The effect on the small bowel of 5-FU and oxaliplatin in combination with radiation using a microcolony survival assay

<p>Abstract</p> <p>Background</p> <p>In locally advanced rectal cancer, 5-Fluorouracil (5-FU)-based chemoradiation is the standard treatment. The main acute toxicity of this treatment is enteritis. Due to its potential radiosensitizing properties, oxaliplatin has recently been incorporated in many clinical chemoradiation protocols. The aim of this study was to investigate to what extent 5-FU and oxaliplatin influence the radiation (RT) induced small bowel mucosal damage when given in conjunction with single or split dose RT.</p> <p>Methods</p> <p>Immune competent balb-c mice were treated with varying doses of 5-FU, oxaliplatin (given intraperitoneally) and total body RT, alone or in different combinations in a series of experiments. The small bowel damage was studied by a microcolony survival assay. The treatment effect was evaluated using the inverse of the slope (D₀) of the exponential part of the dose-response curve.</p> <p>Results</p> <p>In two separate experiments the dose-response relations were determined for single doses of RT alone, yielding D₀values of 2.79 Gy (95% CI: 2.65 - 2.95) and 2.98 Gy (2.66 - 3.39), for doses in the intervals of 5-17 Gy and 5-10 Gy, respectively. Equitoxic low doses (IC5) of the two drugs in combination with RT caused a decrease in jejunal crypt count with significantly lower D₀: 2.30 Gy (2.10 - 2.56) for RT+5-FU and 2.27 Gy (2.08 - 2.49) for RT+oxaliplatin. Adding both drugs to RT did not further decrease D₀: 2.28 Gy (1.97 - 2.71) for RT+5-FU+oxaliplatin. A clearly higher crypt survival was noted for split course radiation (3 × 2.5 Gy) compared to a single fraction of 7.5 Gy. The same difference was seen when 5-FU and/or oxaliplatin were added.</p> <p>Conclusion</p> <p>Combining 5-FU or oxaliplatin with RT lead to an increase in mucosal damage as compared to RT alone in our experimental setting. No additional reduction of jejunal crypt counts was noted when both drugs were combined with single dose RT. The higher crypt survival with split dose radiation indicates a substantial recovery between radiation fractions. This mucosal-sparing effect achieved by fractionation was maintained also when chemotherapy was added.</p

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC

Prospective study of daily low-dose nedaplatin and continuous 5-fluorouracil infusion combined with radiation for the treatment of esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum) and continuous infusion of 5-fluorouracil (5-FU) with radiation in patients with esophageal squamous cell carcinoma.</p> <p>Methods</p> <p>Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day) was administered daily and 5-FU (500 mg/body/day) was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival.</p> <p>Results</p> <p>Twenty-two patients (72.7%) completed the regimen of chemoradiotherapy. Twenty patients (60.6%) achieved a complete response, 10 patients (30.3%) a partial response. One patient (3.0%) had a stable disease, and 2 (6.1%) a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%). For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8%) and the median number of courses was 3 (range, 1-5). The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease.</p> <p>Conclusion</p> <p>The treatment used in our study may yield a high complete response rate and better survival for each stage of esophageal squamous cell carcinoma.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00197444</p

Residual hepatocellular carcinoma after oxaliplatin treatment has increased metastatic potential in a nude mouse model and is attenuated by Songyou Yin

<p>Abstract</p> <p>Background</p> <p>The opposite effects of chemotherapy, which enhance the malignancy of treated cancers such as hepatocellular carcinoma (HCC), are not well understood. We investigated this phenomenon and corresponding mechanisms to develop a novel approach for improving chemotherapy efficacy in HCC.</p> <p>Methods</p> <p>Human hepatocellular carcinoma cell lines HepG2 (with low metastatic potential) and MHCC97L (with moderate metastatic potential) were used for the in vitro study. An orthotopic nude mouse model of human HCC was developed using MHCC97L cells. We then assessed the metastatic potential of surviving tumor cells after in vitro and in vivo oxaliplatin treatment. The molecular changes in surviving tumor cells were evaluated by western blot, immunofluorescence, and immunohistochemistry. The Chinese herbal extract Songyou Yin (composed of five herbs) was investigated in vivo to explore its effect on the metastatic potential of oxaliplatin-treated cancer cells.</p> <p>Results</p> <p>MHCC97L and HepG2 cells surviving oxaliplatin treatment showed enhanced migration and invasion in vitro. Residual HCC after in vivo oxaliplatin treatment demonstrated significantly increased metastasis to the lung (10/12 vs. 3/12) when re-inoculated into the livers of new recipient nude mice. Molecular changes consistent with epithelial-mesenchymal transition (EMT) were observed in oxaliplatin-treated tumor tissues and verified by in vitro experiments. The Chinese herbal extract Songyou Yin (4.2 and 8.4 g/kg) attenuated EMT and inhibited the enhanced metastatic potential of residual HCC in nude mice (6/15 vs. 13/15 and 3/15 vs. 13/15, respectively).</p> <p>Conclusions</p> <p>The surviving HCC after oxaliplatin treatment underwent EMT and demonstrated increased metastatic potential. Attenuation of EMT by Songyou Yin may improve the efficacy of chemotherapy in HCC.</p

NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery).</p> <p>Methods</p> <p>A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis.</p> <p>Results</p> <p>A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant <it>GSTP1 </it>(Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, <it>p </it>= 0.047).</p> <p>Conclusions</p> <p>The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01316328">NCT01316328</a></p

Local Hyperthermia and Radiation: A biologically-oriented clinical scheduling

In a series of animal tumor studies, heat was directly delivered into the tumor mass with an interstitial applicator. After hyperthermia (44°-45°C for 45 minutes) or radiation alone (3x10 Gy), only a slight delay in tumor growth was observed, while the combined treatment, either simultaneous or sequential (i.e., heat delivered four hours after irradiation), appeared to be the most effective. The cure rate in the two combined treatment groups was 100%, in contrast to the lack of cure in the first two groups. The simultaneous use of heat and x-ray appeared to be slightly more effective than the sequential schedule; in all cases, no increase in radiation effects on normal tissue could be observed. For clinical studies, 47 patients with a total of 101 neck node metastases from head and neck cancer have been treated in order to compare tumor response to at least two different combinations of treatment modalities in the same patient. All patients were irradiated according to a multiple daily fractionation (MDF) scheme (2+1.5+1.5 Gy/day, 4-hour intervals, 5 days/week), and hyperthermia (42°-43°C, 45 minutes) was delivered every other day Immediately after the second daily radiation fraction, by means of an external applicator operating at 500 MHz. With this schedule, heat is delivered simultaneously with the second and sequentially with the first and third radiation fractions. In halfthe patients, misonidazole was also administered (1.2 g/m2 up to a total dose of 12 g/m2). The data indicate that multimodality treatments seem to be more effective than conventional fractionation or MDF alone. In particular, the best response was obtained when MDF was combined with both misonidazole and hyperthermia. No increased radiation reactions have ever been observed in patients treated with hyperthermia also; all side effects depend mainly on misonidazole toxicity

Hyperthermia and paclitaxel--epirubicin chemotherapy: enhanced cytotoxic effect in a murine mammary adenocarcinoma.

Multimodality therapy is considered of great interest in the treatment of locally advanced solid tumours. In previous experiments, paclitaxel (TX) and epirubicin (EP) were combined with different schedules, obtaining a superadditive effect on the growth of a murine mammary carcinoma. In the present study, the authors have analysed the possible use of hyperthermia (HT) to increase the efficacy of TX and EP combinations. Tumours were transplanted into the right hind foot of female hybrid (C3D2F1) mice. Both TX and EP were administered i.p in two different doses. Hyperthermia was applied using a water bath at 43.2 degrees C for 1 h. Results were analysed in terms of Tumour Growth Delay (TGD). The maximum tolerated doses in combined protocols were TX 45 mg/kg and EP 9 mg/kg, with an interval time of 24h between the two administrations. TGDs of some of the schedules performed are reported: EP + HT = 11 days, TX + HT = 16 days, TX + EP (with an interval time of 24 h) = 14 days, and TX + EP + HT = 22 days. In the experimental model, HT significantly increases the effects of both TX and EP. TX + EP + HT treatment is the most effective (significantly different from TX + EP), but not in a significant way when compared to TX + HT treatment. These results suggest the possible use of a TX + HT protocol for local tumour response, whereas EP could be added in order to achieve a better systemic control