced lipolysis in adipocytes, apoptosis of preadipocytes may be important for loss of adipose tissue.Results: Sera from cachectic cancer patients induced apoptosis in cultured human preadipocytes at a higher rate than sera from non-cachectic cancer patients (control group). There was a tendency towards increased mRNA levels of the pro-apoptotic Bcl-2 gene Bax after incubation of preadipocytes with cachectic sera. Moreover, the mRNA levels of anti-apoptotic Bcl-XL and pro-apoptotic Bcl-XS were increased and decreased, respectively, as compared to incubation with control sera. However, lipolysis was not enhanced in cultured human adipocytes after incubation with sera from cachectic cancer patients as compared to non-cachectic cancer patients.Methods: Serum samples from cachectic cancer patients (n=8) and non-cachectic cancer patients (n=6) were collected. Human SGBS (Simpson-Golabi-Behmel syndrome) preadipocytes and differentiated adipocytes were incubated in the presence of serum from cachectic and non-cachectic (control) cancer patients. Induction of apoptosis and necrosis was examined by cell staining with Hoechst 342 (HO342) and propidium iodide (PI), respectively. Expression of pro- and anti-apoptotic Bcl-2 genes was measured by quantitative RT-PCR. Lipolysis was monitored by measuring the release of radiolabeled fatty acids.Conclusion: Our in vitro data suggest that apoptosis of preadipocytes can be increased by serum-borne factors in cancer cachexia. Death or survival of preadipocytes may depend on the balance of pro- and anti-apoptotic mediators. Further studies of patients with cancer cachexia will be needed to reveal if the disease involves loss of adipose tissue due to apoptosis of preadipocytes. We could not show that serum-borne factors associated with cachexia have a major impact on lipolysis in cultured human adipocytes.Adipobiology 2009; 1: 57-66

Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer

Background Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. Methods In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). Results In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). Conclusion In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression

Liver transplantation for secondary liver tumours: The difficult balance between survival and recurrence

Assessing the balance between survival and recurrence after transplantation for secondary liver tumours should be based on the type of cancer in question. For neuroendocrine liver metastases, high recurrence rates are clearly related to reduced long-term survival. For colorectal liver metastases, experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumours should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilising extended criteria donors and partial liver transplantation could be considered for this indication

The Potential Role of Liver Transplantation as a Treatment Option in Colorectal Liver Metastases

Liver resection is the only potentially curative treatment option in patients with liver metastases from colorectal cancer, but only about 20% of the patients are resectable. Liver transplantation of patients with unresectable liver metastases was attempted in the early era but it was abandoned due to poor survival. During the last decade, several case reports, a controlled pilot study, and a retrospective cohort study indicated that prolonged disease-free survival and overall survival can be obtained in a proportion of these patients. Strict selection criteria have not yet been well defined, but tumor load, response to chemotherapy, pretransplant carcinoembryonic antigen level, and time interval from resection of the primary tumor to transplant are all factors related to outcome. Carefully selected patients may obtain 5-year overall survival that approaches conventional indications for liver transplant. The scarcity of liver grafts is a significant problem, but this can possibly to some extent be addressed by use of extended criteria grafts and novel surgical techniques. There is an increasing interest in liver transplantation in these patients in the transplant community, and currently 4 clinical trials are active and are recruiting

Early increase in circulating carbonic anhydrase IX during neoadjuvant treatment predicts favourable outcome in locally advanced rectal cancer

Background Locally advanced rectal cancer (LARC) comprises heterogeneous tumours with predominant hypoxic components. The hypoxia-inducible metabolic shift causes microenvironmental acidification generated by carbonic anhydrase IX (CAIX) and facilitates metastatic progression, the dominant cause of failure in LARC. Methods Using a commercially available immunoassay, circulating CAIX was assessed in prospectively archived serial serum samples collected during combined-modality neoadjuvant treatment of LARC patients and correlated to histologic tumour response and progression-free survival (PFS). Results Patients who from their individual baseline level displayed serum CAIX increase above a threshold of 224 pg/ml (with 96 % specificity and 39 % sensitivity) after completion of short-course neoadjuvant chemotherapy (NACT) prior to long-course chemoradiotherapy and definitive surgery had significantly better 5-year PFS (94 %) than patients with below-threshold post-NACT versus baseline alteration (PFS rate of 56 %; p < 0.01). This particular CAIX parameter, ΔNACT, was significantly correlated with histologic ypT0–2 and ypN0 outcome (p < 0.01) and remained an independent PFS predictor in multivariate analysis wherein it was entered as continuous variable (p = 0.04). Conclusions Our results indicate that low ΔNACT, i.e., a weak increase in serum CAIX level following initial neoadjuvant treatment (in this case two cycles of the Nordic FLOX regimen), might be used as risk-adapted stratification to postoperative therapy or other modes of intensification of the combined-modality protocol in LARC. Trial registration ClinicalTrials.gov NCT0027869

Transplant oncology: assessment of response and tolerance to systemic chemotherapy for metastatic colorectal cancer after liver transplantation - a retrospective study

Solid organ recipients have a 2–5 fold increased risk of malignancy compared to the general population. Because of the broader indications for transplantation, it is anticipated that an increasing number of organ graft recipients will present with malignancy. There are limited data about responses and tolerance to chemotherapy in solid organ transplanted patients. Twenty‐three of 46 colorectal cancer (CRC) patients with nonresectable liver metastases who had undergone liver transplantation (LT) in three different studies were included. All patients had received chemotherapy both prior to LT and after LT, at recurrence of metastatic CRC (mCRC). Adverse reactions (grades 3–4) and clinical and radiological outcome were retrospectively registered. Overall survival was determined from start of palliative chemotherapy after LT. No graft rejection was observed. Chemotherapy for mCRC was overall well‐tolerated and there was no increased bone marrow toxicity registered after LT; however, mucositis and diarrhea were more frequent in post‐LT chemotherapy. Median overall survival from start of palliative chemotherapy after LT was 13 months. No graft loss was observed when chemotherapy for mCRC was given to LT recipients who had developed nonresectable metastases. Overall, the chemotherapy for mCRC was well‐tolerated, induced responses, and long‐term survival was obtained in some patients

Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks

Organ toxicity in cancer therapy is likely caused by an underlying disposition for given pathophysiological mechanisms in the individual patient. Mechanistic data on treatment toxicity at the patient level are scarce; hence, probabilistic and translational linkages among different layers of data information, all the way from cellular targets of the therapeutic exposure to tissues and ultimately the patient’s organ systems, are required. Throughout all of these layers, untoward treatment effects may be viewed as perturbations that propagate within a hierarchically structured network from one functional level to the next, at each level causing disturbances that reach a critical threshold, which ultimately are manifested as clinical adverse reactions. Advances in bioinformatics permit compilation of information across the various levels of data organization, presumably enabling integrated systems biology-based prediction of treatment safety. In view of the complexity of biological responses to cancer therapy, this communication reports on a “top-down” strategy, starting with the systematic assessment of adverse effects within a defined therapeutic context and proceeding to transcriptomic and proteomic analysis of relevant patient tissue samples and computational exploration of the resulting data, with the ultimate aim of utilizing information from functional connectivity networks in evaluation of patient safety in multimodal cancer therapy