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Summary: Background: We hypothesized excess resistance factor (“active resistance”) gives a dose–response curve (DRC) shoulder, deficiency of a factor required for drug sensitivity (“saturable passive resistance”) gives a DRC terminal plateau, and alteration of a factor gives decreased DRC slope. Method: We used response rates from published non-small cell lung cancer (NSCLC) clinical studies to estimate mean percent tumor cell kill in each study (assuming cell kill is proportional to tumor volume change) and performed regression and meta-regression analyses of percent cell survival and patient survival vs planned dose-intensity. Results: As single agents, cell kill approached that of combinations only at highest doses. While DRC shape varied between single agents, DRCs for all combinations tested flattened at higher doses. Patient median survival times also failed to vary significantly with dose for any combination. Conclusions: DRC flattening at higher doses suggests therapy efficacy is limited by deficiency/saturation of factors required for cell killing. Based on this and other clinical observations, we hypothesize: (1) active resistance may modulate cell killing at lower doses, but ability to overcome this by increasing doses is limited by saturable passive resistance (e.g. by non-cycling cells). (2) Cells surviving initial chemotherapy may upregulate active resistance mechanisms (permitting growth despite therapy). (3) If active resistance mechanisms are insufficient for growth/survival, cells may survive until therapy cessation by downregulating metabolism/cycling, becoming temporarily quiescent. This could help explain broad cross-resistance between agents and would imply that improved targeting of non-cycling cells will be required for major improvement in therapy efficacy. [Copyright &y& Elsevier]

Purpose: To assess the effect of treatment waiting time on clinical outcome for patients with cervix cancers treated with radical radiotherapy. Methods and materials: A retrospective analysis was conducted on all cervix cancer patients treated with radical radiotherapy between 1990 and 2001 at the Ottawa Regional Cancer Centre. Analyses were performed according to the three following separate definitions of waiting times: interval from start of radiotherapy to (1) date of initial biopsy, (2) date of examination under anesthesia, and (3) date of radiation oncology consultation. Associations between waiting times and patient characteristics and disease control were investigated using t-tests, analyses of variance, and Cox regression analyses. Results: A total of 195 patients were studied. The vast majority of patients were treated within 5, 6, and 8 weeks of their consultation (91%), examination under anesthesia (88%), and biopsy (81%), respectively. On average, delays between initial biopsy and treatment start were greater for older patients (p = 0.025) (5.8 weeks for <40 years old vs. 6.6 weeks for >70 years old) and those with smaller tumors (p < 0.001) (5.0 weeks for >4 cm vs. 6.3 weeks for ≤4 cm). Univariate analysis revealed no adverse effect of treatment delay on tumor control. Multivariate analysis, with the inclusion of multiple prognostic tumor and treatment parameters, revealed an adverse effect of treatment delay on survival outcomes. Conclusions: Longer radiotherapy waiting times were found to be associated with diminished survival outcomes for patients treated radically for cervix cancer. The significance of this observed association requires further investigation. [Copyright &y& Elsevier]

Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. Results: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs. [Copyright &y& Elsevier]

Purpose: To determine if there is an association between the degree of prostate trauma during prostate brachytherapy and development of acute urinary toxicity.Methods and materials: In a consecutive prospective cohort of permanent 125I prostate brachytherapy patients, the number of times each needle was repositioned was tracked, and the dosimetry plans were used to determine the number of times needles within 1 cm of the urethra were manipulated. Additionally, prostate volume, total number of needles, number of needles/prostate volume, and the number of periurethral needle manipulations/prostate volume were determined. The need for catheterization beyond 24 hours and the Radiation Therapy Oncology Group (RTOG) urinary toxicity score at 4 weeks were recorded. The independent samples t test was used to search for a correlation between these parameters and the recorded toxicity scores.Results: Twenty-eight consecutive implant patients were evaluated in the study. Median (range) values were as follows: prostate volume 35 cc ( range, 15–51 cc), number of needles per patient 32 (range, 21–41), number of needle manipulations per patient 94.5 ( range, 55–147), and number of periurethral needle manipulations 42 (range, 17–65). The only significant association between urinary toxicity and these variables was for the number of periurethral needle manipulations (p = 0.025).Conclusions: These data provide evidence that needle prostate trauma during brachytherapy contributes to acute urinary toxicity. [Copyright &y& Elsevier]