Andrew K. Lee

Mortality After Cure of Testicular Seminoma

PURPOSE To determine the incidence of potentially treatment-related mortality in long-term survivors of testicular seminoma treated by orchiectomy and radiation therapy (XRT). PATIENTS AND METHODS From all 477 men with stage I or II testicular seminoma treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) with post-orchiectomy megavoltage XRT between 1951 and 1999, 453 never sustained relapse of their disease. Long-term survival for these 453 men was evaluated with the person-years method to determine the standardized mortality ratio (SMR). SMRs were calculated for all causes of death, cardiac deaths, and cancer deaths using standard US data for males. RESULTS After a median follow-up of 13.3 years, the 10-, 20-, 30-, and 40-year actuarial survival rates were 93%, 79%, 59%, and 26%, respectively. The all-cause SMR over the entire observation interval was 1.59 (99% CI, 1.21 to 2.04). The SMR was not excessive for the first 15 years of follow-up: SMR, 1.30 (95% CI, 0.93 to 1.77); but beyond 15 years the SMR was 1.85 (99% CI, 1.30 to 2.55). The overall cardiac-specific SMR was 1.61 (95% CI, 1.21 to 2.24). The cardiac SMR was significantly elevated only beyond 15 years (P <.01). The overall cancer-specific SMR was 1.91 (99% CI, 1.14 to 2.98). The cancer SMR was also significant only after 15 years of follow-up (P <.01). An increased mortality was evident in patients treated with and without mediastinal XRT. CONCLUSION Long-term survivors of seminoma treated with post-orchiectomy XRT are at significant excess risk of death as a result of cardiac disease or second cancer. Management strategies that minimize these risks but maintain the excellent hitherto observed cure rates need to be actively pursued.

Patient selection, cancer control, and complications after salvage local therapy for postradiation prostate-specific antigen failure: a systematic review of the literature.

Among men who experience prostate‐specific antigen (PSA) failure after external beam radiation or brachytherapy (RT), many will harbor occult micrometastases; however, a significant minority will have a true local‐only failure and, thus, potentially may benefit from a salvage local therapy. Those most likely to have a local‐only failure initially have low‐risk disease (PSA < 10 ng/mL, Gleason score ≤6, clinical T1c or T2a tumor status), pretreatment PSA velocity < 2.0 ng/mL per year at the time of initial presentation, interval to PSA failure > 3 years, PSA doubling time > 12 months, negative bone scan and pelvic imaging, and positive rebiopsy. In addition, men with presalvage PSA levels > 10 ng/mL, presalvage T3/T4 disease, or presalvage Gleason scores ≥7 on a rebiopsy sample without significant RT effects are unlikely to be cured by salvage local therapy. Based on a review of all series of post‐RT salvage prostatectomy, cryosurgery, and brachytherapy published in English since 1990, morbidity can be substantial. Although urinary incontinence appeared to be greater after salvage prostatectomy (41%) or cryosurgery (36%) than after brachytherapy (6%), patients who received salvage brachytherapy faced a 17% risk of grade 3 or 4 genitourinary complications and a fistula risk that averaged 3.4% across all series. From this review, the authors concluded that prospective randomized studies are needed to determine the relative efficacy of the 3 major local salvage modalities and that additional research is needed to identify factors associated with an increased risk of significant complications to improve patient selection and to augment the benefit/risk ratio associated with attempts to cure local‐only recurrences after radiation therapy. Cancer 2007.

LONG-TERM FAILURE PATTERNS AND SURVIVAL IN A RANDOMIZED DOSE-ESCALATION TRIAL FOR PROSTATE CANCER. WHO DIES OF DISEASE?

PURPOSE To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer. MATERIALS AND METHODS A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors. RESULTS Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence. CONCLUSIONS Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease.

Clinical follow‐up after bilateral risk reducing (‘prophylactic’) mastectomy: mental health and body image outcomes

Background: In Manchester, approximately 120 women at ≥1: 4 lifetime risk of breast cancer have considered preventative surgery since 1992. Women treated within the Manchester protocol receive two genetic counselling sessions, a psychological assessment and a surgical consultation pre‐operatively and annual follow‐up post‐operatively. The vast majority of women have breast reconstruction.

Risk of Secondary Malignant Neoplasms From Proton Therapy and Intensity-Modulated X-Ray Therapy for Early-Stage Prostate Cancer

PURPOSE To assess the risk of a secondary malignant neoplasm (SMN) from proton therapy relative to intensity-modulated radiation therapy (IMRT) using X-rays, taking into account contributions from both primary and secondary sources of radiation, for prostate cancer. METHODS AND MATERIALS A proton therapy plan and a 6-MV IMRT plan were constructed for 3 patients with early-stage adenocarcinoma of the prostate. Doses from the primary fields delivered to organs at risk of developing an SMN were determined from treatment plans. Secondary doses from the proton therapy and IMRT were determined from Monte Carlo simulations and available measured data, respectively. The risk of an SMN was estimated from primary and secondary doses on an organ-by-organ basis by use of risk models from the Committee on the Biological Effects of Ionizing Radiation. RESULTS Proton therapy reduced the risk of an SMN by 26% to 39% compared with IMRT. The risk of an SMN for both modalities was greatest in the in-field organs. However, the risks from the in-field organs were considerably lower with the proton therapy plan than with the IMRT plan. This reduction was attributed to the substantial sparing of the rectum and bladder from exposure to the therapeutic beam by the proton therapy plan. CONCLUSIONS When considering exposure to primary and secondary radiation, proton therapy can reduce the risk of an SMN in prostate patients compared with contemporary IMRT.

Influence of obesity on biochemical and clinical failure after external-beam radiotherapy for localized prostate cancer.

Several reports have shown that obesity is associated with increased risk of biochemical failure after radical prostatectomy. However, limited information is available regarding the impact of obesity on prostate cancer progression after radiotherapy. The current study sought to determine whether obesity was an independent predictor of biochemical failure (BF) and clinical recurrence (CF) among patients treated with external‐beam radiotherapy (EBRT).

Prostate Specific Antigen Bounce Phenomenon After External Beam Radiation for Clinically Localized Prostate Cancer.

PURPOSE We characterize the prostate-specific antigen (PSA) bounce in patients who underwent external beam radiation therapy for prostate cancer and correlate the PSA bounce with the development of biochemical disease progression. MATERIALS AND METHODS In this study 964 patients received full dose radiation therapy alone. Followup PSA values were obtained 3 months after completion of radiotherapy and every 3 to 6 months thereafter. Median followup of the entire study group was 48 months. All time intervals were calculated from the completion date of radiation therapy. PSA bounce was defined as an initial increase in serum PSA of at least 0.5 ng./ml., followed by a decrease to pre-bounce baseline serum PSA values no more than 60 months after external beam radiation therapy. RESULTS Of the 964 patients 119 (12%) had a PSA bounce. PSA bounce was unrelated to age, race, pretreatment PSA, Gleason score, clinical T stage or radiation dose. Mean time to PSA bounce was 9 months from the time of therapy. The respective 1 and 5-year biochemical disease-free survival rates were 100% and 82.1% for patients with PSA bounce and 93.9% and 57.7% for those without PSA bounce (p = 0.0001). CONCLUSIONS Of men with prostate cancer treated with external beam radiation therapy 12% experienced a transient increase in PSA (PSA bounce) followed by a return to pre-bounce levels after radiation. The PSA bounce phenomenon was not predictive of time to biochemical recurrence.

A beam-specific planning target volume (PTV) design for proton therapy to account for setup and range uncertainties

PURPOSE To report a method for explicitly designing a planning target volume (PTV) for treatment planning and evaluation in heterogeneous media for passively scattered proton therapy and scanning beam proton therapy using single-field optimization (SFO). METHODS AND MATERIALS A beam-specific PTV (bsPTV) for proton beams was derived by ray-tracing and shifting ray lines to account for tissue misalignment in the presence of setup error or organ motion. Range uncertainties resulting from inaccuracies in computed tomography-based range estimation were calculated for proximal and distal surfaces of the target in the beam direction. The bsPTV was then constructed based on local heterogeneity. The bsPTV thus can be used directly as a planning target as if it were in photon therapy. To test the robustness of the bsPTV, we generated a single-field proton plan in a virtual phantom. Intentional setup and range errors were introduced. Dose coverage to the clinical target volume (CTV) under various simulation conditions was compared between plans designed based on the bsPTV and a conventional PTV. RESULTS The simulated treatment using the bsPTV design performed significantly better than the plan using the conventional PTV in maintaining dose coverage to the CTV. With conventional PTV plans, the minimum coverage to the CTV dropped from 99% to 67% in the presence of setup error, internal motion, and range uncertainty. However, plans using the bsPTV showed minimal drop of target coverage from 99% to 94%. CONCLUSIONS The conventional geometry-based PTV concept used in photon therapy does not work well for proton therapy. We investigated and validated a beam-specific PTV method for designing and evaluating proton plans.

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

OBJECTIVE To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. METHODS AND MATERIALS Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. RESULTS 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). CONCLUSIONS Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.

A Comprehensive Comparison of IMRT and VMAT Plan Quality for Prostate Cancer Treatment

PURPOSE We performed a comprehensive comparative study of the plan quality between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) for the treatment of prostate cancer. METHODS AND MATERIALS Eleven patients with prostate cancer treated at our institution were randomly selected for this study. For each patient, a VMAT plan and a series of IMRT plans using an increasing number of beams (8, 12, 16, 20, and 24 beams) were examined. All plans were generated using our in-house-developed automatic inverse planning (AIP) algorithm. An existing eight-beam clinical IMRT plan, which was used to treat the patient, was used as the reference plan. For each patient, all AIP-generated plans were optimized to achieve the same level of planning target volume (PTV) coverage as the reference plan. Plan quality was evaluated by measuring mean dose to and dose-volume statistics of the organs at risk, especially the rectum, from each type of plan. RESULTS For the same PTV coverage, the AIP-generated VMAT plans had significantly better plan quality in terms of rectum sparing than the eight-beam clinical and AIP-generated IMRT plans (p < 0.0001). However, the differences between the IMRT and VMAT plans in all the dosimetric indices decreased as the number of beams used in IMRT increased. IMRT plan quality was similar or superior to that of VMAT when the number of beams in IMRT was increased to a certain number, which ranged from 12 to 24 for the set of patients studied. The superior VMAT plan quality resulted in approximately 30% more monitor units than the eight-beam IMRT plans, but the delivery time was still less than 3 min. CONCLUSIONS Considering the superior plan quality as well as the delivery efficiency of VMAT compared with that of IMRT, VMAT may be the preferred modality for treating prostate cancer.