R. Pearcey

Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer : A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials

BACKGROUND After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered. PATIENTS AND METHODS We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics. RESULTS On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non-platinum-based (HR = 0.77, P = .009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity. CONCLUSION These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.

Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in Patients With Advanced Squamous Cell Cancer of the Cervix

PURPOSE To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix

It is unclear whether blood transfusion can overcome the negative impact of anemia before or during radiotherapy (RT) in patients with carcinoma of the cervix. The objective of this retrospective study was to examine the impact of anemia and blood transfusion on 605 patients with carcinoma of the cervix treated with radical RT at 7 centers across Canada in 1989, 1990, and 1992.

ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma

BACKGROUND Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkins lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths. METHODS We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkins lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival. RESULTS The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P=0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P=0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P=0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkins lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkins lymphoma or early toxic effects from the treatment and 20 were related to another cause. CONCLUSIONS Among patients with Hodgkins lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.).

Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule?

PURPOSE A literature review and analysis was performed to determine whether or not efficacious high dose rate (HDR) brachytherapy fractionation schedules exist for the treatment of cervical cancer. METHODS AND MATERIALS English language publications from peer reviewed journals were assessed to calculate the total contribution of dose to Point A from both the external and intracavitary portions of radiation for each stage of cervical cancer. Using the linear quadratic formula, the biologically effective dose to the tumor, using an alpha/beta = 10, was calculated to Point A (Gy10) in order to determine a dose response relationship for local control and survival. Significant complications were assessed by calculating the dose to the late-responding tissues at Point A using an alpha/beta = 3 (Gy3) as a surrogate for normal tissue tolerance, since few publications list the actual bladder and rectal doses. RESULTS For all stages combined, the median external beam fractionation schedule to Point A was 40 Gy in 20 fractions, while the median HDR fractionation schedule was 28 Gy in 4 fractions. For stages IB, IIB, and IIIB the median biologically effective dose to Point A (Gy10) was 96, 96 and 100 Gy10s, respectively. No correlation was identified between Point A BED (Gy10s) to either survival or pelvic control. A dose response relationship could also not be identified when correlating Point A Gy3s to complications. CONCLUSION A dose response relationship could not be identified for either tumor control nor late tissue complications. These findings do not necessarily question the validity of the linear quadratic model, as much as they question the quality of the current HDR brachytherapy literature as it is currently presented and reported. Most of the HDR publications report inadequate details of the dose fractionation schedules. Only a minority of publications report significant complications using the actuarial method. In the future, all HDR publications for the treatment of cervical cancer should provide accurate fractionation details for each stage of disease, while reporting actuarial complication rates. The optimal fractionation schedule for treating cervical cancer using HDR brachytherapy is still unknown, and presently can be based only on single institutions with significant experience.

A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer

PURPOSE This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer. METHODS AND MATERIALS Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ. RESULTS Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease. CONCLUSION Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.

Exercise preferences of endometrial cancer survivors: a population-based study.

Exercise has gained recognition as an effective supportive care intervention for cancer survivors, yet participation rates are low. Knowledge of the specific exercise counseling and programming preferences of cancer survivors may be useful for designing effective interventions. In this study, we examined the exercise preferences of 386 endometrial cancer survivors. Participants completed a questionnaire that included measures of past exercise behavior, exercise preferences, and medical and demographic information. Some key findings were as follows: (a) 76.9% of participants said they were interested or might be interested in doing an exercise program and (b) 81.7% felt they were able or likely able to actually do an exercise program. Participants also indicated that walking was their preferred activity (68.6%) and moderate exercise was their preferred intensity (61.1%). Logistic regression analyses showed that meeting public health guidelines for exercise, being overweight or obese, receiving adjuvant treatment, months since diagnosis, income, marital status, and level of education all influenced exercise preferences. These results suggest that endometrial cancer survivors have unique exercise preferences that are moderated by a number of demographic and medical variables. These findings may have implications for the design and implementation of clinical and population-based exercise interventions for endometrial cancer survivors.

Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer

BACKGROUND AND PURPOSE This paper investigates the outcome using different dose/fractionation schedules in high dose rate (HDR) post-operative vaginal vault radiotherapy in patients with low to intermediate risk endometrial cancer. MATERIALS AND METHODS The world literature was reviewed and thirteen series were analyzed representing 1800 cases. RESULTS A total of 12 vaginal vault recurrences were identified representing an overall vaginal control rate of 99.3%. A wide range of dose fractionation schedules and techniques have been reported. In order to analyze a dose response relationship for tumor control and complications, the biologically effective doses to the tumor and late responding tissues were calculated using the linear quadratic model. A threshold was identified for complications, but not vaginal control. While dose fractionation schedules that delivered a biologically effective dose to the late responding tissues in excess of 100 Gy(3) (LQED=60 Gy) predicted for late complications, dose fractionation schedules that delivered a modest dose to the vaginal surface (50 Gy(10) or LQED=30 Gy) appeared tumoricidal with vaginal control rates of at least 98%. CONCLUSIONS By using convenient, modest dose fractionation schedules, HDR vaginal vault - brachytherapy yields very high local control and extremely low morbidity rates.

Impact of Adoption of Chemoradiotherapy on the Outcome of Cervical Cancer in Ontario: Results of a Population-Based Cohort Study

PURPOSE To describe the adoption of concurrent cisplatin-based chemoradiotherapy (C-CRT), and to evaluate its impact on the outcome of cervical cancer in Ontario. METHODS We used a population-based cancer registry to identify the 4,069 patients with invasive carcinoma of the cervix diagnosed in Ontario between 1992 and 2001. We linked electronic records of treatment to the registry. We described time trends in the use of C-CRT, and we compared survival before and after widespread adoption of C-CRT. RESULTS Over the study period, the proportion of patients treated with primary radical radiotherapy (RT) remained constant at approximately 42%. Between 1992 and 1998, less than 10% of RT cases received chemotherapy. Early in 1999, there was rapid adoption of C-CRT. Between 1999 and 2001, more than 60% of RT cases received C-CRT. There was a contemporaneous increase in overall 3-year survival from 71.1% in the 1995 to 1998 cohort to 75.9% in the 1999 to 2001 cohort (P = .03). There was no change in survival in patients treated with surgery alone. However, there was a significant increase in 3-year survival from 58.6% in the 1995 to 1998 cohort to 69.8% in the 1999 to 2001 cohort (P < .01) in the subpopulation of patients treated with primary RT +/- chemotherapy. CONCLUSION The adoption of C-CRT was associated with a significant improvement in overall survival of cervical cancer at the population level. The magnitude of the benefit of C-CRT in the general population was consistent with the results of the relevant clinical trials.

Planning target volume margins for prostate radiotherapy using daily electronic portal imaging and implanted fiducial markers

BackgroundFiducial markers and daily electronic portal imaging (EPI) can reduce the risk of geographic miss in prostate cancer radiotherapy. The purpose of this study was to estimate CTV to PTV margin requirements, without and with the use of this image guidance strategy.Methods46 patients underwent placement of 3 radio-opaque fiducial markers prior to prostate RT. Daily pre-treatment EPIs were taken, and isocenter placement errors were corrected if they were ≥ 3 mm along the left-right or superior-inferior axes, and/or ≥ 2 mm along the anterior-posterior axis. During-treatment EPIs were then obtained to estimate intra-fraction motion.ResultsWithout image guidance, margins of 0.57 cm, 0.79 cm and 0.77 cm, along the left-right, superior-inferior and anterior-posterior axes respectively, are required to give 95% probability of complete CTV coverage each day. With the above image guidance strategy, these margins can be reduced to 0.36 cm, 0.37 cm and 0.37 cm respectively. Correction of all isocenter placement errors, regardless of size, would permit minimal additional reduction in margins.ConclusionsImage guidance, using implanted fiducial markers and daily EPI, permits the use of narrower PTV margins without compromising coverage of the target, in the radiotherapy of prostate cancer.