Ewa Szumacher

Feasibility study : watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression

PURPOSE We assessed the feasibility of a watchful waiting protocol with selective delayed intervention using clinical, prostate specific antigen (PSA) or histological progression as treatment indications for clinically localized prostate cancer. MATERIALS AND METHODS In this prospective, single arm cohort study patients with favorable clinical parameters (stage T1b to T2b N0M0, Gleason score 7 or less and PSA 15 ng./ml. or less) are conservatively treated with watchful waiting. When a patient meets disease progression criteria, arbitrarily defined by the 3 parameters of the rate of PSA increase, clinical progression or histological upgrade on repeat prostate biopsy, appropriate treatment is implemented. Patients are followed every 3 months for the first 2 years and every 6 months thereafter. Serum PSA measurement and digital rectal examination are done at each visit and repeat prostate biopsy is performed 18 months after study enrollment. RESULTS Since November 1995, the study has accrued 206 patients with a median followup of 29 months (range 2 to 66). Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons. There was clinical, PSA and histological progression in 16, 15 and 5 cases, respectively. The estimated actuarial probability of remaining on the surveillance protocol was 67% at 2 years and 48% at 4. The probability of remaining progression-free was 81% and 67% at 2 and 4 years, respectively. CONCLUSIONS A policy of watchful waiting with selectively delayed intervention based on predefined criteria of disease progression is feasible. This strategy offers the benefit of an individualized approach based on the demonstrated risk of clinical or biochemical progression with time and, thus, it may decrease the burden of therapy in patients with indolent disease, while providing definitive therapy for those with biologically active disease.

Palliation of bone metastases: a survey of patterns of practice among Canadian radiation oncologists☆

BACKGROUND Palliative radiotherapy constitutes nearly 50% of the workload in radiotherapy. Surveys on the patterns of practice in radiotherapy have been published from North America and Europe. Our objective was to determine the current pattern of practice of radiation oncologists in Canada for the palliation of bone metastases. METHOD A survey was sent to 300 practicing radiation oncologists in Canada. Five case scenarios were presented. The first three were patients with a single symptomatic site: breast cancer patient with pelvic metastasis, lung cancer male with metastasis to L3 and L1, respectively. The last two were breast and prostate cancer patients with multiple symptomatic bone metastases. RESULTS A total of 172 questionnaires were returned (57%) for a total of 860 responses. For the three cases with a single painful bone metastasis, over 98% would prescribe radiotherapy. The doses ranged from a single 8 to 30 Gy in ten fractions. Of the 172 respondents, 117 (68%) would use the same dose fractionation for all three cases, suggesting that they had a standard dose fractionation for palliative radiotherapy. The most common dose fractionation was 20 Gy in five fractions used by 84/117 (72%), and 8 Gy in one fraction by 19/117 (16%). In all five case scenarios, 81% would use a short course of radiotherapy (single 8 Gy, 17%; 20 Gy in five fractions, 64%), while 10% would prescribe 30 Gy in ten fractions. For the two cases with diffuse symptomatic bone metastases, half body irradiation (HBI) and radionuclides were recommended more frequently in prostate cancer than in breast cancer (46/172 vs. 4/172, P<0. 0001; and 93/172 vs. 10/172, P<0.0001, respectively). Strontium was the most commonly recommended radionuclide (98/103=95%). Since systemic radionuclides are not readily available in our health care system, 41/98 (42%) of radiation oncologists who would recommend strontium were not familiar with the dose. Bisphosphonates were recommended more frequently in breast cancer than in prostate cancer 13/172 (8%) vs. 1/172 (0.6%), P=0.001. CONCLUSION Local field external radiotherapy remains the mainstay of therapy, and the most common fractionation for bone metastases in Canada is 20 Gy in five fractions compared with 30 Gy in ten fractions in the US. Despite randomized trials showing similar results for single compared with fractionated radiotherapy, the majority of us still advocate five fractions. The frequency of employing a single fractionation has not changed since the last national survey in 1992. Nearly 70% use a standard dose fractionation to palliate localized painful metastasis by radiotherapy, independent of the site of involvement or tumor type. The pattern of practice of palliative radiotherapy for bone metastases in Canada is different to that reported previously from the US. The reasons why the results of randomized studies on bone metastases have no impact on the patterns of practice are worth exploring.

Is single fraction 15 Gy the preferred high dose-rate brachytherapy boost dose for prostate cancer?

BACKGROUND AND PURPOSE High dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer. MATERIALS AND METHODS Results of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15 Gy HDR in one fraction followed by 37.5 Gy EBRT in 15 fractions over 3 weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10 Gy, 1 week apart, followed by 45 Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2 years. RESULTS The Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72 months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p=0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols. CONCLUSIONS The Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15 Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease.

Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Men With Intermediate-Risk Prostate Cancer: Analysis of Short- and Medium-Term Toxicity and Quality of Life

PURPOSE To determine the short- and medium-term effects of a single high-dose-rate brachytherapy fraction of 15 Gy and hypofractionated external beam radiation therapy for prostate cancer. METHODS AND MATERIALS Eligible patients had localized prostate cancer with a Gleason score of 7 and a prostate-specific antigen (PSA) concentration of <20 ng/ml or a Gleason score of 6 with a PSA concentration of 10 to 20 ng/ml. Patients received high-dose-rate brachytherapy as a single 15-Gy dose, followed by external beam radiation therapy at 37.5 Gy in 15 fractions, and were followed prospectively for toxicity (using Common Terminology Criteria for Adverse Events version 3.0), urinary symptoms (using the International Prostate Symptom Score [IPSS]), erectile function (with the International Index of Erectile Function [IIEF]), and health-related quality of life (with the Expanded Prostate Cancer Index Composite [EPIC]). Clinical examinations and PSA measurements were performed at every visit, and prostate biopsies were repeated at 2 years. The trial accrued 125 patients, with a median follow-up of 1.14 years. RESULTS Acute grade 2 and 3 genitourinary toxicity occurred in 62% and 1.6% of patients, respectively, and acute grade 2 gastrointestinal toxicity occurred in 6.5% of patients. No grade 3 late toxicity has occurred: 47% of patients had grade 2 genitourinary and 10% of patients had grade 2 gastrointestinal toxicity. Median IPSSs rose from 5 at baseline to 12 at 1 month and returned to 7 at 3 months. Of the total number of patients who were initially potent (IIEF, >21), 8% of patients developed mild to moderate dysfunction, and 27% of patients developed severe erectile dysfunction. Baseline EPIC bowel, urinary, and sexual bother scores decreased by 9, 7, and 19 points, respectively, at 1 year. No patient has experienced biochemical failure, and 16 of the first 17 biopsy results showed no malignancy. CONCLUSIONS Treatment is well tolerated in the short and medium term, with low toxicity and encouraging early indicators of disease control.

Phase II study assessing the effectiveness of Biafine cream as a prophylactic agent for radiation-induced acute skin toxicity to the breast in women undergoing radiotherapy with concomitant CMF chemotherapy

PURPOSE To assess the efficacy of Biafine cream in preventing Grade 2 acute radiation dermatitis, according to the National Cancer Institute of Canada skin radiation toxicity criteria in patients undergoing concomitant adjuvant chemotherapy and radiotherapy to the breast. METHODS AND MATERIALS Sixty patients participated in this study. Patients were treated with a lumpectomy followed by concomitant chemotherapy and radiotherapy to the breast. Biafine cream was applied daily, starting on the first day and ending 2 weeks post-radiotherapy. Patients underwent weekly skin assessments throughout radiotherapy and at 2 and 4 weeks after treatment. Outcome measures were assessed using a Skin Assessment Questionnaire that was scored according to the National Cancer Institute of Canada skin radiation toxicity criteria and a self-administered questionnaire that evaluated skin symptoms. RESULTS The maximum skin toxicity observed during the course of treatment was as follows: less than Grade 2 toxicity, 15% (9 patients); Grade 2, 83% (50 patients); Grade 3, 2% (1 patient); Grade 4, 0% (0 patients). The majority of the radiation dermatitis was observed after 3 weeks of radiotherapy. CONCLUSION The majority of patients who underwent concomitant chemo- and radiotherapy for breast cancer developed Grade 2 radiation dermatitis with the use of Biafine cream. However, no treatment delays or interruptions were observed because of skin toxicity.

Hypofractionated concomitant intensity-modulated radiotherapy boost for high-risk prostate cancer: late toxicity.

PURPOSE To report the acute and late toxicities of patients with high-risk localized prostate cancer treated using a concomitant hypofractionated, intensity-modulated radiotherapy boost combined with long-term androgen deprivation therapy. METHODS AND MATERIALS A prospective Phase I-II study of patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level ≥ 20 ng/mL, or Gleason score 8-10. A dose of 45 Gy (1.8 Gy/fraction) was delivered to the pelvic lymph nodes with a concomitant 22.5 Gy prostate intensity-modulated radiotherapy boost, to a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions within 5 weeks. Image guidance was performed using three gold seed fiducials. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, and Radiation Therapy Oncology Group late morbidity scores were used to assess the acute and late toxicities, respectively. Biochemical failure was determined using the Phoenix definition. RESULTS A total of 97 patients were treated and followed up for a median of 39 months, with 88% having a minimum of 24 months of follow-up. The maximal toxicity scores were recorded. The grade of acute gastrointestinal toxicity was Grade 0 in 4%, 1 in 59%, and 2 in 37%. The grade of acute urinary toxicity was Grade 0 in 8%, 1 in 50%, 2 in 39%, and 3 in 4%. The grade of late gastrointestinal toxicity was Grade 0 in 54%, 1 in 40%, and 2 in 7%. No Grade 3 or greater late gastrointestinal toxicities developed. The grade of late urinary toxicity was Grade 0 in 82%, 1 in 9%, 2 in 5%, 3 in 3%, and 4 in 1% (1 patient). All severe toxicities (Grade 3 or greater) had resolved at the last follow-up visit. The 4-year biochemical disease-free survival rate was 90.5%. CONCLUSIONS A hypofractionated intensity-modulated radiotherapy boost delivering 67.5 Gy in 25 fractions within 5 weeks combined with pelvic nodal radiotherapy and long-term androgen deprivation therapy was well tolerated, with low rates of severe toxicity. The biochemical control rate at early follow-up has been promising. Additional follow-up is needed to determine the long-term biochemical control and prostate biopsy results.

Fractionated stereotactic radiotherapy for the treatment of vestibular schwannomas: combined experience of the Toronto-Sunnybrook Regional Cancer Centre and the Princess Margaret Hospital

PURPOSE To evaluate the efficacy and toxicity of fractionated stereotactic radiotherapy (FSRT) for vestibular schwannomas in patients treated at two university-affiliated hospitals. METHODS AND MATERIALS Thirty-nine patients were treated between April 1996 and September 2000. The median age was 56 years (range: 29-80), and median maximal tumor diameter was 20 mm (range: 9-40). A total of 11 patients had fifth and/or seventh cranial nerve dysfunction before irradiation; 2 patients had only facial weakness, 5 patients had only facial numbness, and 4 patients had both facial weakness and numbness. Thirty-three patients were treated with primary FSRT, and 6 patients were treated for recurrent or persistent disease after previous surgery. All patients were treated with 6-MV photons using a stereotactic system with a relocatable frame. The 39 patients received 50 Gy in 25 fractions over 5 weeks. Median follow-up was 21.8 months (range: 4.4-49.6). RESULTS Local control was achieved in 37 patients (95%). Two patients experienced deterioration of their symptoms at 3 and 20 months as a result of clinical progression in one case and tumor progression in the other and underwent surgery post FSRT. A total of 19/28 (67.9%) patients preserved serviceable hearing after FSRT. Deterioration of the facial and trigeminal nerves was observed in only 2 patients who were treated with surgery post FSRT. CONCLUSION FSRT provided excellent tumor control with minimal morbidity and good hearing preservation in this cohort of patients. Longer follow-up is required to confirm long-term control rates.

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer

PURPOSE To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. METHODS AND MATERIALS Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. RESULTS By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. CONCLUSION EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.

Prospective patient-based assessment of effectiveness of palliative radiotherapy for bone metastases.

PURPOSE The primary objective of this report is to prospectively evaluate pain control provided by palliative radiotherapy for all irradiated patients with bone metastases by using their own assessments. MATERIALS AND METHODS A prospective database was set up for all patients referred for palliative radiotherapy for bone metastases. Patients were asked to rate their pain intensity using an 11 categorical point scale (0=lack of pain, 10=worst pain imaginable). Analgesic consumption during the preceding 24 h was recorded and converted into equivalent total daily dose of oral morphine. For those who received radiotherapy, follow-up was conducted via telephone interviews at week 1, 2, 4, 8 and 12 post treatment using the same pain scale and analgesic diary. Radiotherapy outcome was initially assessed by pain score alone. Complete response (CR) was defined as a pain score of 0. Partial response (PR) was defined as a reduction of score > or =2 or a> or =50% reduction of the pre-treatment pain score. We further analyzed outcomes using integrated pain and analgesic scores. Response was defined as either a reduction of pain score > or =2 with at least no increase in analgesics or at least stable pain score with a > or =50% reduction in analgesic intake. RESULTS One hundred and five patients were treated with palliative radiotherapy. When response evaluation was by pain score alone, the PR rates at 2, 4, 8 and 12 weeks were 44, 42, 30 and 38%, respectively; while the CR rates were 24, 32, 31 and 29%, respectively. The overall response rate at 12 weeks was 67%. When assessed by the integrated pain and analgesic scores, the response rates were 50, 46, 43 and 43%, respectively. CONCLUSION The response rate in our patient population is comparable with those reported in clinical trials. This is important when counselling our patients on the expected effectiveness of radiotherapy outside of clinical trials. Our observations confirm the generalizability of the trials conducted to date. While randomized trials still remain the gold standard of research, observational studies can serve as useful adjuncts to randomized trials to confirm the efficacy and guide the design of new controlled trials.

Prospective Assessment of Symptom Palliation for Patients Attending a Rapid Response Radiotherapy Program: Feasibility of Telephone Follow-Up

Clinical trials generally include motivated patients with relatively good performance status. This can result in an overestimation of the effectiveness of an intervention. Clinic follow-up protocols for outcome assessment after palliative treatments suffer from high attrition rates. In this study, the feasibility of telephone follow-up for the assessment of symptom palliation in patients receiving outpatient palliative radiotherapy as a tool to evaluate outcome was examined. Patients referred for palliative radiotherapy were asked to rate their symptom distress using the modified Edmonton Symptom Assessment System (ESAS) at initial consultation. Patient demographics and analgesic consumption were collected. For those who received radiotherapy, follow-up was conducted through telephone interviews at week 1, 2, 4, 8, and 12 post-treatment using the same modified ESAS and analgesic diary. One hundred ninety patients received radiotherapy to 256 sites from January to August 1999. Seventy-eight patients (41%) died during the 12-week follow-up period. The percentage of surviving patients responding to the telephone interview ranged from 63% to 68% during the 12-week study. Telephone follow-up is a feasible tool for the prospective outcome assessment of symptom palliation in this population. It compares well to clinic visits or mailed questionnaires. However, to improve the follow-up rates, other modalities may also need to be implemented.