Sandra Gardner

A Multicenter Randomized Trial of Breast Intensity-Modulated Radiation Therapy to Reduce Acute Radiation Dermatitis

PURPOSE Dermatitis is a frequent adverse effect of adjuvant breast radiotherapy. It is more likely in full-breasted women and when the radiation is distributed nonhomogeneously in the breast. Breast intensity-modulated radiation therapy (IMRT) is a technique that ensures a more homogeneous dose distribution. PATIENTS AND METHODS A multicenter, double-blind, randomized clinical trial was performed to test if breast IMRT would reduce the rate of acute skin reaction (notably moist desquamation), decrease pain, and improve quality of life compared with standard radiotherapy using wedges. Patients were assessed each week during and up to 6 weeks after radiotherapy. RESULTS A total of 358 patients were randomly assigned between July 2003 and March 2005 in two Canadian centers, and 331 were included in the analysis. Breast IMRT significantly improved the dose distribution compared with standard radiation. This translated into a lower proportion of patients experiencing moist desquamation during or up to 6 weeks after their radiation treatment; 31.2% with IMRT compared with 47.8% with standard treatment (P = .002). A multivariate analysis found the use of breast IMRT (P = .003) and smaller breast size (P < .001) were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain (P = .002) and a reduced quality of life (P = .003). CONCLUSION Breast IMRT significantly reduced the occurrence of moist desquamation compared with a standard wedged technique. Moist desquamation was correlated with increased pain and reduction in the quality of life.

Phase I/II Study of a Five-fraction Hypofractionated Accelerated Radiotherapy Treatment for Low-risk Localised Prostate Cancer: Early Results of pHART3

AIMS Most men with low-risk localised prostate cancer prefer treatments with high control rates and minimal disruption to their lives. Hypofractionating external radiation treatments can theoretically maintain high bioequivalent tumour doses, decrease treatment visits and decrease acute and late toxicities. The aim of this study was to assess the toxicity and feasibility of a hypofractionated accelerated regimen for these patients. MATERIALS AND METHODS The present study was a phase I/II study in which patients with T1-2b, Gleason < or = 6 and prostate-specific antigen (PSA) < or = 10 ng/ml prostate cancer received 35Gy in five fractions, once a week over 29 days. Treatment was delivered with intensity-modulated radiotherapy on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4mm clinical target volume to planning target volume margin. RESULTS As of January 2008, the target accrual of 30 patients had been reached and all had completed treatment and at least 6 months of follow-up. Dose-volume histogram objectives were achievable in all patients. Treatment was very well tolerated with no grade 3 or 4 genitourinary toxicity, gastrointestinal toxicity nor fatigue observed (95% confidence interval 0-12%). As a group, compared with baseline, the following additional grade 2 toxicities were observed: 13% genitourinary, 7% gastrointestinal and 10% fatigue. At 6 months all scores had returned to or improved over baseline. The median PSA before treatment was 6.0 ng/ml. At 6 months, the median PSA was 1.8 ng/ml and 75% had a PSA < or = 3.0 ng/ml. CONCLUSIONS This novel technique using standard linear accelerators seems feasible and is well tolerated. Further follow-up will be carried out to document late toxicity and efficacy.

Phase I/II Trial of Metronomic Chemotherapy With Daily Dalteparin and Cyclophosphamide, Twice-Weekly Methotrexate, and Daily Prednisone As Therapy for Metastatic Breast Cancer Using Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor Levels As Markers of Response

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

Mastery and Coping Moderate the Negative Effect of Acute and Chronic Stressors on Mental Health-Related Quality of Life in HIV

Acute and chronic life stressors have a detrimental effect on the health of people living with HIV. Psychosocial resources such as mastery, coping, and social support may play a critical role in moderating the negative effects of stressors on health-related quality of life. A total of 758 participants provided baseline enrolment data on demographics (age, gender, ethnicity, sexual orientation, education, employment, income), clinical variables (CD4 counts, viral load, AIDS-defining condition, time since HIV diagnosis), psychosocial resources (mastery, coping, social support), life stressors (National Population Health Survey [NPHS] Stress Questionnaire), and health-related quality of life (SF-36). We performed hierarchical multivariate regression analyses to evaluate the potential moderating effects of psychosocial resources on the relationship between stressors and health-related quality of life. The top three stressors reported by participants were trying to take on too many things at once (51%), not having enough money to buy the things they needed (51%), and having something happen during childhood that scared them so much that they thought about it years later (42%). Life stressors were significantly and inversely associated with both physical and mental health-related quality of life. Mastery and maladaptive coping had significant moderating effects on mental health but not on physical health. These results suggest that developing interventions that improve mastery and reduce maladaptive coping may minimize the negative impact of life stressors on the mental health of people with HIV. They also highlight that it is important for clinicians to be mindful of the impact of life stressors on the health of patients living with HIV.

Mastery Moderates the Negative Effect of Stigma on Depressive Symptoms in People Living with HIV

Stigma continues to have a negative effect on the care, treatment, and support of people living with HIV. This study presents baseline data from 825 participants taking part in a cohort study that collects data on the clinical profile and social determinants of health of people with HIV. We performed multivariate regression analysis to evaluate whether mastery and social support moderated the negative effect of stigma on depressive symptoms. Stigma was associated with depressive symptoms after controlling for potential demographic and clinical confounders. In addition, higher levels of mastery and social support were associated with lower levels of depression. However, only mastery moderated the negative effects of stigma on depressive symptoms. For individuals with high levels of mastery, greater exposure to stigma does not translate into greater distress. Interventions targeting the mental health concerns of people with HIV should increase their focus on improving people’ sense of personal control.

Prospective Assessment of Gastrointestinal and Genitourinary Toxicity of Salvage Radiotherapy for Patients With Prostate-Specific Antigen Relapse or Local Recurrence After Radical Prostatectomy

PURPOSE To assess the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity of salvage radiotherapy (RT). METHODS AND MATERIALS A total of 75 patients with prostate-specific antigen relapse or clinically isolated local recurrence after radical prostatectomy were accrued between 1998 and 2002 for a Phase II study to evaluate the efficacy of salvage RT plus 2-year androgen suppression. Acute and late GI and GU toxicity was prospectively assessed using the National Cancer Institute Expanded Common Toxicity Criteria Version 2. For acute toxicity, prevalence was examined. For late toxicity, cumulative incidences of Grade 2 or higher and Grade 3 toxicity were calculated. RESULTS Median age was 67 years at the time of salvage RT. Median time from radical prostatectomy to RT was 36.2 months. Median follow-up was 45.1 months. Seventy-five patients were available for acute toxicity analysis, and 72 for late toxicity. Twelve percent and 40% had preexisting GI and GU dysfunction before RT, respectively. Sixty-eight percent, 21%, and 5% experienced Grade 1, 2, and 3 acute GI or GU toxicity, respectively. Cumulative incidences of Grade 2 or higher late GI and GU toxicity at 36 months were 8.7% and 22.6%, and Grade 3 late GI and GU toxicity, 1.6% and 2.8%, respectively. None had Grade 4 late toxicity. The severity of acute GU toxicity (Grade < 2 vs. >/= 2) was a significant predictor factor for Grade 2 or higher late GU toxicity after adjusting for preexisting GU dysfunction. CONCLUSION Salvage RT generally was well tolerated. Grade 3 or higher late GI or GU toxicity was uncommon.

EFFICACY OF SALVAGE RADIOTHERAPY PLUS 2-YEAR ANDROGEN SUPPRESSION FOR POSTRADICAL PROSTATECTOMY PATIENTS WITH PSA RELAPSE

PURPOSE To determine the efficacy of a combined approach of radiotherapy (RT) plus 2-year androgen suppression (AS) as salvage treatment for prostate-specific antigen (PSA) relapse after radical prostatectomy (RP). METHODS AND MATERIALS Seventy-five patients with PSA relapse after RP were treated with salvage RT plus 2-year AS, as per a pilot, prospective study. AS started within 1 month after completion of salvage RT and consisted of nilutamide for 4 weeks and buserelin acetate depot subcutaneously every 2 months for 2 years. Relapse-free rate including freedom from PSA relapse was estimated using the Kaplan-Meier method. PSA relapse was defined as a PSA rise above 0.2 ng/mL with two consecutive increases over a minimum of 3 months. A Cox regression analysis was performed to evaluate prognostic factors for relapse. RESULTS Median age of the cohort was 63 years at the time of salvage RT. Median follow-up from salvage RT was 6.4 years. All achieved initially complete PSA response (< 0.2) with the protocol treatment. Relapse-free rate including the freedom from PSA relapse was 91.5% at 5 years and 78.6% at 7 years. Overall survival rate was 93.2% at both 5 and 7 years. On Cox regression analysis, pT3 stage and PSA relapse less than 2 years after RP were significant prognostic factors for relapse. CONCLUSION The combined treatment of salvage RT plus 2-year AS yielded an encouraging result for patients with PSA relapse after RP and needs a confirmatory study.

Testosterone Recovery After Prolonged Androgen Suppression in Patients With Prostate Cancer

PURPOSE We prospectively examined the extent and timing of testosterone recovery in patients with prostate cancer treated with 2 years of androgen suppression. MATERIALS AND METHODS A total of 153 patients with pT3N0M0 prostate cancer or positive margins after radical prostatectomy, or with prostate specific antigen relapse were treated with radiation to the prostate bed plus 2 years of androgen suppression as per a phase II study. Androgen suppression consisted of nilutamide for 4 weeks plus busereline acetate bimonthly for 2 years. Serum testosterone was measured at baseline, every 4 months during androgen suppression and every 6 months after androgen suppression during followup. Testosterone recovery to supracastrate levels, and to baseline and/or normal levels was estimated using Kaplan-Meier methods. Prognostic factors for testosterone recovery were examined. RESULTS A total of 121 patients who completed 2 years of androgen suppression and 20 patients who received shorter durations of androgen suppression (median 16 months) were available for testosterone recovery analysis. Median followup after finishing androgen suppression was 38.9 months. All patients achieved castrate levels on androgen suppression. At 36 months after completion of androgen suppression 93.2% and 71.5% had recovery to supracastrate (median time 12.7 months), and to baseline and/or normal testosterone levels (median time 22.3 months), respectively. On multivariate analysis younger age (younger than 60 years, p = 0.0006) and shorter androgen suppression duration (less than 2 years, p = 0.028) were prognostic for faster recovery to baseline and/or normal testosterone levels after adjusting for baseline testosterone levels (p = 0.447). CONCLUSIONS Testosterone recovery after prolonged androgen suppression is protracted. Older age and longer duration of androgen suppression result in significantly longer recovery times to baseline and/or normal testosterone levels.

The value of periodic follow-up in the detection of recurrences after radical treatment in locally advanced head and neck cancer.

AIMS To determine the value of routine follow-up in detecting and salvaging recurrence after radical treatment of locally advanced head and neck squamous cell carcinoma and to identify clinical or pathological prognostic factors that predicted for survival. MATERIALS AND METHODS A retrospective medical chart review was conducted at the Odette Cancer Centre between January 2000 and May 2006. Two hundred and twenty-three patients with advanced (stage III or IV) squamous cell carcinoma of the head and neck who were treated with curative intent were reviewed. Recurrences were divided into local, regional or distant recurrences. The detection method for each recurrence was categorised as self or physician detected. A self-detected recurrence arose from symptoms that led to investigations that confirmed a recurrence (even if initiated at the time of a routine visit), whereas a physician-detected recurrence was found during the routine follow-up examination and was asymptomatic. RESULTS There was no evidence to suggest a significant improvement in disease-free or overall survival in the physician-detected versus patient-detected groups. Regional and distant recurrences were only detected by physicians in one-fifth of cases and, overall, patients self-detected their own recurrence in two-thirds of the cases that experienced disease progression within the sample. Of the 12 clinical/pathological variables considered, only the response to treatment and perineural invasion were associated with survival. CONCLUSIONS Current surveillance methods do not appear to improve cancer control in the stage III/IV head and neck squamous cell carcinoma population. However, technological advances and biomarker development may lead to surveillance technique enhancements. Also, post-treatment follow-up remains important for the evaluation of treatment results, emotional support and management of late complications. Among the clinical and pathological factors considered, only the treatment response and perineural invasion predicted survival.

Fractionated (split dose) radiosurgery in patients with recurrent brain metastases: implications for survival

Radiosurgery is conventionally prescribed for brain metastases with a single dose of radiation. Fractionation has been advocated to improve tumour control. A multivariate analysis of prognostic factors including fractionation has been performed in two consecutive prospective radiosurgery protocols with and without fractionation in order to identify an association, if any, between fractionation and survival. A surgically applied stereotactic head frame was used. Radiosurgery planning was based on a contrast-enhanced CT. Sixty-nine patients underwent the two-fraction regimen and 35 patients had a single treatment. Multivariate analysis showed that the presence of extracranial malignancy, performance status, multiple brain metastases, patient gender and the time from the initial treatment to radiosurgery were independent determinants for survival. Fractionation was also an independent determinant with two-fraction patients surviving a median of 30 weeks versus single fraction patients who survived a median of 16 weeks. Fractionated radiosurgery was associated with improved survival and deserves further investigation.