Carol Marquez

Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation

PURPOSEnTirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues.nnnMETHODS AND MATERIALSnTirapazamine 9 mg/m2 to 21 mg/m2 was given i.v. 1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 i.v. after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment.nnnRESULTSnSubjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping.nnnCONCLUSIONnMuscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing.

Effect of filgrastim (G-CSF) in hodgkin's disease patients treated with radiation therapy

PURPOSEnTo evaluate the effect of filgrastim (recombinant human G-CSF) on radiation-induced neutropenia in a well defined, homogenous patient population.nnnMETHODS AND MATERIALSnSeven patients who were to receive large field subdiaphragmatic irradiation after thoracic mantle fields for treatment of Hodgkins disease entered this study. They received daily subcutaneous (SC) injections of filgrastim during subdiaphragmatic irradiation. Total white blood cell (WBC) and absolute neutrophil cell (ANC) counts were measured and compared to a historical series of patients, and hematological toxicity was assessed. The endpoints of the study were nadir WBC and ANC counts and time to WBC and ANC recovery.nnnRESULTSnCompared to the historical series, filgrastim significantly increased the WBC and ANC throughout the period of subdiaphragmatic irradiation. Nadir WBC (5.98 +/- 1.24/mm3) and ANC (4.71 +/- 1.07/mm3) in the Filgrastim group were approximately two times those of the historical series (3.32 +/- 1.06/mm3 and 2.39 +/- 0.97/mm3 respectively; p < 0.002). Nadir platelet counts were not affected by filgrastim therapy. Three of seven patients reported mild musculoskeletal pain, but there was no other apparent toxicity.nnnCONCLUSIONnCompared to the historical series, filgrastim therapy significantly increased WBC and ANC during extended field radiation therapy and was well tolerated. It may be clinically useful in other groups of patients who are likely to develop profound neutropenia during large field irradiation.

Gray Zone Coping with Knife: Post-operative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma

A 47-year-old woman presented to her primary care physician with right arm pain and paresthesias, prompting cervical magnetic resonance imaging. Imaging revealed C6-7 spinal stenosis and an incidental T2 hyperintense left thyroid nodule measuring 1.9 cm (Fig. 1). A neck ultrasound scan revealed a 3.2 2.8 cm spongiform left thyroid nodule and a 0.7 0.6mm inferior right isthmus nodule. Fine needle aspiration of the left thyroid nodule demonstrated abundant mixed lymphoid cells. The patient underwent left hemithyroidectomy with pathology showing a 2.2 2.0-cm nodular lymphocyte predominant Hodgkin lymphoma (Fig. 2). The posterior and inferior surgical margins were negative but less than 0.1 mm from the inked margin. Postoperative positron emission tomographyecomputed tomography demonstrated no evidence of residual locoregional or distant disease.

Does the number of surgical excisions before delivering intraoperative radiotherapy (IORT) affect skin toxicity

72 Background: The TARGIT-A trial allowed administration of IORT both pre- and post-pathology. The advantage of post-pathology is the ability to determine eligibility based on margins, pathologic tumor size and nodal status, prior to delivering radiation. However, it is unclear whether having more than one operation before IORT is associated with worse skin toxicity. In this study, we aimed to examine the relationship of the number of operations and skin toxicities in women receiving IORT.nnnMETHODSnWe conducted a retrospective analysis of 57 consecutive patients who underwent IORT from 2009-2013. All patients received 20 Gy in 1 fraction prescribed to the applicator surface using the Carl Zeiss Intrabeam System. Skin toxicities were determined using CTCAE 4.0 and RTOG criteria. In addition, infection, skin erythema, desquamation, symptomatic seroma, and necrosis were scored individually and used as outcome measures. Pearsons Chi-squared test was used to assess the association of the number of operations and skin toxicities. A multivariate analysis was performed and included age, applicator size, max skin dose, number of operations, DM, HTN, BMI, co-morbidity, and depth from skin on mammogram as variables.nnnRESULTSnThe median follow-up was 11 months (range 1-33). The median age and applicator size were 68 yrs (range 49-85) and 4 cm (range 2.5-5). 20 (35%) patients had 1 operation (lumpectomy, SLNB and Intrabeam all in 1 setting). 36 (63%) patients had 2 operations (initial surgery, followed by Intrabeam +/- margin re-excision). One (2%) patient had 3 operations (initial surgery, re-excision, followed by Intrabeam). On univariate analysis, the number of operations was associated with increased infection (p = 0.044), but not other skin toxicities. On multivariate analysis, the association was no longer significant (p = 0.97).nnnCONCLUSIONSnOur study suggests that delivering IORT post-pathology was not associated with worse acute or late skin complications. Delivering IORT after the initial operation decreases the uncertainty of margin status and avoids the controversy of excising an irradiated positive margin and/or the need for additional whole breast radiation.