Incidence Of Gastrointestinal Toxicity Research Articles

Establishment of a prediction model for severe acute radiation enteritis associated with cervical cancer radiotherapy.

Cervical cancer is one of the most common gynecological malignant tumors. Radiation enteritis (RE) leads to radiotherapy intolerance or termination of radiotherapy, which negatively impacts the therapeutic effect and seriously affects the quality of life of patients. If the incidence of RE in patients can be predicted in advance, and targeted clinical preventive treatment can be carried out, the side effects of radiotherapy in cervical cancer patients can be significantly reduced. Furthermore, accurate prediction of RE is essential for the selection of individualized radiation dose and the optimization of the radiotherapy plan. To analyze the relationships between severe acute RE (SARE) of cervical cancer radiotherapy and clinical factors and dose-volume parameters retrospectively. We included 50 cervical cancer patients who received volumetric modulated arc therapy (VMAT) from September 2017 to June 2018 in the Department of Radiotherapy at The First Affiliated Hospital Soochow University. Clinical and dose-volume histogram factors of patients were collected. Logistic regression analysis was used to evaluate the predictive value of each factor for SARE. A nomogram to predict SARE was developed (SARE scoring system ≥ 3 points) based on the multiple regression coefficients; validity was verified by an internal verification method. Gastrointestinal and hematological toxicity of cervical cancer VMAT gradually increased with radiotherapy and reached the peak at the end of radiotherapy. The main adverse reactions were diarrhea, abdominal pain, colitis, anal swelling, and blood in the stool. There was no significant difference in the incidence of gastrointestinal toxicity between the radical and postoperative adjuvant radiotherapy groups (P > 0.05). There were significant differences in the small intestine V20, V30, V40, and rectal V40 between adjuvant radiotherapy and radical radiotherapy after surgery (P < 0.05). Univariate and multivariate analyses revealed anal bulge rating (OR: 14.779, 95%CI: 1.281-170.547, P = 0.031) and disease activity index (DAI) score (OR: 53.928, 95%CI: 3.822-760.948, P = 0.003) as independent predictors of SARE. Anal bulge rating (> 0.500 grade) and DAI score (> 2.165 points) can predict SARE. The nomogram shows potential value in clinical practice.

P1318: THE IMPACT OF MELPHALAN DOSING IN COMBINATION WITH FLUDARABINE IN CLINICAL OUTCOMES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROMES RECEIVING ALLO-HCT

Background: Allogenic hematopoietic cell transplant (allo-HCT) is the only curative treatment option for many adults with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Fludarabine (Flu) and melphalan (Mel) reduced intensity conditioning (RIC) regimen is frequently used for older patients and those with comorbidities. Mel dosing based on body surface area raised concerns for patient under- or overdosing in prior report. Aims: Here we studied the impact of Mel dose per kilogram of actual body weight (mg/kg) on clinical outcomes of allo-HCT. Methods: We retrospectively evaluated patients with AML or MDS who underwent allo-HCT from an 8/8 HLA matched donor and received Flu/Mel (Mel dose of 100-140 mg/m2). The objectives were to compare overall survival (OS), relapsed free survival (RFS), non-relapse mortality (NRM), relapse, grade II-IV acute graft vs host disease (aGVHD), chronic GVHD (cGVHD), mucositis and gastrointestinal (GI) toxicity based on Mel mg/kg dosing. We calculated the median Mel mg/kg dose and compared the outcomes of patients receiving median and above versus below median dose. Results: From January 2008 to December 2020, 345 patients underwent allo-HCT with Flu/Mel, all patients received peripheral blood graft, 209 patients transplanted for AML and 136 for MDS. Patient characteristics are presented in Table 1. Median dose of Mel was 3.28 mg/kg (range, 1.61-6.21 mg/kg);173 patients received Mel ≥ 3.28 mg/kg and 172 patients received Mel < 3.28 mg/kg. Median follow up time for the entire study cohort was 36.5 months. For the Mel ≥ 3.28 mg/kg vs. Mel < 3.28 mg/kg groups, median OS was 57.5 months (95% CI: 39.5 – N.E) vs. 46.6 months (95% CI: 28.2 – 109.5, p=0.49) and median RFS was 51.4 months (95% CI: 30.7 – 70.4) vs. 29.7 months (95% CI: 18.1 – 98.0, p=0.36). Similarly, there were no significant differences between the Mel ≥ 3.28 mg/kg and Mel < 3.28 mg/kg groups in 2-year rates of relapse (19.9% vs. 23.8%, p=0.3) and NRM (20.9% vs. 25.4%, p=0.94; Figure 1D). The cumulative incidences of day 100 grade II-IV aGVHD (39.9% vs. 39.0%, p=0.86), grade III-IV aGVHD (9.2% and 9.3%, p=0.99) and moderate/severe cGVHD (67.6% vs.58.4%, p=0.19) were also similar for patients receiving Mel ≥ 3.28 mg/kg vs. Mel < 3.28 mg/kg. On multivariable analysis, the Mel dose/kg had no independent impact on OS, RFS, relapse, NRM, acute and chronic GVHD outcomes. OS was worse with KPS ≤ 80 (HR, 1.51, p=0.014) and HCT-CI ≤ 3 (HR, 1.68, p=0.004), while RFS was worse with KPS ≤ 80 (HR, 1.5, p=0.012), HCT-CI ≥ 3 (HR, 1.72, p=0.002) and high/very high DRI (HR, 1.36, p=0.046). KPS ≤ 80 (HR1.75, p=0.006) and HCT-CI ≥ 3 (HR,1.67, p=0.023) were also associated with higher NRM. Cumulative incidence of any grade mucositis for Mel ≥ 3.28 mg/kg vs. Mel < 3.28 mg/kg was 33.5% vs. 29.1% (p=0.37) and of grade III mucositis was 12.1% vs. 24.0%. None of the study patients experienced grade IV mucositis. Incidence of GI toxicity with non-infectious diarrhea following Flu/Mel chemotherapy of any grade was 65.3% vs. 60.5%, (p=0.35) and of grade III was 16.8% vs. 19.2% for patients received Mel ≥ 3.28 mg/kg vs. Mel < 3.28 mg/kg, respectively. We observed no grade IV GI toxicity on our study patients. Image:Summary/Conclusion: Our study showed no significate influence of Mel mg/kg dose on clinical outcomes of allo-HCT in patients with AML and MDS receiving Flu/Mel RIC. Similarly, mucositis and GI toxicities were not affected by the Mel mg/kg dose. These findings support Mel dosing based on body surface area when combined with Flu as RIC regimen used for allo-HCT.

Chemotherapy induced gastrointestinal toxicities.

Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.

Pharmacogenomic Single Nucleotide Polymorphism (SNP) Variants As Predictors of Toxicity Phenotypes in the Treatment of Acute Childhood Leukemia

Introduction: Despite cure rates in acute lymphoblastic leukemia (ALL) exceeding 90% in clinical trials, morbidity due to drug toxicities is high. Genetic polymorphisms can influence gene expression and activity, impacting pharmacokinetics and causing inter-individual variation in drug levels, which contributes to toxicity if levels are high or relapse if levels are low. We hypothesize that pharmacogenomic testing will identify patient specific variations in genes involved in metabolism of cytotoxic agents. This knowledge will allow clinicians to optimize therapy by providing pharmacogenomics based biomarkers related to increased toxicities. Data has shown that treatment interruptions and omissions due to toxicities affect outcomes and morbidities in children with cancer.Objective: To correlate pharmacogenomic biomarkers with toxicity phenotypes in children receiving therapy for ALL.Methods: This cross-sectional study involved subjects at a tertiary academic center (Fig. 1A). Subjects aged 1 year to 26 years with ALL treated after May 2012 were eligible. A total of 75 patients treated between 2012 and 2020 were included. Pharmacogenomic testing was performed on peripheral blood. Genomic DNA was tested for 118 single-nucleotide polymorphisms (SNP) in 55 genes for transport and metabolism of cytarabine, vincristine, methotrexate, dauno/doxorubicin, and mercaptopurine/thioguanine were analyzed using the Sequenom-based genotyping that uses MALDI-TOF based chemistry. SNPs were tested using logistic regression models for association with toxicities in additive, dominant, and recessive modes of inheritance. CTCAE v4.0 was used for grading all toxicities during the first 100 days of therapy. For endocrine (endo) and neurological (neuro) toxicities, 25 patients exhibited between grade 1-3 toxicities. For gastrointestinal (GI) toxicities, 25 patients exhibited between grade 2-3 toxicities. For hematological (heme) toxicities, 11 patients exhibited between grade 2-4 toxicities. Odds ratio and 95% confidence interval were calculated for each test and SNPs with association P-value <0.05 were considered significant. To conduct multivariable SNP combinations analysis, SNPs with univariate association p-value <0.1 were selected for each toxicity, and then SNP combinations (up to 3 SNPs per model) were tested for association with each toxicity. The combination model with the 1000 permutation p-value <0.05 and lowest BIC value was selected to build a SNP score after considering the mode of inheritance and the direction of association with the toxicity for the individual genotypes. A SNP score was generated by summation of genotype scores for the individual SNPs passing the top model. Patients were further classified into either of the 3 following SNP score groups: >0, 0 or <0.Results: For a GI toxicity score derived from 3 SNPs (TYMS-rs151264360, FPGS-rs1544105, and GSTM5-rs3754446), patients with >0 score had 79% incidence of GI toxicity (N=67) as compared to 10% in patients with score of 0 and 8% in patients with score <0 (p=2.07E-05, Fig 1B). For the SNP score (AKR1C3-rs6621365, ABCB1-rs4148737, and CTPS1-rs12067645) generated for heme toxicity, higher SNP scores were associated with high toxicity (p=0.003, Figure 1C). For neurotoxicity, the 3 SNPs (DCTD-rs6829021, SCL28A3-rs17343066, and CTPS1-rs12067635) involved were all in cytarabine metabolic pathway and predicted greater neurotoxicity (56%) with a score of >0; no toxicity was observed in patients with neurotoxicity score of <0 (p=0.0005, Fig. 1D). For SNP endo toxicity score (AKR1C3-rs1937840, TYMS-rs2853539, and CTS-rs648743), we observed 91% incidence of endo toxicity in patients with toxicity score of >0 (p=4.7E-08, Fig. 1E). None of the patients with a score of <0 experienced endo toxicity.Discussion: We identified germline SNPs predictive of toxicity phenotypes in a cohort of 75 subjects with ALL. The results of our multivariable SNP combination analysis suggest susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. Instead of a single SNP approach, identification of combinations of mutations in drug pathways increases the robustness of predicting a patient's response to chemotherapy. Our results provide promising SNP models that can help establish clinically relevant biomarkers allowing for individualization of cancer therapy to optimize treatment for each patient. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

English

BACKGROUND Breast cancer is a systemic disease that requires treatment with surgery, chemotherapy, radiation, endocrine therapy and biological therapy. Neoadjuvant chemotherapy is the recent treatment of locally advanced breast cancer. The purpose of this study was to assess the acute toxicity of paclitaxel-based dose-dense and conventional neoadjuvant chemotherapy in locally advanced female breast cancer patients. METHODS In this study, neoadjuvant paclitaxel was given to a hundred locally advanced breast malignancies of female patients. Three weekly paclitaxel 200 mg/m2 ( 4 courses) was given for fifty patients and weekly paclitaxel 80 mg/m2 (10 courses) was given for fifty patients along with four-course of three weekly doxorubicin 50 mg/m2 given in both arms. Chemotherapy-induced acute toxicities in both arms were assessed weekly. RESULTS There was a significant increase in the incidence of anaemia in weekly chemotherapy patients at 7th week (28 % verse 10 %, P - value 0.022) and neutropenic infection at 11th week (28 % verse 10 %, P - value 0.022). There was a non-statistically significant increase in the incidence of leukopenia, thrombocytopenia and paraesthesia and myalgia in the weekly arm. There was a significant increase in the incidence of gastrointestinal toxicity like grade 3 stomatitis (at 4th - week), nausea and vomiting (at 4th, 7th, and 11th week ) in three weekly chemotherapy patients. CONCLUSIONS In this study, acute neurological and haematological toxicities were more in the weekly neoadjuvant chemotherapy arm and acute gastrointestinal toxicities were more in the three weekly neoadjuvant chemotherapy arm. KEYWORDS Acute Toxicity, Neoadjuvant Paclitaxel Chemotherapy, Locally Advanced Breast Malignancy.

Outcome and safety analysis of endometrial cancer patients treated with postoperative 3D-conformal radiotherapy or intensity modulated radiotherapy

Background We sought to analyze the toxicity rates and the treatment outcomes in endometrial cancer (EC) patients treated with postoperative three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). Material and methods The clinical data of 646 EC patients treated with postoperative adjuvant 3DCRT (265 patients, 41%) or with IMRT (381 patients, 59%) between April 2007 and August 2019 were retrospectively analyzed. The primary endpoints were treatment-related acute and late gastrointestinal (GI) and genitourinary (GU) toxicities. The secondary endpoints were LC and overall survival (OS) and disease-free survival (DFS). Results Median follow-up time was 37 months. The rates for acute GI and GU toxicities of any grade for the entire group were 55.6% and 46.8%, respectively. Acute grade ≥2 GI toxicity was significantly less in patients treated with IMRT compared to those treated with 3DCRT (11.0% vs. 19.2%, p=.004). However, no significant difference grade ≥2 GU toxicities was observed between the 3DCRT and IMRT groups (15.1% vs. 11.0%; p=.15). Acute grade ≥2 GI and GU toxicities were higher in patients receiving systemic chemotherapy, while paraaortic field irradiation increases only the risk of acute grade ≥2 GI toxicity. Estimated 3-year late grade ≥3 GI toxicity rates in the 3DCRT- and IMRT-treated patients were 4.6% and 1.9% (p= .03), respectively. The patients treated with adjuvant ChT had higher rates of late serious GI complications than those without adjuvant ChT. No significant difference in terms of survival and disease control was observed between the 3DCRT and IMRT treatment groups. No significant factor for LC was found in the multivariate analysis. Conclusion In this multicentric study involving one of largest patient population, we found that IMRT-treated EC patients showed comparable clinical outcomes but with a lower incidence of GI toxicities compared with those treated with 3DCRT.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8–5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0–56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3–7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Cancer and microbiota in elderly patients: challenges and management

Aging is a major risk factor of cancers. In recent years, several studies highlighted a change in the diversity and the abundance of the intestinal microbiota associated with aging. Moreover, epidemiological studies, experimental and clinical studies have suggested that the microbiota is implicated in cancer physiopathology and could modulate the efficacy and the tolerance of oncological treatments, for example the incidence of gastrointestinal toxicity and infectious disease. In this review, our objective was first to described the main studies that have focused on the composition of the microbiota associated with aging, cancer and during cancer therapies. Second, we discussed challenges and perspectives on cancer management and research, in elderly patients. Finally, we assume that further studies will confirm that the composition of the intestinal microbiota could be considered as a biomarker of frailty that could be used to optimize cancer management in elderly patients.

Evaluation of High-Dose Melphalan Toxicity by Age in Patients Undergoing Autologous Stem Cell Transplant for Multiple Myeloma

Introduction Melphalan 200 mg/m2 on day -2 (Mel 200) is the standard conditioning regimen in autologous stem cell transplant (ASCT) for multiple myeloma (MM). This regimen is associated with significant gastrointestinal (GI) toxicity, including diarrhea, vomiting, and mucositis; therefore the dose may be reduced to 100-140 mg/m2 based on performance status or age. As the true difference in GI toxicity in older vs. younger patients is unknown, dose reductions may unnecessarily compromise efficacy outcomes. The objective of this study was to define the incidence of GI toxicity in patients age ≥ 60 vs. patients age Objectives Review dose adjustments for melphalan conditioning prior to ASCT in MM. Identify toxicities associated with melphalan conditioning for ASCT in MM. Compare melphalan toxicity between patients age ≥ 60 vs. patients age Methods A retrospective cohort study was conducted via medical record review of adult patients treated with Mel 200 followed by first ASCT for MM from September 2012 to September 2017. The primary endpoint was incidence of GI toxicity, defined by Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher diarrhea or grade 3 or higher mucositis during transplant admission. Secondary endpoints included subdivided primary endpoints, complete response rates, and measurements of recovery. Subgroup analyses were performed for patients age ≥ 65, and patients with renal impairment. Results A total of 167 patients were included, with 116 patients in the age Conclusion This single-center, retrospective medical record review demonstrated that patients older than age 60, particularly those 60 to 65 years of age, may receive Mel 200 with no difference in the incidence of GI toxicity compared to younger patients. Further study in a larger population of patients age 65 or older is needed to establish conclusions in this patient population.

Nationwide, Multicenter, Retrospective Study on High-Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

To present, analyze, and discuss results of a nationwide, multicenter, retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for low-, intermediate-, and high-risk prostate cancer. From 1995 through 2013, 524 patients, 73 (14%) with low-risk, 207 (40%) with intermediate-risk, and 244 (47%) with high-risk prostate cancer, were treated with HDR-BT as monotherapy at 5 institutions in Japan. Dose fractionations were 27Gy/2 fractions for 69 patients (13%), 45.5Gy/7 fractions for 168 (32%), 49Gy/7 fractions for 149 (28%), 54Gy/9 fractions for 130 (25%), and others for 8 (2%). Of these patients, 156 (30%) did not receive androgen deprivation therapy, and 202 patients (39%) did receive androgen deprivation therapy <1year, 112 (21%) for 1-3years, and 54 (10%) for >3years. Median follow-up time was 5.9years (range, 0.4-18.1years), with a minimum of 2years for surviving patients. After 5years, respective actuarial rates of no biochemical evidence of disease, overall survival, cause-specific survival, and metastasis-free survival for all patients were 92%, 97%, 99%, and 94%. For low/intermediate/high-risk patients, the 5-year no biochemical evidence of disease rates were 95%/94%/89%, the 5-year overall survival rates were 98%/98%/94%, the 5-year cause-specific survival rates were 98%/100%/98%, and the 5-year metastasis-free survival rates were 98%/95%/90%, respectively. The cumulative incidence of late grade 2 to 3 genitourinary toxicity at 5years was 19%, and that of late grade 3 was 1%. The corresponding incidences of gastrointestinal toxicity were 3% and 0% (0.2%). No grade 4 or 5 of either type of toxicity was detected. The findings of this nationwide, multicenter, retrospective study demonstrate that HDR-BT as monotherapy was safe and effective for all patients with low-, intermediate-, and high-risk prostate cancer.

Fractionated high-dose-rate brachytherapy as monotherapy in prostate cancer: Does implant displacement and its correction influence acute and late toxicity?

PurposeIn fractionated high-dose-rate brachytherapy (HDR-BT) for prostate cancer (PCa) with one implant for several fractions, dose delivery relies on reproducibility of catheter positions. However, caudal displacement of implanted catheters does occur between fractions and needs to be corrected. Our protocol prescribes correction of displacements > 3 mm. We investigated whether displacement and its corrections influence acute and late toxicity incidences. Methods and MaterialsWe analyzed 162 PCa patients treated with HDR-BT monotherapy between 2007 and 2013. The implant remained in situ between the 4 fractions. Catheter displacement was assessed before each fraction using lateral X-ray images and corrected if needed. Genitourinary (GU) and gastrointestinal (GI) acute and late toxicities were assessed using clinical record forms and patient self-assessment questionnaires. ResultsImplant displacement corrections (DC) were needed in 71 patients (43.8%) whereas no DCs were needed in 91 patients (56.2%). No statistically significant differences were seen in acute and late grade ≥ 2 GU and GI toxicity incidences between DC and no DC groups. The maximum displacement nor the number of corrections had any influence on toxicity. ConclusionsThe occurrence and subsequent correction of implant displacements exceeding 3 mm during fractionated HDR-BT monotherapy for PCa did not lead to increased incidences of acute or late GU and GI toxicity. This indicates that our clinical protocol to correct displacements > 3 mm results in safe treatment regarding organ at risk toxicity.

Intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation

Prostate cancer (PC) is the most common cancer in men in the UK. Radiotherapy (RT) is a recognised treatment for PC and high-dose conformal radiotherapy (CRT) is the recommended standard of care for localised or locally advanced tumours. Intensity-modulated radiotherapy (IMRT) allows better dose distributions in RT. This report evaluates the clinical effectiveness and cost-effectiveness of IMRT for the radical treatment of PC. The following databases were searched: MEDLINE (1950-present), EMBASE (1980-present), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982-present), BIOSIS (1985-present), the Cochrane Database of Systematic Reviews (1991-present), the Cochrane Controlled Trials Register (1991-present), the Science Citation Index (1900-present) and the NHS Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, Health Technology Assessment) (1991-present). MEDLINE In-Process & Other Non-Indexed Citations was searched to identify any studies not yet indexed on MEDLINE. Current research was identified through searching the UK Clinical Research Network, National Research Register archive, the Current Controlled Trials register and the Medical Research Council Clinical Trials Register. In addition, abstracts of the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, and European Society for Therapeutic Radiology and Oncology conferences were browsed. A systematic literature review of the clinical effectiveness and cost-effectiveness of IMRT in PC was conducted. Comparators were three-dimensional conformal radiotherapy (3DCRT) or radical prostatectomy. Outcomes sought were overall survival, biochemical [prostate-specific antigen (PSA)] relapse-free survival, toxicity and health-related quality of life (HRQoL). Fifteen electronic bibliographic databases were searched in January 2009 and updated in May 2009, and the reference lists of relevant articles were checked. Studies only published in languages other than English were excluded. An economic model was developed to examine the cost-effectiveness of IMRT in comparison to 3DCRT. Four scenarios were modelled based on the studies which reported both PSA survival and late gastrointestinal (GI) toxicity. In two scenarios equal PSA survival was assumed for IMRT and 3DCRT, the other two having greater PSA survival for the IMRT cohort. As there was very limited data on clinical outcomes, the model estimates progression to clinical failure and PC death from the surrogate outcome of PSA failure. No randomised controlled trials (RCTs) of IMRT versus 3DCRT in PC were available, but 13 non-randomised studies comparing IMRT with 3DCRT were found, of which five were available only as abstracts. One abstract reported overall survival. Biochemical relapse-free survival was not affected by treatment group, except where there was a dose difference between groups, in which case higher dose IMRT was favoured over lower dose 3DCRT. Most studies reported an advantage for IMRT in GI toxicity, attributed to increased conformality of treatment compared with 3DCRT, particularly with regard to volume of rectum treated. There was some indication that genitourinary toxicity was worse for patients treated with dose escalated IMRT, although most studies did not find a significant treatment effect. HRQoL improved for both treatment groups following radiotherapy, with any group difference resolved by 6 months after treatment. No comparative studies of IMRT versus prostatectomy were identified. No comparative studies of IMRT in PC patients with bone metastasis were identified. The strength of the conclusions of this review are limited by the lack of RCTs, and any comparative studies for some patient groups. The comparative data of IMRT versus 3DCRT seem to support the theory that higher doses, up to 81 Gy, can improve biochemical survival for patients with localised PC, concurring with data on CRT. The data also suggest that toxicity can be reduced by increasing conformality of treatment, particularly with regard to GI toxicity, which can be more easily achieved with IMRT than 3DCRT. Whether differences in GI toxicity between IMRT and 3DCRT are sufficient for IMRT to be cost-effective is uncertain, depending on the difference in incidence of GI toxicity, its duration and the cost difference between IMRT and 3DCRT.

Melphalan 200 Mg/m2 (Mel200) Versus Melphalan 100 Mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients: A Prospective, Randomized Phase III Study

Background. Several trials have shown the superiority of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100.Aims. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM).Methods. Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone- doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2. All MEL courses were followed by stem cell reinfusion.Results. Two-hundred and ninety-eight patients (median age 57) were randomly assigned either to MEL200 (149 patients) or to MEL100 (149 patients). All patients were evaluated for response, EFS and OS in intention-to-treat analysis. Patient characteristics were similar in both groups with the exception of chromosomal 13 deletion, present in 69% of MEL200 and 45% of MEL100 patients (p=0.02). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. The very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). The median follow-up for censored patients was 40.5 months. The 4-years EFS was 44.5% in the MEL200 and 18.3% in the MEL100 group (HR=0.71, 95% CI 0.53–0.95, p=0.02). The 5-years overall survival (OS) was 59.2% in the MEL200 and 44.7% in the MEL100 group (HR=0.78, 95% CI 0.52–1.16, p=0.22). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were reported in 38% of MEL200 patients and in 19% of MEL100 patients (p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups.Conclusions. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS. Mel200 was associated with less gastrointestinal toxicity, including mucositis.

A Prospective, Randomized, Phase III Study of Melphalan 200 mg/m2 (Mel200) Versus Melphalan 100 mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients.

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM). Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone-doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2, both followed by stem cell reinfusion. Two-hundred and ninety-eight patients (median age 57) were randomized, 149 to MEL200 and 149 to MEL100. All patients were evaluated for response, EFS and OS. Patient characteristics were similar in both groups. Chromosomal 13 was deleted in 69% of MEL200 and 45% of MEL100 patients (p=0.015). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. In intention-to-treat analysis, the very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). After a median follow-up of 30.5 months, the 3-years EFS was 46% in the MEL200 and 26% in the MEL100 group (HR=0.7, 95% CI 0.51–0.97, p=0.03). The 3-years overall survival (OS) was 81% in the MEL200 and 73% in the MEL100 group (HR=0.69, 95% CI 0.42–1.13, p=0.14). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were more frequent in the MEL200 patients (38% versus 19%, p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS.

CNOP (Mitoxantrone) Chemotherapy Is Inferior to CHOP (Doxorubicin) in the Treatment of Patients with Aggressive Non-Hodgkin Lymphoma (Review).

Introduction: Mitoxantrone (M), an anthracenedion, was introduced in the early/mid 1980s as a more tolerable alternative to anthracyclines. This agent has a broad anti-tumour activity including lymphoma with potentially less cardiotoxicity than doxorubicin (D), which may be of particular importance in the elderly patient population. However, an important issue is whether M is as efficacious as D in the treatment of NHL patients.Methods: Through search of several relevant databases and direct contacts with lymphoma investigators worldwide, we identified seven randomized studies of previously untreated patients comparing CHOP and CNOP chemotherapy in aggressive NHL. In this analysis we included five trials where (D;50mg/m2) was compared with (M;10–12mg/m2; table) and the interval between chemotherapy courses was 3–4 weeks. Patients reported in the Pavlovsky article were included in the Bezwoda report, why analyses were performed separately with either but not both of these reports. Odds ratios of complete remission (CR) and overall survival (OS) were pooled using a fixed effects model.Results: CHOP was significantly superior to CNOP with regard to both CR rate and OS (figure a–b). No formal testing of side effects could be made. However, myelosuppression was similar with both regimens as was the incidence of infections and neutropenic fever episodes. In addition, clinical evidence of symptomatic congestive heart failure was not more frequent among patients treated with CHOP. In contrast, the incidence of gastrointestinal toxicity and alopecia was significantly higher in this patient group.Conclusion: CHOP chemotherapy is more efficacious than CNOP at equitoxic (myelosuppression) doses leading to higher CR rates and improved survival. This regimen is, however, also associated with more alopecia and gastrointestinal toxicity. [Display omitted] [Display omitted]

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of < or =2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m(2). The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m(2). Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m(2). Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 +/- 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC(0-infinity)) > 20 ng h/mL and 0 of 10 patients with an AUC(0-infinity) < or = 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m(2). The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m(2)). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

The combination of capecitabine and oxaliplatin in metastatic colorectal cancer.

Introduction Two randomized phase III studies were conducted in France comparing the combination of 5-fluorouracil (5-FU)/leucovorin (LV) regimen with or without oxaliplatin as first-line treatment for patients with metastatic colorectal cancer.1,2 Although each study employed a different schedule of administration of 5-FU/LV, both studies showed that the combination of 5-FU/LV plus oxaliplatin (FOLFOX regimen) resulted in a significantly improved overall response rate (RR; 53% vs. 16%1; P < 0.001 and 51% vs. 22%2; P = 0.0001) and median time to disease progression (8.7 months vs. 6.1 months1; P = 0.048 and 9.0 months vs. 6.2 months2; P = 0.0003) compared with patients treated with 5-FU/LV alone. In these studies, the overall survival was not significantly prolonged with the addition of oxaliplatin to 5-FU/LV. • Daily oral dosing with capecitabine results in sustained intracellular exposure to 5-FU that mimics continuous intravenous (I.V.) infusion of 5-FU. 3 The combined results of 2 large phase III studies in 1207 metastatic colorectal cancer patients comparing oral capecitabine with 5-FU/LV as first-line therapy showed that treatment with capecitabine led to a better overall RR (26% vs. 17%; P < 0.0002) compared with treatment with 5-FU/LV. 4 Furthermore, treatment with capecitabine also resulted in an improved toxicity profile, with the incidence of gastrointestinal toxicity (diarrhea, nausea, and stomatitis) significantly reduced (P < 0.001) compared with treatment with 5-FU/LV. oxaliplatin in place of 5-FU/LV. Further rationale for combining oxaliplatin with capecitabine includes preclinical evidence of synergistic activity of oxaliplatin with fluoropyrimidines as well as their single-agent efficacies in colorectal cancer, easier administration, and good safety profile.5

Technetium-99m labelled macroaggregated albumin arterial catheter perfusion scintigraphy: prediction of gastrointestinal toxicity in hepatic arterial chemotherapy.

Gastrointestinal toxicity from hepatic arterial infusion (HAI) of floxuridine in patients with liver metastases is probably due to extrahepatic perfusion or to partial escape of the drug from first-pass liver extraction. The aim of this study was to verify the role of technetium-99m-labelled macroaggregated albumin (99mTc-MAA) arterial catheter perfusion scintigraphy at the beginning of each chemotherapy cycle in decreasing or preventing gastrointestinal toxicity. We studied 167 consecutive patients. On the basis of the scintigraphic follow-up and the presence or absence of an intrahepatic arteriovenous shunt (IHAVS), we classified our patients into the following groups: (1) FU+ hepatic distribution pattern (DP), comprising 29 patients with regular scintigraphic follow-up who showed the expected distribution pattern at each control or a distribution pattern with transient alterations (extrahepatic escape) promptly reversed by the replacement of the catheter. Among these 29 patients there was one case of gastrointestinal toxicity. (2) FU- hepatic DP, comprising 128 patients who were evaluated with 99mTc-MAA only at the beginning of the first chemotherapy cycle, showed the expected distribution pattern and underwent HAI with no further scintigraphic evaluation. Among these 128 patients there were 28 cases of gastrointestinal toxicity. (3) FU+ pulmonary DP, comprising three patients with abnormally elevated pulmonary uptake (higher than 5%) and with regular scintigraphic follow-up. There were two cases of gastrointestinal toxicity among these three patients. (4) FU- pulmonary DP, comprising seven patients with abnormally elevated pulmonary uptake and without regular scintigraphic follow-up. There were four cases of gastrointestinal toxicity among these seven patients. The incidence of toxicity was significantly higher in group FU- hepatic DP than in group FU+ hepatic DP (21.9% vs 3.4%, P<0.05). In both the FU+ pulmonary DP and FU- pulmonary DP groups, the incidence of gastrointestinal toxicity was higher than 50%, with no significant difference between them. We conclude that, when performing 99mTc-MAA perfusion scintigraphy, the presence of an abnormally elevated pulmonary uptake (IHAVS higher than 5%) is the most relevant positive prognostic index for the development of gastrointestinal toxicity. Furthermore, in the absence of abnormal pulmonary uptake (IHAVS lower than 5%), strict scintigraphic follow-up is useful since it is able to promptly diagnose the presence of extrahepatic abdominal perfusion and thus to prevent the occurrence of gastrointestinal toxicity.