Differences In Overall Toxicity Research Articles

Comparison of adverse reactions of spiramycin versus pyrimethamine/sulfadiazine treatment of toxoplasmosis in pregnancy: is spiramycin really the drug of choice for unproven infection of the fetus?

Background Therapeutic regimens for the treatment of toxoplasmosis are not standardized. Treatment strategy mainly at the end of the second and the beginning of the third trimester, especially in cases of negative prenatal diagnosis, is the least uniform. In some situations, the choice of treatment may be ambiguous, and adverse drug reactions of the therapy should be taken into consideration. Methods Adverse drug reactions of anti-toxoplasma therapy with spiramycin (n = 77) versus pyrimethamine/sulfadiazine (n = 35) were compared in 112 pregnant women. Results Up to 36.6% of women reported adverse reactions to the treatment overall (n = 41). Out of those 38.9% (n = 30) were treated with spiramycin and 31.4% (n = 11) with pyrimethamine/sulfadiazine. Toxic allergic reactions were the only indication for discontinuation of treatment in 8.9% of patients (n = 10), where 9.1% (n = 7) were reported in spiramycin and 8.6% (n = 3) in pyrimethamine/sulfadiazine cohort. Neurotoxic complications (acral paraesthesia) were significantly more frequent during the therapy with spiramycine in 19.5% (n = 15) compared to no cases in pyrimethamine/sulfadiazine group (p = .003). Other adverse drug reactions, such as gastrointestinal discomfort, nephrotoxicity, vaginal discomfort were reported, but the differences between the cohorts were not significant. Conclusions The superiority of one of the therapeutic regimens was not statistically demonstrated, since the differences in overall toxicity or incidence of toxic allergic reactions between the cohorts were not confirmed (p = .53 and p = 1.00, respectively). However, although the isolated neurotoxicity of spiramycin was the only significant adverse reaction demonstrated in this study, pyrimethamine/sulfadiazine therapy should be preferred, because it is known to be more effective and with limited adverse reactions.

Chemotherapy for elderly colorectal cancer patients at a tertiary hospital in South Africa.

Introductionsurgical treatment of colorectal cancer (CRC) in elderly patients has improved, but data on the tolerability and benefits of adjuvant and palliative chemotherapy in this growing population remains scarce.Methodswe conducted a retrospective study to compare chemotherapy-associated toxicities in CRC patients aged < 70 years and ≥ 70 years at Tygerberg Hospital (South Africa). We also assessed tumor-related mortality, progression free survival (PFS), and overall survival (OS) including predictive factors of OS.Resultsa total of 50 patients received either adjuvant or palliative chemotherapy. There was no difference in overall toxicity between the two groups. Out of the 50 patients, 8 (16%) had Grade 3-4 toxicity. 4 of these patients made up 15% of the < 70 years age group, whereas the other 4 made up 17% of the ≥ 70 years age group. The mean follow-up time was 47.5 months (95% CI 41.5 - 53.5 months). The 5-year over-all survival rate for stage II and III patients < 70 years and ≥ 70 years were 80.9% and 69.5%, respectively, and not significantly different (P = 0.52). Furthermore, the 5-year progression-free survival rates of the < 70 and ≥ 70 age groups were 70.7% and 58.8%, respectively, and also not statistically significantly different (P = 0.49). For stage IV patients, there were no significant differences in survival between the two age groups.Conclusionthe benefits from adjuvant and palliative chemotherapy for elderly CRC patients are similar to that of younger patients. Therefore, standardized adjuvant and palliative chemotherapy is recommended for elderly patients.

1737O - Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on the experimental thoracic radiotherapy (TRT) arms of CALGB 30610 (Alliance) / RTOG 0538

BackgroundThe optimal TRT regimen for LSCLC remains to be defined. CALGB 30610/RTOG 0538 started as a 3 arm study designed to discontinue one of 2 experimental TRT arms based on interim toxicity assessment, while the remaining arm would be compared against standard 4500 cGy (twice-daily) TRT. MethodsPer protocol, the interim endpoint was calculated based on treatment related grade 3+ non-hematologic toxicity, grade 4 hematologic toxicity, failure to complete 4 cycles of chemotherapy, and any grade 5 toxicity. The analysis included the initial 70 patients assigned to each of the 7000 cGy (once daily) and the 6120 cGy (concomitant boost) study arms. The initial analysis was conducted May 21, 2012 and an updated analysis of the same patient population was performed April 15, 2019. ResultsThere was not a significant difference in toxicity scoring between the regimens, either in the 2012 assessment or the updated analysis. Overall grade 3, 4, and 5 treatment related adverse events were 21.4%, 54.3%, and 0% for 7000 cGy TRT compared with 20.0%, 57.1% and 1.4% for 6120 cGy TRT, while rates of non-hematologic toxicity were 10.0%. 12.9% and 0% for 7000 cGy TRT compared with 12.9%, 14.3%, and 1.4% with 6120 cGy TRT. Grade 3 pneumonitis was reported in 2 patients (2.9 %) in each cohort. Grade 4 dyspnea was observed in 4 patients (5.7 %) in the 6120 cGy cohort but was not reported in patients treated with 7000 cGy. ConclusionsBoth TRT regimens, 7000 cGy daily and 6120 cGy concomitant boost, concurrent with cisplatin and etoposide chemotherapy, appear to be tolerable without unexpected toxicity. A decision to discontinue the 6120 cGy arm in December 2012 was based on the toxicity distribution, as a significant difference in overall toxicity was not observed. Further details of toxicity and the scoring system applied will be presented. The phase III portion of the study comparing 7000 cGy TRT to 4500 cGy TRT is near completion. Clinical trial identificationCALGB 30610 / RTOG 0538 Identifier: NCT00632853. Legal entity responsible for the studyAlliance for Clinical Trials in Oncology. FundingNational Cancer Institute. Support: U10CA180821, U10CA180882, U10CA180868, U10CA180820, U10CA233330, U10CA180888; https://acknowledgments.alliancefound.org. DisclosureAll authors have declared no conflicts of interest.

Efficacy of a Propolis-Based Syrup (FARINGEL) in Preventing Radiation-Induced Esophagitis in Locally Advanced Lung Cancer

Aim: To evaluate the efficacy of a propolis-based syrup, FARINGEL®, in preventing radiation-induced esophagitis in locally advanced lung cancer patients. Methods. Patients were treated with concurrent chemoradiotherapy (CRT) using involved-field radiotherapy (RT). Every patient received FARINGEL at the beginning of CRT until the first follow-up. The data of the study group were compared with the data of a control group treated without the administration of the syrup. Results: Forty-five patients were enrolled. Forty-one (91.1%) completed the protocol and were evaluable for esophagitis. Grade ≥2 toxicity occurred in 9/41 patients (22%). No differences in overall toxicity were detected between the study group and the control group (n = 55, 60.9 vs. 54.5%; p = ns). Grade 2–3 esophagitis was lower in the study group in comparison with the control group (22 and 38%, respectively), but statistical significance was not reached (p = 0.09). However, the onset of grade ≥2 esophagitis was delayed in the study group compared to the control group, occurring at higher doses of RT (41.8 vs. 25.4 Gy; p < 0.001). Furthermore, the mean number of interruption days for esophagitis was lower in the study group than in the control group (0.6 ± 2.0 vs. 2.1 ± 3.6; p = 0.025). Conclusion: FARINGEL was well-tolerated and delayed esophagitis that was induced by CRT for locally advanced lung cancer.

Effectiveness and toxicity of high-dose cyclophosphamide in obese versus non-obese patients receiving allogeneic hematopoietic stem cell transplant.

To determine if there is a difference in toxicity and effectiveness between obese and non-obese patients who receive high-dose cyclophosphamide (Cy) prior to allogeneic hematopoietic stem cell transplant (allo-HCT). Patients were included in this study if they were at least 18 years of age and received high-dose Cy in combination with total body irradiation (CyTBI) or busulfan (BuCy) prior to allo-HCT between 1 January 2008 and 29 February 2012. The primary endpoint was the difference in overall toxicity between obese and non-obese patients. Secondary objectives examined differences in effectiveness between groups assessed by relapse at day +100, relapse at 1 year, death at 1 year, chimerisms at days +30, +60, and +90, and incidence of acute graft versus host disease (aGVHD). Sixty-one patients met the inclusion criteria, 28 obese and 33 non-obese. Overall toxicity was greater in obese patients compared to non-obese patients (82% vs. 52%, OR 4.3 [95% CI 1.3-14.1]; p = 0.01), which was driven by a greater incidence of renal dysfunction (79% vs. 48%, OR 3.9 [95% CI 1.3-12.1]; p = 0.02). There were no differences in rates of grade 3 or 4 toxicity, hepatic dysfunction, or any measure of effectiveness between groups. Obese patients receiving high-dose Cy and allo-HCT are at increased risk for toxicity, although there appears to be no difference in the rate of relapse or survival between obese and non-obese patients.

Reply to Intra‐arterial chemotherapy for head and neck cancer

Thank you for the opportunity to respond to the letter by Rasch et al. We are pleased they have provided additional data from a subset analysis, which sheds light on the true value of intra-arterial (IA) cisplatin chemoradiation. The subset analysis included all patients who were eligible for unilateral infusion based on the more stringent Dutch criteria, and whose primary tumor volume exceeded a total of 30 mL. It is striking to observe that local control was significantly better in the IA group compared with the intravenous group among this cohort of patients (hazard ratio [HR], 0.17; 95% confidence interval [95% CI], 0.05-0.60 [P = .0025]). Although this benefit from IA treatment was limited to the 14 of 26 patients with a large (>30 mL) tumor not extending across the midline (HR, 0.14; 95% CI, 0.03-0.72), no significant benefit was observed in the remaining 3 groups. This led Rasch et al to conclude that there is no overall difference between IA versus intravenous cisplatin chemoradiation. However, had most of the 30 patients with high-volume disease who were receiving bilateral IA infusions been treated with a unilateral approach using the less stringent North American criteria, it is our opinion that the rate of local disease control would likely have been improved. In addition, there were 29 patients in the low-volume group who received bilateral infusions and again, some of them may have benefited from a unilateral IA infusion. As we previously pointed out in the editorial1 accompanying their article,2 bilateral IA infusions are required in <5% of patients and clearly are suboptimal for local disease control. Given that 56% of patients in the IA arm received a bilateral infusion, we believe that the negative effect of the suboptimal infusions may be very real in this trial. Although patients with low tumor volume and positivity for the human papillomavirus have a better prognosis, randomized trials are still required to determine whether less intensive chemoradiation protocols are feasible for such subsets. On the contrary, if there is no apparent difference in overall toxicity between the 2 regimens, as shown in the Dutch trial, we believe that the more intensive IA cisplatin chemoradiation protocol is an option that many patients would chose. K. Thomas Robbins MD*, Stephen B. Howell MD , * Division of Otolaryngology Head and Neck Surgery, Southern Illinois University School of Medicine, Simmons Cancer Institute at SIU, Springfield, Illinois, Department of Medicine, Moores UCSD Cancer Center, University of California at San Diego, San Diego, California.

Interim safety analysis of a phase II study of erlotinib (E) alone or combined with fulvestrant (F) in previously treated patients with advanced non-small cell lung cancer (NSCLC)

19091 Background: Laboratory work shows that NSCLC cells and primary tumors express estrogen receptors (ER) that contribute to growth promotion (Stabile et al. Cancer Res. 62: 2141, 2002; Weinberg et al. Cancer Res. 65: 11287, 2005). Preclinical evaluation demonstrates considerable interaction between the ER and EGFR pathways with additive effects on NSCLC cell lines when both pathways are inhibited. We designed a phase II study to evaluate whether inhibition of ER with the ER downregulator, fulvestrant (F), could add to the anti-tumor efficacy of EGFR inhibition with erlotinib (E). The study design includes an interim safety analysis after 5 patients receive E+F, as no safety data with this combination was available at study onset. Methods: Men and women (pre- and post-menopausal) with advanced NSCLC and at least one prior chemotherapy regimen are randomly assigned in a 2:1 ratio to receive E (150 mg PO qd) with or without high-dose F (500 mg IM q2wk x 3, then q4wk). The primary endpoint is response rate at 2 months. Secondary endpoints include correlation between response and ERα, ERβ, EGF/HER-1 receptor and HER-2/neu expression. Results: 14 patients have been enrolled, 9 assigned to E+F (one withdrew prior to therapy) and 5 to E. On the E+F arm, 1 patient withdrew at d18 for a grade 3 rash. On the E arm, 1 patient had visible progression of a chest wall mass at d28. All remaining patients completed at least 8 weeks of therapy. One patient receiving E+F developed a GI bleed complicated by MI at d95. No other grade 3 or 4 toxicities were seen. The most common toxicity was rash, with little difference in overall toxicity between the two arms. Conclusions: In this group of previously treated men and women with NSCLC, the tolerability of E+F is acceptable. Therefore, the Data Safety and Monitoring Board allowed the study to continue. Per protocol, we can now expand the study beyond UCLA, and we plan to involve the TORI research network to help complete accrual and evaluate for efficacy of the combination in men and women with advanced NSCLC. [Supported by NIH Lung Cancer SPORE P50-CA90388 and P50-CA90440, AstraZeneca, Genentech, Stiles Program] Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Genentech™ BioOncology

The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases

To systematically review the evidence for the use of stereotactic radiosurgery in adult patients with brain metastases. Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncology (ASCO) (1997-2004), ASTRO (1997-2004), and the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. For patients with newly diagnosed brain metastases, managed with whole-brain radiotherapy alone vs. whole-brain radiotherapy and radiosurgery boost, there were three randomized controlled trials, zero prospective studies, and seven retrospective series (which satisfied inclusion criteria). For patients with up to three (<4 cm) newly diagnosed brain metastases (and in one study up to four brain metastases), radiosurgery boost with whole-brain radiotherapy significantly improves local brain control rates as compared with whole-brain radiotherapy alone (Level I-III evidence). In one large randomized trial, survival benefit with whole-brain radiotherapy was observed in patients with single brain metastasis. In this trial, an overall increased ability to taper down on steroid dose and an improvement in Karnofsky performance status was seen in patients who were treated with radiosurgery boost as compared with patients treated with whole-brain radiotherapy alone. However, Level I evidence regarding overall quality of life outcomes using a validated instrument has not been reported. All randomized trials showed improved local control with the addition of radiosurgery to whole-brain radiotherapy. For patients with multiple brain metastases, there is no overall survival benefit with the use of radiosurgery boost to whole-brain radiotherapy (Level I-III evidence). Radiosurgery boost is associated with a small risk of early or late toxicity. In patients treated with radiosurgery alone (withholding whole-brain radiotherapy) as initial treatment, there were 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series. There is Level I to Level III evidence that the use of radiosurgery alone does not alter survival as compared to the use of whole-brain radiotherapy. However, there is Level I to Level III evidence that omission of whole-brain radiotherapy results in poorer intracranial disease control, both local and distant (defined as remaining brain, outside the radiosurgery field). Quality of life outcomes have not been adequately reported. Radiosurgery is associated with a small risk of early or late toxicity. Radiosurgery as salvage for patients with brain metastases was reported in zero randomized trials, one prospective study, and seven retrospective series. Based on Level I-III evidence, for selected patients with small (up to 4 cm) brain metastases (up to three in number and four in one randomized trial), the addition of radiosurgery boost to whole-brain radiotherapy improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain metastasis, radiosurgery boost with whole-brain radiotherapy improves survival. There is a small risk of toxicity associated with radiosurgery boost as compared with whole-brain radiotherapy alone. In selected patients treated with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, local and distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I-III evidence). Whether neurocognition or quality of life outcomes are different between initial radiosurgery alone vs. whole-brain radiotherapy (with or without radiosurgery boost) is unknown, because this has not been adequately tested. There was no statistically significant difference in overall toxicity between those treated with radiosurgery alone vs. whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized study. There is insufficient evidence as to the clinical benefit/risks radiosurgery used in the setting of recurrent or progressive brain metastases, although radiographic responses are well-documented.

Tandem screening of toxic compounds on GFP-labeled bacteria and cancer cells in microtiter plates

A 96-well fluorescence-based assay has been developed for the rapid screening of potential cytotoxic and bacteriocidal compounds. The assay is based on detection of green fluorescent protein (GFP) in HeLa human carcinoma cells as well as gram negative ( Escherichia coli) and gram positive bacteria ( Mycobacterium avium). Addition of a toxic compound to the GFP marked cells resulted in the loss of the GFP fluorescence which was readily detected by fluorometry. Thirty-nine distinct naphthoquinone derivatives were screened and several of these compounds were found to be toxic to all cell types. Apart from differences in overall toxicity, two general types of toxic compounds were detected, those that exhibited toxicity to two or all three of the cell types and those that were primarily toxic to the HeLa cells. Our results demonstrate that the parallel screening of both eukaryotic and prokaryotic cells is not only feasible and reproducible but also cost effective.

Patient characteristics compete with dose as predictors of acute treatment toxicity in early phase clinical trials.

The purpose of this study was to identify patient characteristics that may be risk factors or markers of susceptibility to adverse treatment effects in cancer Phase I and II clinical trials. A total of 459 patients enrolled in 23 therapeutic Phase I and II studies at the Fox Chase Cancer Center were included in the analysis. Patient-specific characteristics, medical and treatment history, doses of experimental agents, and graded toxicities were extracted from case report forms. We developed a novel summary measure, the toxicity index (TI), to better discriminate patients on the basis of their overall toxicity experiences. Mixed model ANOVA was used to model TI on the basis of data from all trials using a specific agent. Generalized estimating equations in the context of binary logistic regression were used to model dose-limiting toxicity. Seventeen pretreatment factors, including performance status, alkaline phosphatase, total bilirubin, serum creatinine, and tobacco use, emerged as significant predictors of toxicity as defined by dose-limiting toxicity or TI. Unexpectedly, dose was not always a predictor of toxicity. Even for values within the normal range, the TI identified serum bilirubin and alkaline phosphatase as predictors of toxicity after treatment with docetaxel and alkaline phosphatase as a predictor for toxicity after treatment with irinotecan. Independent of dose, certain pretreatment characteristics, including measures of organ function that are in the normal range, were found to be predictors of treatment toxicity. Because of its sensitivity to differences in overall toxicity, the TI should prove to be a useful tool for identifying predictors of chemotherapy-related toxicity.

ANTITUMOR-ACTIVITY AND TOXICITY OF CONTINUOUS-INFUSION VERSUS BOLUS ADMINISTRATION OF BLEOMYCIN IN 2 HETEROTRANSPLANTED HUMAN TESTICULAR CANCER CELL-LINES

The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity.

The relative toxicity of nonsteroidal antiinflammatory drugs

Toxicity Index scores were computed from symptoms, laboratory abnormalities, and hospitalizations attributed to nonsteroidal antiinflammatory drug (NSAID) therapy in 2,747 patients with rheumatoid arthritis receiving 5,642 courses of 11 NSAIDs over 8,481 patient-years. Substantial differences in overall toxicity were found, the differences between drugs often being clinically significant (2-3 times as toxic) and highly statistically significant. The results strengthened after adjustment for differing patient characteristics, held generally across multiple ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data bank centers, and persisted after use of different techniques for the weighting of side effects. The most toxic side effects were experienced by patients taking indomethacin (mean +/- SEM score 3.99 +/- 0.58), tolmetin sodium (3.96 +/- 0.74), and meclofenamate sodium (3.86 +/- 0.66). Least toxic were coated or buffered aspirin (1.19 +/- 0.10), salsalate (1.28 +/- 0.34), and ibuprofen (1.94 +/- 0.43). The most toxic drugs were generally taken in the lowest relative doses. There are statistical differences in overall toxicity between different NSAIDs as used in rheumatoid arthritis, and these differences are both clinically and statistically significant.