Faculty Bibliography

PURPOSE/OBJECTIVE:To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS/METHODS:Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6-60 months). RESULTS:Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of >/= late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of >/= late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively. CONCLUSIONS:These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.

BACKGROUND:The 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma defined Stage IB as disease with invasion of less than one-half of the myometrium, although most of the data on prognostic factors are based on invasion of the inner one-third, middle one-third, or outer one-third of the myometrium. The objective of this study was to determine whether the depth of myometrial invasion is correlated with outcome in patients with Stage IB endometrial carcinoma. METHODS:Between November, 1987 and June, 1998, 251 patients with Stage IB endometrioid adenocarcinoma of the uterus underwent simple hysterectomy followed by intravaginal brachytherapy. The depth of myometrial invasion was less than or equal to one-third (Group I) in 191 of 251 patients (79%) and greater than one-third to less than one-half (Group II) in 52 of 251 patients (21%). Comprehensive surgical staging (CSS) was done in 12% of patients. The two groups were balanced with regard to age (< 60 years vs. > or = 60 years), FIGO grade, lower uterine segment involvement (LUSI), CSS, and the use of postoperative external-beam radiation. The rate of capillary-like space invasion (CLSI), however, was 9% in Group I compared with 25% in Group II (P = 0.002). The median follow-up was 58 months. RESULTS:The overall 5-year actuarial local-regional control (LRC), disease free (DFS) survival, and overall survival (OS) rates were 95%, 92%, and 92%, respectively. These end points, however, did not vary significantly between the two groups. The 5-year LRC, DFS, and OS rates in Groups I and II were 96% versus 95%, respectively (P = 0.9); 92% versus 94%, respectively (P = 0.7); and 92% versus 90%, respectively (P = 0.5). On multivariate analysis, the influence on outcome of age, grade, amount of myometrial invasion, LUSI, and CLSI was evaluated. Only age > or = 60 years and FIGO Grade 3 were correlated with poor DFS (P = 0.02 and P = 0.03, respectively) and OS (P = 0.001 and P = 0.01, respectively). CONCLUSIONS:Based on this study, in patients with Stage IB endometrial carcinoma, the amount of myometrial invasion, defined as invasion less than or equal to one-third of the myometrium versus invasion greater than one-third and less than one-half of the myometrium, did not appear to influence outcome. Age > or = 60 years and FIGO Grade 3, however, emerged as independent prognostic factors for poor DFS and OS.

PURPOSE: To identify the role of p53 pathway alteration(s) as predictors of treatment outcome in patients with advanced, resectable, squamous cell carcinoma (SCC) of the larynx and pharynx treated with larynx preservation (LP) intent. PATIENTS AND METHODS: Seventy-one patients treated on two consecutive LP protocols were studied based on availability of representative tissues. We analyzed the expression pattern of p53, its upstream regulator mdm2, and downstream transcriptional target p21/WAF1 by immunohistochemistry. Positive phenotype was defined as >or= 20% of tumor cells showing nuclear immunoreactivity. Results were correlated with treatment outcomes. RESULTS: Positive phenotype was observed in 35 (49%) of 71 cases for p53, in 52 (74%) of 70 for mdm2, and in 37 (54%) of 68 for p21. There was no correlation between p53 phenotype and p21 nuclear accumulation. The mdm2-negative phenotype was most predictive of major response at the primary tumor site (P =.088). p53-positive phenotype was associated with worse local control with LP (LCLP; 49% v 23%, P =.053) and inferior overall survival (OS; 51% v 29%, P =.017) at 5 years. On Cox regression analysis, p53-positive phenotype predicted inferior OS (P =.033) and showed a trend for worse LCLP (P =.102). When analyzed in a multivariate model as continuous variables, p53 showed a stronger correlation with inferior OS (P <.01), and mdm2 was associated with worse OS (P <.01). CONCLUSION: Among the three markers studied, our data support p53 phenotype as the most informative predictor of unfavorable outcomes in the LP setting, and suggest a role for mdm2 phenotype that requires further exploration. Our analysis does not support a p53-dependent mechanism for p21 expression. Prospective and larger studies are necessary before integration of these molecular markers as part of molecular staging and predictors for organ preservation or other outcomes

Intensity-modulated radiation therapy (IMRT) represents a new paradigm in radiation treatment planning and delivery for treatment of prostate cancer with enormous potential. Preliminary data indicate that this highly conformal treatment technique can effectively reduce acute and late-occurring toxicities, improving the quality of life of the treated patient and serving as the optimal dose escalation tool. IMRT produces radiation distributions capable of delivering different dose prescriptions to multiple target sites, providing a new opportunity for differential dose painting to increase the dose selectively to specific, image-defined regions within the prostate. Clinical trials will be necessary to define more clearly the true extent of improved tumor control and reduction in normal tissue complications with IMRT in the treatment of prostate cancer.

PURPOSE/OBJECTIVE:The objective of this report is to re-evaluate the role of the Anderson nomograms in treatment planning for permanent prostate implants. The incentive for revisiting this topic concerns three issues: (1) Although nomograms continue to be used in many centers for ordering seeds, few centers use them during treatment planning; (2) Whereas nomograms were designed to deliver a minimum peripheral dose for a uniform distribution of seeds in the gland, many practitioners use peripheral seed loading patterns to reduce urethral toxicity; and (3) As preoperative and intraoperative treatment planning is becoming standard, the apparent role of nomograms is diminished. The nomogram method is reviewed in terms of: (1) total activity predicted, (2) target coverage (as planned in the operating room and as calculated from postimplant computed tomography studies), and (3) reproducibility (i.e., patient-to-patient and planner-to-planner variability). In each case, the computer-optimization system for intraoperative planning currently in use at our institution was taken as the "gold standard." METHODS AND MATERIALS/METHODS:We compared for the same patient the results of nomogram planning to those yielded by genetic algorithm (GA) optimization in terms of total activity predicted (n = 20 cases) and percent target coverage (n = 5 cases). Furthermore, we examined retrospectively the dosimetry of 61 prostate implants planned with the GA (n = 27) and the current implementation of Anderson nomograms (n = 34). RESULTS:Nomogram predictions of the total activity required are in good agreement (within 10%) with the GA-planned activity. However, computer-optimized plans consistently yield superior plans, as reflected in both pre- and postimplant analyses. We find also that user (specifically, treatment planner) implementation of the nomograms may be a major source of variability in nomogram planning-a difficulty to which robust computer optimization is less prone. CONCLUSIONS:Nomograms continue to be useful tools for predicting the total required activity for volume implants, and thus for performing an independent check of this quantity. Not unexpectedly, computer optimization remains the preferred planning method. Generally, nomogram-guided implants do not incorporate structures other than the treatment volume into the planning process. Further yet, they deliver a lower dose than that prescribed and result in greater variability among plans than computer-optimized treatments. In summary, nomograms (1) remain an efficient quality assurance tool for computer-generated plans, (2) serve as a good predictor of the number of seeds required for ordering purposes, and (3) provide a simple and dependable backup planning method in case the intraoperative planning system fails.

BACKGROUND AND PURPOSE/OBJECTIVE:We fit phenomenological tumor control probability (TCP) models to biopsy outcome after three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer patients to quantify the local dose-response of prostate cancer. MATERIALS AND METHODS/METHODS:We analyzed the outcome after photon beam 3D-CRT of 103 patients with stage T1c-T3 prostate cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) (prescribed target doses between 64.8 and 81Gy) who had a prostate biopsy performed >or=2.5 years after end of treatment. A univariate logistic regression model based on D(mean) (mean dose in the planning target volume of each patient) was fit to the whole data set and separately to subgroups characterized by low and high values of tumor-related prognostic factors T-stage (<T2c vs. >or=T2c), Gleason score (<or=6 vs. >6), and pre-treatment prostate-specific antigen (PSA) (<or=10 ng/ml vs. >10 ng/ml). In addition, we evaluated five different classifications of the patients into three risk groups, based on all possible combinations of two or three prognostic factors, and fit bivariate logistic regression models with D(mean) and the risk group category to all patients. Dose-response curves were characterized by TCD(50), the dose to control 50% of the tumors, and gamma(50), the normalized slope of the dose-response curve at TCD(50). RESULTS:D(mean) correlates significantly with biopsy outcome in all patient subgroups and larger values of TCD(50) are observed for patients with unfavorable compared to favorable prognostic factors. For example, TCD(50) for high T-stage patients is 7Gy higher than for low T-stage patients. For all evaluated risk group definitions, D(mean) and the risk group category are independent predictors of biopsy outcome in bivariate analysis. The fit values of TCD(50) show a clear separation of 9-10.6Gy between low and high risk patients. The corresponding dose-response curves are steeper (gamma(50)=3.4-5.2) than those obtained when all patients are analyzed together (gamma(50)=2.9). CONCLUSIONS:Dose-response of prostate cancer, quantified by TCD(50) and gamma(50), varies by prognostic subgroup. Our observations are consistent with the hypothesis that the shallow nature of clinically observed dose-response curves for local control result from a patient population that is a heterogeneous mixture of sub-populations with steeper dose-response curves and varying values of TCD(50). Such results may eventually help to identify patients, based on their individual pre-treatment prognostic factors, that would benefit most from dose-escalation, and to guide dose prescription.

PURPOSE/OBJECTIVE:Adjuvant radiation therapy (RT) has been shown to improve local control in patients with high-grade soft tissue sarcoma (STS) of the extremity. This study sought to define the optimal management in patients with stage II-B (high-grade, size < or = 5 cm) tumors. PATIENTS AND METHODS/METHODS:Between July 1982 and December 1998, 204 adult patients with primary stage II-B STS underwent limb-sparing surgery with negative microscopic margins. Eighty-eight patients (43%) received RT; 116 (57%) did not. The RT and no-RT groups were balanced with regard to age, site (upper v lower extremity), whether patients had prior unplanned excision, and location (central, i.e., shoulder/groin v non-central). The RT group had more deep tumors (P =.03). Adjuvant RT was delivered with brachytherapy in 60% and external-beam radiation in 40% of patients. RESULTS:With a median follow-up of 67 months, the 5-year local control, distant relapse-free survival, and disease-specific survival rates were 82%, 80%, and 88%, respectively. There was no significant difference in local control between the RT and no-RT groups (84% v 80%, respectively, P =.3). Tumor depth, site, and prior unplanned excision did not correlate with local control. The only independent predictors of poor local control were central tumor location (relative risk [RR] = 3; 95% confidence interval [CI], 2 to 7; P =.005) and age more than 50 years (RR = 6; 95% CI, 2 to 13; P =.001). CONCLUSION/CONCLUSIONS:In this retrospective study, adjuvant RT did not significantly improve local control in patients with stage II-B STS of the extremity. The outcome of patients with central tumor location was poor, and efforts to identify the optimal local treatment approach for such patients are warranted.

Using multiple computed tomography (CT) scans, 50 patients undergoing prostate radiotherapy were tested for clinically significant time trends in the target and surrounding critical structures. Significant trends were observed toward increasing bladder volume and increasing bowel-to-planning target volume separation; however, no trends were observed in the prostate, seminal vesicles, or rectum. The subset of patients undergoing hormone therapy was also tested and did not independently exhibit any significant time trends.

PURPOSE/OBJECTIVE:To determine the expected time to serum testosterone normalization after short-course neoadjuvant androgen deprivation therapy (NAAD) and three-dimensional conformal radiotherapy for patients with localized prostate cancer and to identify pretreatment predictors that correlated with the time to testosterone normalization. METHODS:Between 1993 and 1999, 88 patients with localized prostate cancer, treated with NAAD and external beam radiotherapy, were prospectively monitored after treatment with sequential testosterone levels. NAAD was administered before and during the entire course of radiotherapy and discontinued at the end of treatment. The median duration of NAAD was 6 months. The actuarial rate of serum testosterone normalization from the end of treatment was evaluated, and the presence or absence of androgen deprivation-related symptoms was correlated with serum testosterone levels. Symptoms assessed included weight gain, loss of libido, breast tenderness, breast enlargement, hot flashes, and fatigue. RESULTS:Serum testosterone levels returned to the normal range in 57 (65%) of the 88 patients and failed to normalize in 31 patients (35%). The median time to normalization was 18.3 months. The actuarial rate of normalization at 3, 6, 12, and 24 months was 10%, 26%, 38%, and 59%, respectively. In a multivariate analysis, a pretreatment testosterone level in the lower range of normal was the only variable that predicted for delayed testosterone normalization after NAAD (p = 0.00047). Among 45 patients with information concerning androgen deprivation-related symptoms recorded 1 year after cessation of NAAD, 24 (53%) had normalized testosterone levels, but in 21 patients (47%), the levels had not yet returned to normal. At 1 year, only 1 (4%) of 24 patients whose testosterone level had returned to normal experienced NAAD-related symptoms compared with 14 (67%) of 21 patients who did not have normal testosterone levels (p <0.001). CONCLUSION/CONCLUSIONS:Testosterone levels often remain depressed for extended periods after cessation of short-course NAAD. Lower baseline testosterone levels predict for a delay in testosterone normalization, and the persistence of symptoms related to androgen deprivation correlates with low testosterone levels.