Lawrence B. Levy

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 and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer

Objectives:To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer. Methods:Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years. Results:The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS. Conclusions:Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

Use of portal images and BAT ultrasonography to measure setup error and organ motion for prostate IMRT: implications for treatment margins

PURPOSE Traditionally, portal images have been used for verification of patient setup. More recently, direct prostate localization using ultrasound imaging has become available. The aim of this study was to use both modalities to measure daily setup error and prostate organ motion and their respective contributions to the overall uncertainty of prostate target localization. METHODS AND MATERIALS Thirty-five patients treated for prostate cancer with intensity-modulated radiotherapy (IMRT) between February 6 and July 2, 2001 underwent daily B-mode acquisition and targeting (BAT) ultrasound localization and weekly orthogonal portal imaging. RESULTS A total of 243 pairs of orthogonal portal films and the corresponding daily BAT images were reviewed. The mean shift +/- standard deviation in the right-left (RL), AP, and superinferior (SI) directions was 0.035 +/- 2.8 mm, -0.23 +/- 3.0 mm, and -0.013 +/- 2.0 mm, respectively, for portal films and -0.82 +/- 3.2 mm, -1.4 +/- 6.4 mm and -1.7 +/- 6.4 mm, respectively, for BAT images taken on the same day as the portal films. The mean prostate organ motion measurements were -0.89 +/- 3.3 mm (RL), -1.3 +/- 5.7 mm (AP), and -1.6 +/- 6.4 mm (SI). Without BAT localization, organ motion would have caused the clinical target volume to move outside the planning target volume margin in 23.3-41.8% of the treatments. Margins necessary to achieve complete coverage of the clinical target volume > 95% of the time without BAT would have been 5.3, 10.4 and 10.4 mm in the RL, AP, and SI dimensions, respectively. CONCLUSIONS Prostate organ motion appears to predominate over setup error as the major component of variation in target localization. Without the use of BAT ultrasound prostate imaging, misses of the prostate can occur in a high percentage of treatments, despite patient setup verification with portal images. Relatively large planning target volume margins in the AP and SI dimensions may be necessary to overcome this.

Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy

BACKGROUND Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor. PATIENTS AND METHODS We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63). CONCLUSION Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.

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.

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.

Late rectal complications after prostate brachytherapy for localized prostate cancer

This review of the literature on late rectal complications after prostate brachytherapy indicated that it is a highly effective treatment modality for patients with clinically localized prostate cancer but can cause chronic radiation proctitis. The most common manifestation of chronic radiation proctitis was anterior rectal wall bleeding, which often occurred within the first 2 years after brachytherapy. It is interesting to note that the rates of late rectal morbidity appear to have declined over time, which may reflect improvements in implantation techniques and imaging. Rectal biopsy as part of the workup to evaluate rectal bleeding can lead to rectal fistula and the need for colostomy, a rare but major complication. The authors recommend 1) screening colonoscopy before brachytherapy for patients who have not had a screening colonoscopy within the preceding 3 years to rule out colorectal malignancies and, thus, facilitate conservative management should rectal bleeding occur; 2) lifestyle modifications during treatment to limit exposure of the rectum to radiation; and 3) conservative management for rectal bleeding that occurs within 2 years after brachytherapy. Cancer 2009.

Bcl-2 IS SIGNIFICANTLY OVEREXPRESSED IN LOCALIZED RADIO- RECURRENT PROSTATE CARCINOMA, COMPARED WITH LOCALIZED RADIO-NAIVE PROSTATE CARCINOMA

PURPOSE We set out to determine whether patients who underwent prostatectomy for recurrence after external-beam radiotherapy for prostate cancer had a higher incidence of alterations in the apoptotic pathway than did patients who underwent surgery as initial treatment. MATERIALS AND METHODS Twenty patients who underwent unsuccessful full-dose external-beam radiotherapy for prostate cancer and subsequently underwent salvage radical surgery (radio-recurrent group), and 20 patients matched for various clinical parameters who underwent only radical prostatectomy for localized or locally advanced prostate cancer (radio-naive group), were studied. Tissue samples were examined for immunoreactivity for p53, p21, Bcl-2, and Ki-67 proteins. Statistically, the two groups were compared using exact logistic regression. RESULTS Fifty-five percent of the tumors from patients initially treated with radiotherapy were noted to overexpress Bcl-2; whereas, in the radio-naive group, no patient had Bcl-2 overexpression (p = 0.0004). More patients who underwent salvage radical surgery were found to have a higher mean proliferative index (Ki-67 staining) (39.6%), compared with patients undergoing prostatectomy alone (22.1%), p = 0.0800. No significant difference was noted in immunohistochemical expression of p53 and p21 between the two groups. CONCLUSIONS Patients undergoing radical prostatectomy after radiotherapy had a significantly higher rate of Bcl-2 overexpression than did patients who underwent surgery as the initial treatment. Alterations in the apoptotic pathway may be important in the development of local recurrence after radiation therapy.

Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design.

PURPOSE To identify characteristics that predict response to chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Between January 1986 and May 1996, 190 chemotherapy-naive patients with advanced or recurrent squamous cell carcinoma of the cervix not amenable to curative radiation therapy or surgery were treated on 14 different chemotherapy protocols at M.D. Anderson Cancer Center. Patients charts were retrospectively reviewed for patient demographics, tumor and treatment characteristics, and patterns of response and survival. RESULTS Of 190 patients, 22 had advanced or persistent disease and 168 had recurrent disease. Patients were treated with platinum-based (n=95) and non-platinum-based (n=95) regimens. The overall response rate was 20.0% (4.2% complete response; 15.8% partial response), with a median response duration of 4.8 months. Race, socioeconomic class, tumor stage and grade, mode of primary treatment, time from primary diagnosis to disease recurrence, initial performance status, and use of platinum-based therapy were not significant predictors of response. Age at time of chemotherapy (P=.001) and site of recurrence (P=.044) were significant determinants by multivariate analysis. Patients who were older were more likely to respond to therapy, and the response rate for patients in whom disease recurred outside the irradiated field was 25.2%, compared with a 5.3% response rate for patients with recurrent disease limited to a previously irradiated field. CONCLUSION The site of disease recurrence and patient age should be taken into account when designing chemotherapy trials and also when considering chemotherapy in the patient with recurrent cervix cancer.

Urinary Side Effects and Complications After Permanent Prostate Brachytherapy: The MD Anderson Cancer Center Experience

OBJECTIVES To evaluate acute and long-term urinary morbidity after permanent prostate brachytherapy at a single tertiary care center. To minimize the risk of long-term urinary morbidity, it is important for clinicians to be able to distinguish acute urinary side effects after prostate brachytherapy from longer-term treatment-related urinary complications. METHODS The medical records of 351 consecutive patients who underwent prostate brachytherapy at the MD Anderson Cancer Center between 1998 and 2006 were analyzed. To evaluate the short-term urinary side effects, the Expanded Prostate Cancer Index Composite questionnaire was administered at baseline and at 1, 4, 8, and 12 months. Long-term urinary complications were scored using a modified Radiation Therapy Oncology Group scale. RESULTS All 4 urinary subdomain scores evaluating acute urinary side effects after treatment (bother, function, incontinence, and irritation or obstruction) had returned to baseline levels by 8 months after implantation. At 5 years, the cumulative risks of late urinary complications by grade were 8.6% for grade 1 complications, 6.5% for grade 2, 1.7% for grade 3%, and 0.5% for grade 4. The most common grade 2 late urinary complications were urethral stricture (4 patients), incontinence requiring daily pads (3 patients), and intermittent hematuria (3 patients). Grade 3 complications were urinary retention requiring self-catheterization (2 patients) and severe frequency with dysuria (2 patients). The only grade 4 event was severe hemorrhagic cystitis. CONCLUSIONS Short-term urinary side effects after prostate brachytherapy are common, follow a predictable course, and typically resolve within 1 year. Conservative management of short-term urinary side effects is recommended to minimize the risk of long-term urinary complications.