Thomas P. Shakespeare

Post-prostatectomy radiation therapy: Consensus guidelines of the Australian and New Zealand Radiation Oncology Genito-Urinary Group

BACKGROUND AND PURPOSE Three randomised trials have demonstrated the benefit of adjuvant post-prostatectomy radiotherapy (PPRT) for high risk patients. Data also documents the effectiveness of salvage radiotherapy following a biochemical relapse post-prostatectomy. The Radiation Oncology Genito-Urinary Group recognised the need to develop consensus guidelines on to whom, when and how to deliver PPRT. MATERIALS AND METHODS Draft guidelines were developed and refined at a consensus conference in June 2006 attended by 63 delegates where urological, radiotherapy and diagnostic imaging experts spoke on aspects of PPRT. Unresolved issues were further developed by working parties and redistributed until consensus was reached. RESULTS Central to the recommendations is that patients with positive surgical margins, seminal vesicle invasion and/or extracapsular extension have a high risk of residual local disease and should be informed of the options of either immediate adjuvant radiotherapy or active surveillance with early salvage in the event of biochemical recurrence. Salvage radiotherapy should be instituted at the earliest confirmation of biochemical recurrence. Detailed contouring guidelines have been developed, defining the regions at risk of residual microscopic disease which should be included in the clinical target volume. The recommended doses are 60-64Gy for adjuvant, and 60-66Gy for salvage radiotherapy. The role of hormone therapy in conjunction with PPRT is yet to be defined. CONCLUSIONS These consensus guidelines have been developed to give clinical and technical guidance to radiation oncologists and urologists in the management of high risk post-prostatectomy patients.

Improving interpretation of clinical studies by use of confidence levels, clinical significance curves, and risk-benefit contours

The process of interpreting the results of clinical studies and translating them into clinical practice is being debated. Here we examine the role of p values and confidence intervals in clinical decision-making, and draw attention to confusion in their interpretation. To improve result reporting, we propose the use of confidence levels and plotting of clinical significance curves and risk-benefit contours. These curves and contours provide degrees of probability of both the potential benefit of treatment and the detriment due to toxicity. Additionally, they provide clinicians with a mechanism of translating the results of studies into treatment for individual patients, thus improving the clinical decision-making process. We illustrate the application of these curves and contours by reference to published studies. Confidence levels, clinical significance curves, and risk-benefit contours can be easily calculated with a hand calculator or standard statistical packages. We advocate their incorporation into the published results of clinical studies.

Patient preference for radiotherapy fractionation schedule in the palliation of painful bone metastases.

PURPOSE The radiotherapeutic management of painful bone metastases is controversial, with several institutional and national guidelines advocating use of single-fraction radiotherapy. We aimed to determine patient choice of fractionation schedule after involvement in the decision-making process by use of a decision board. PATIENTS AND METHODS Advantages and disadvantages of two fractionation schedules (24 Gy in six fractions v 8 Gy in one fraction) used in the randomized Dutch Bone Metastasis Study were discussed with patients using a decision board. Patients were asked to choose a fractionation schedule, to give reasons for their choice, and to indicate level of satisfaction with being involved in decision making. RESULTS Sixty-two patients were entered. Eighty-five percent (95% confidence interval, 74% to 93%) chose 24 Gy in six fractions over 8 Gy in one fraction (P <.0005). Variables including age, sex, performance status, tumor type, pain score, and paying class were not significantly related to patient choice. Multiple fractionation was chosen for lower re-treatment rates (92%) and fewer fractures (32%). Single-fraction treatment was chosen for cost (11%) and convenience (89%). Eighty-four percent of patients expressed positive opinions about being involved in the decision-making process. CONCLUSION Decision board instruments are feasible and acceptable in an Asian population. The vast majority of patients preferred 24 Gy fractionated radiotherapy compared with a single fraction of 8 Gy. These results indicate the need for further research in this important area and serve to remind both clinicians and national or institutional policy makers of the importance of individual patient preference in treatment decision making.

Patients’ preference for radiotherapy fractionation schedule in the palliation of symptomatic unresectable lung cancer†

The palliative radiotherapeutic management of unresectable non‐small‐cell lung cancer is controversial, with various fractionation (Fx) schedules available. We aimed to determine patient’s choice of Fx schedule after involvement in a decision‐making process using a decision board. A decision board outlining the various advantages and disadvantages apparent in the Medical Research Council study of Fx schedules (17 Gy in two fractions vs 39 Gy in 13 fractions) was discussed with patients who met Medical Research Council eligibility criteria. Patients were then asked to indicate their preferred Fx schedules, reasons and their level of satisfaction with being involved in the decision‐making process. Radiation oncologists (RO) could prescribe radiotherapy schedules irrespective of patients’ preferences. Of 92 patients enrolled, 55% chose the longer schedule. English‐speaking patients were significantly more likely to choose the longer schedule (P = 0.02, 95% confidence interval: 1.2–7.6). Longer Fx was chosen because of longer survival (90%) and better local control (12%). Shorter Fx was chosen for shorter overall treatment duration (80%), cost (61%) and better symptom control (20%). In all, 56% of patients choosing the shorter schedule had their treatment altered by the treating RO, whereas only 4% of patients choosing longer Fx had their treatment altered (P < 0.001). Despite this, all (100%) patients were satisfied with being involved in the decision‐making process. The decision board was useful in aiding decision‐making, with both Fx schedules being acceptable to patients. Interestingly, despite the longer average survival associated with longer Fx, nearly half of the patients believed that this was not as important as a shorter duration of treatment and lower cost. Despite patients’ preferences, there were significant alterations of preferred schedules because of RO’s own biases.

Outcomes of Adjuvant Chemoradiotherapy After a Radical Gastrectomy and a D2 Node Dissection for Gastric Adenocarcinoma

Purpose:Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery. Methods:After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists. Results:Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1–60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute – Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths. Conclusion:In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

Adjuvant fractionated high-dose-rate intracavitary brachytherapy after external beam radiotherapy in Tl and T2 nasopharyngeal carcinoma.

The value of high‐dose‐rate intracavitary brachytherapy (HDRIB) for persistent or recurrent nasopharyngeal carcinoma has been well described; however, the benefit of routine adjuvant fractionated HDRIB following external beam radiation therapy (EBRT) has not been completely determined. The objective of this analysis was to evaluate the outcome of two fractions of adjuvant HDRIB treatment in Tl and T2 nasopharyngeal carcinoma.

Tailoring distant metastatic imaging for patients with clinically localized undifferentiated nasopharyngeal carcinoma

PURPOSE The 2000 practice guidelines of the National Comprehensive Cancer Network recommend World Health Organization Type 2-3 nasopharyngeal carcinoma (NPC) be staged for distant disease using chest X-ray and bone scan. Our aim was to evaluate these modalities plus liver ultrasonography for American Joint Committee on Cancer/International Union Against Cancer 1997 clinical Stage I-IVB NPC. METHODS AND MATERIALS Between February 1999 and May 2002, all patients with clinical (examination plus CT/MRI of head and neck) Stage I-IVB undifferentiated NPC were prospectively evaluated for distant disease with chest X-ray, liver ultrasonography, and bone scan. Suspicious lesions underwent confirmatory investigation, and patients were reevaluated at 4 months. RESULTS In the 139 patients evaluated, the positive yield was 3.6% and prevalence was 5.8% (0.7% lung, 2.2% skeletal, and 2.9% liver metastases). The prevalence increased by N stage (p = 0.004) and overall stage (p = 0.05). Compared with N3 disease (odds ratio 1.0), the odds of metastases for N0, N1, and N2 disease was 0, 0.12, and 0.33, respectively. The positive yield was 0%, 1.8%, 4.8%, and 14.3% for N0, N1, N2, and N3 disease, respectively. CONCLUSION This is the first study to evaluate the use of distant staging investigations for American Joint Committee on Cancer/International Union Against Cancer 1997 staged NPC. We recommend alterations to the 2000 National Comprehensive Cancer Network guidelines as follows: high-risk (N3) disease should be fully staged with chest X-ray, bone scan, and liver ultrasonography; intermediate risk (N1 and N2) disease may be staged using all three modalities on an institutional basis. No evidence supports distant imaging for low-risk (N0 or Stage I) disease.

Estimating risks of radiotherapy complications as part of informed consent: the high degree of variability between radiation oncologists may be related to experience.

PURPOSE Estimating the risks of radiotherapy (RT) toxicity is important for informed consent; however, the consistency in estimates has not been studied. This study aimed to explore the variability and factors affecting risk estimates (REs). METHODS AND MATERIALS A survey was mailed to Australian radiation oncologists, who were asked to estimate risks of RT complications given 49 clinical scenarios. The REs were assessed for association with oncologist experience, subspecialization, and private practice. RESULTS The REs were extremely variable, with a 50-fold median variability. The least variability (sevenfold) was for estimates of late, small intestinal perforation/obstruction after a one-third volume received 50 Gy with concurrent 5-fluorouracil (RE range 5-35%). The variation between the smallest and largest REs in 17 scenarios was >or=100-fold. The years of experience was significantly associated with REs of soft/connective-tissue toxicity (p = 0.01) but inversely associated with estimates of neurologic/central nervous system toxicity (p = 0.08). Ninety-six percent of respondents believed REs were important to RT practice; only 24% rated evidence to support their estimates as good. Sixty-seven percent believed national/international groups should pursue the issue further. CONCLUSION Enormous variability exists in REs for normal tissue complications due to RT that is influenced by the years of experience. Risk estimation is perceived as an important issue without a good evidence base. Additional studies are strongly recommended.

Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

PURPOSE Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. METHODS AND MATERIALS We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. RESULTS There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). CONCLUSION Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery.

A study of complications arising from different methods of anesthesia used in high-dose-rate brachytherapy for cervical cancer.

The purpose of this report is to review the complications related to different methods of anesthesia for high-dose-rate (HDR) brachytherapy for cervical carcinoma. All patients diagnosed with cervical cancer between 1999 and 2002 treated with 3-channel HDR brachytherapy were entered. Complications due to anesthesia for each fraction of brachytherapy were graded using the Common Toxicity Criteria. Eighty-four fractions of brachytherapy were delivered to 18 patients: 19 fractions with patients under general anesthesia (GA), 41 with patients under topical anesthesia and sedation, 5 with patients under paracervical nerve block, and 19 with patients under conscious sedation. Thirteen complications were reported: 12 related to GA and 1 due to paracervical nerve block. Of complications due to GA, 7 were grade 1 and 5 were grade 2. The complication due to paracervical nerve block (seizure) was grade 3. GA had significantly more complications than topical anesthesia or conscious sedation (both P < 0.001). HDR brachytherapy for cervical cancer under GA has significantly more complications than other methods. Given the increasing use of fractionated 3-channel brachytherapy, further investigation of risks and benefits of anesthetic techniques is required.