Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer.

PURPOSE: To identify predictors of distant metastases (DM) among patients who develop an isolated prostate-specific antigen (PSA) relapse after definitive external-beam radiotherapy for clinically localized prostate cancer. MATERIALS AND METHODS: A total of 1,650 patients with clinical stage T1 to T3 prostate cancer were treated with high-dose three-dimensional conformal radiotherapy. Of these, 381 patients subsequently developed three consecutive increasing PSA values and were characterized as having a biochemical relapse. The median follow-up time was 92 months from the completion of radiotherapy. RESULTS: The 5-year incidence of DM after an established PSA relapse was 29%. In a multivariate analysis, PSA doubling time (PSA-DT; P < .001), the clinical T stage (P < .001), and Gleason score (P = .007) were independent variables predicting for DM after established biochemical failure. The PSA-DT for favorable-, intermediate-, and unfavorable-risk patients who developed a biochemical failure was 20.0, 13.2, and 8.2 months, respectively (P < .001). The 3-year incidence of DM for patients with PSA-DT of 0 to 3, 3 to 6, 6 to 12, and more than 12 months was 49%, 41%, 20%, and 7%, respectively (P < .001). Patients with PSA-DT of 0 to 3 and 3 to 6 months demonstrated a 7.0 and 6.6 increased hazard of developing DM or death, respectively, compared with patients with a DT more than 12 months. CONCLUSION: In addition to clinical stage and Gleason score, PSA-DT was a powerful predictor of DM among patients who develop an isolated PSA relapse after external-beam radiotherapy for prostate cancer. Patients who develop biochemical relapse with PSA-DT < or = 6 months should be considered for systemic therapy or experimental protocols because of the high propensity for rapid DM development.

Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results.

PURPOSE: To report preliminary clinical and dosimetric data from intensity-modulated radiotherapy (IMRT) for malignant gliomas. METHODS AND MATERIALS: Fifty-eight consecutive high-grade gliomas were treated between January 2001 and December 2003 with dynamic multileaf collimator IMRT, planned with the inverse approach. A dose of 59.4-60 Gy at 1.8-2.0 Gy per fraction was delivered. A total of three to five noncoplanar beams were used to cover at least 95% of the target volume with the prescription isodose line. Glioblastoma accounted for 70% of the cases, and anaplastic oligodendroglioma histology (pure or mixed) was seen in 15% of the cases. Surgery consisted of biopsy only in 26% of the patients, and 80% received adjuvant chemotherapy. RESULTS: With a median follow-up of 24 months, 85% of the patients have relapsed. The median progression-free survival time for anaplastic astrocytoma and glioblastoma histology was 5.6 and 2.5 months, respectively. The overall survival time for anaplastic glioma and glioblastoma was 36 and 9 months, respectively. Ninety-six percent of the recurrences were local. No Grade IV/V late neurologic toxicities were noted. A comparative dosimetric analysis revealed that regardless of tumor location, IMRT did not significantly improve target coverage compared with three-dimensional planning. However, IMRT resulted in a decreased maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively, owing to its improved dose conformality. The mean brainstem dose also decreased by 7%. Intensity-modulated radiotherapy delivered with a limited number of beams did not result in an increased dose to the normal brain. CONCLUSIONS: It is unlikely that IMRT will improve local control in high-grade gliomas without further dose escalation compared with conventional radiotherapy. However, it might result in decreased late toxicities associated with radiotherapy.

Adenovirus-mediated heat-activated antisense Ku70 expression radiosensitizes tumor cells in vitro and in vivo.

Ku70 is one component of a protein complex, Ku70 and Ku80, that functions as a heterodimer to bind DNA double-strand breaks and activates DNA-dependent protein kinase. Our previous study with Ku70-/- and Ku80-/- mice, and cell lines has shown that Ku70- and Ku80-deficiency compromises the ability of cells to repair DNA double-strand breaks, increases radiosensitivity of cells, and enhances radiation-induced apoptosis. In this study, we examined the feasibility of using adenovirus-mediated, heat-activated expression of antisense Ku70 RNA as a gene therapy paradigm to sensitize cells and tumors to ionizing radiation. First, we performed experiments to test the heat inducibility of heat shock protein (hsp) 70 promoter and the efficiency of adenovirus-mediated gene transfer in rodent and human cells. Replication-defective adenovirus vectors were used to introduce a recombinant DNA construct, containing the enhanced green fluorescent protein (EGFP) under the control of an inducible hsp70 promoter, into exponentially growing cells. At 24 h after infection, cells were exposed to heat treatment, and heat-induced EGFP expression at different times was determined by flow cytometry. Our data clearly show that heat shock at 42 degrees C, 43 degrees C, or 44 degrees C appears to be equally effective in activating the hsp70 promoter-driven EGFP expression (>300-fold) in various tumor cells. Second, we have generated adenovirus vectors containing antisense Ku70 under the control of an inducible hsp70 promoter. Exponentially growing cells were infected with the adenovirus vector, heat shocked 24 h later, and the radiosensitivity determined 12 h after heat shock. Our data show that heat shock induces antisense Ku70 RNA, reduces the endogenous Ku70 level, and significantly increases the radiosensitivity of the cells. Third, we have performed studies to test whether Ku70 protein level can be down-regulated in a solid mouse tumor (FSa-II), and whether this results in enhanced radiosensitivity in vivo, as assessed by in vivo/in vitro colony formation and by the tumor growth delay. Our data demonstrate that heat-shock-induced expression of antisense Ku70 RNA attenuates Ku70 protein expression in FSa-II tumors, and significantly sensitizes the FSa-II tumors to ionizing radiation. Taken together, our results suggest that adenovirus-mediated, heat-activated antisense Ku70 expression may provide a novel approach to radiosensitize human tumors.

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer.

PURPOSE: There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 years after three-dimensional conformal radiation therapy (CRT). PATIENTS AND METHODS: We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-year probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients. RESULTS: After three-dimensional CRT, 159 patients developed metastasis. At 5 years, 11% of patients experienced metastasis by cumulative incidence analysis (95% CI, 9% to 13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81. CONCLUSION: A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 years after three-dimensional CRT.

Patterns of failure using a conformal radiation therapy tumor bed boost for medulloblastoma.

PURPOSE: To assess the patterns of failure for patients with medulloblastoma receiving a conformal tumor bed boost rather than a boost to the entire posterior fossa. PATIENTS AND METHODS: From 1994 to 2002, 32 consecutive patients with newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer Center (New York, NY) received a conformal boost to the tumor bed in conjunction with craniospinal radiation therapy. Twenty-eight patients also received chemotherapy. The median age was 9 years (range, 3 to 34 years), and the male to female ratio was 3:1. Twenty-seven patients had standard-risk disease, and five patients had high-risk disease. Craniospinal doses ranged from 23.4 to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy. RESULTS: With a median follow-up of 56 months, six patients have relapsed; five relapsed outside of the posterior fossa, and one failed within the posterior fossa, outside of the high-dose boost volume. Five-year actuarial disease-free and overall survival rates were 84% and 85%, respectively. Freedom from posterior fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from distant failure was 84% at 5 years, with a trend for improvement when full-dose craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose (23.4 Gy) of radiation (100% v 63%, respectively; P =.06). No other predictive variables were identified. CONCLUSION: Conformal treatment to the tumor bed allows for significant sparing of critical structures. The posterior fossa failure rate in this series is similar to that reported when the entire posterior fossa is treated. This approach should be investigated further in a phase III trial.

Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study.

PURPOSE: To determine dosimetric factors for lung, lung subregions, and heart that correlate with radiation pneumonitis (Radiation Therapy Oncology Group Grade 3 or more) in the 78 evaluable patients from a Phase I dose escalation study (1991-2003) of three-dimensional conformal radiation therapy (3D-CRT) of non-small-cell lung cancer. METHODS AND MATERIALS: There were 10 > or = Grade 3 pneumonitis cases within 6 months after treatment. Dose-volume factors analyzed for univariate correlation with > or = Grade 3 pneumonitis were mean dose (MD), effective uniform dose (d(eff)), normal tissue complication probability (NTCP), parallel model f(dam) and V(D) for 5 < or = D < or = 60 Gy for whole, ipsilateral, contralateral, upper and lower halves of the lungs and heart D05, and mean and maximum doses. RESULTS: The most significant variables (0.005 < p < 0.006) were ipsilateral lung V(D) for D < 20 Gy. Also significant (p < 0.05) for ipsilateral lung were V(D) for D < 50 Gy, MD, f(dam) and d(eff); for total lung V(D) (D < 50 Gy), MD, f(dam), d(eff) and NTCP; for lower lung V(D) (D < 60 Gy), MD, f(dam) and d(eff). All variables for upper and contralateral lung were insignificant, as were heart variables. CONCLUSIONS: Previously reported correlations between severe pneumonitis and whole lung V13 and with other dose-volume factors of total lung and lower lung are confirmed. The most significant correlations were for (V05-V13) in ipsilateral lung.

Whole pelvic radiotherapy for prostate cancer using 3D conformal and intensity-modulated radiotherapy.

PURPOSE: To investigate the correlations between observed clinical morbidity and dosimetric parameters for whole pelvic radiotherapy (WPRT) for prostate cancer using either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between December 1996 and January 2002, 27 patients with prostate adenocarcinoma were treated with conformal WPRT as part of their definitive treatment. WPRT was delivered with 3D-CRT in 14 patients and with IMRT in 13 patients. For each of the patients treated with IMRT, optimized conventional two-dimensional (2D) and 3D-CRT plans were retrospectively generated for the whole pelvic phase of the treatment. Dose-volume histograms for the bowel, bladder, and rectum were compared for the three techniques. Acute toxicities were evaluated for all 27 patients, and late toxicities were evaluated for 25 patients with sufficient follow-up. Toxicities were scored according to the Radiation Therapy Oncology Group morbidity grading scales. Median follow-up was 30 months. RESULTS: Three-dimensional-CRT resulted in a 40% relative reduction (p < 0.001) in the volume of bowel receiving 45 Gy compared with 2D, and IMRT provided a further 60% reduction relative to 3D-CRT (p < 0.001). Compared with either 2D or 3D-CRT, IMRT reduced the volume of rectum receiving 45 Gy by 90% (p < 0.001). Overall, 9 patients (33%) experienced acute Grade 2 gastrointestinal (GI) toxicity, and only 1 of these patients was treated with IMRT. Antidiarrhea medication was required for 6 patients (22%). However, 5 of these 6 patients also received chemotherapy, and none were treated with IMRT. No Grade 3 or higher acute or late GI toxicities were observed. No cases of late radiation enteritis were observed. Acute and late genitourinary toxicity did not appear significantly increased by the addition of conformal WPRT. CONCLUSIONS: Compared to conventional 2D planning, conformal planning for WPRT resulted in significant reductions in the doses delivered to the bowel, rectum, and bladder. IMRT was superior to 3D-CRT in limiting the volume of bowel and rectum within high-dose regions. These dosimetric findings correlated with low rates of acute and late GI morbidity.

Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report.

PURPOSE: The use of image-guided and stereotactic intensity-modulated radiotherapy (IMRT) techniques have made the delivery of high-dose radiation to lesions within close proximity to the spinal cord feasible. This report presents clinical and physical data regarding the use of IMRT coupled with noninvasive body frames (stereotactic and image-guided) for multifractionated radiotherapy. METHODS AND MATERIALS: The Memorial Sloan-Kettering Cancer Center (Memorial) stereotactic body frame (MSBF) and Memorial body cradle (MBC) have been developed as noninvasive immobilizing devices for paraspinal IMRT using stereotactic (MSBF) and image-guided (MBC) techniques. Patients were either previously irradiated or prescribed doses beyond spinal cord tolerance (54 Gy in standard fractionation) and had unresectable gross disease involving the spinal canal. The planning target volume (PTV) was the gross tumor volume with a 1 cm margin. The PTV was not allowed to include the spinal cord contour. All treatment planning was performed using software developed within the institution. Isocenter verification was performed with an in-room computed tomography scan (MSBF) or electronic portal imaging devices, or both. Patients were followed up with serial magnetic resonance imaging every 3-4 months, and no patients were lost to follow-up. Kaplan-Meier statistics were used for analysis of clinical data. RESULTS: Both the MSBF and MBC were able to provide setup accuracy within 2 mm. With a median follow-up of 11 months, 35 patients (14 primary and 21 secondary malignancies) underwent treatment. The median dose previously received was 3000 cGy in 10 fractions. The median dose prescribed for these patients was 2000 cGy/5 fractions (2000-3000 cGy), which provided a median PTV V100 of 88%. In previously unirradiated patients, the median prescribed dose was 7000 cGy (5940-7000 cGy) with a median PTV V100 of 90%. The median Dmax to the cord was 34% and 68% for previously irradiated and never irradiated patients, respectively. More than 90% of patients experienced palliation from pain, weakness, or paresthesia; 75% and 81% of secondary and primary lesions, respectively, exhibited local control at the time of last follow-up. No cases of radiation-induced myelopathy or radiculopathy have thus far been encountered. CONCLUSIONS: Precision stereotactic and image-guided paraspinal IMRT allows the delivery of high doses of radiation in multiple fractions to tumors within close proximity to the spinal cord while respecting cord tolerance. Although preliminary, the clinical results are encouraging.

Does registration of PET and planning CT images decrease interobserver and intraobserver variation in delineating tumor volumes for non-small-cell lung cancer?

PURPOSE: To compare tumor volume delineation using registered positron emission tomography (PET)/CT vs. side-by-side image sets. METHODS AND MATERIALS: A total of 19 patients with non-small-cell lung cancer had 18-fluorine-deoxyglucose (FDG)-PET scans registered with planning CT scans. The disease was Stage I-II in 26%, IIIA in 42%, and IIIB in 32%. Two radiation oncologists contoured 9 tumor volumes using registered images (registered) and 10 using separate FDG-PET images as a guide (nonregistered). A third physician, who had done the treatment planning for these patients a median of 40 months before using registered images, repeated all contours: 10 on registered images (registered/registered) and 9 without registration (registered/nonregistered). Each pair of volumes (A and B) was compared. Quantitative comparison used the concordance index, (A intersection B)/(A union or logical sum B). For qualitative analysis, pairs of volumes were projected onto digitally reconstructed radiographs. The differences were graded as insignificant, minor, moderate, or major. RESULTS: The median interobserver percentage of concordance among nonregistered pairs was 61% vs. 70% in the registered group (p <0.05). On qualitative analysis, in the nonregistered group, the differences were insignificant in 5, minor in 3, and moderate in 2 of 10. The differences in the registered group were insignificant in 7 and minor in 2 of 9. The median intraobserver percentage of concordance in the registered/nonregistered group was 58% vs. 71% in the registered/registered group (p = 0.10). On qualitative analysis, the intraobserver differences in the registered/nonregistered group were insignificant in 2, minor in 2, moderate in 0, and major in 5 of 9. In the registered/registered group, the differences were insignificant in 2, minor in 6, moderate in 2, and major in 0 of 10. CONCLUSION: Registration of FDG-PET and planning CT images results in greater consistency in tumor volume delineation.

Intensity-modulated radiation therapy for prostate cancer.

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.

Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer.

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.

Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh.

PURPOSE: Fracture of the femur is one of the late complications of adjuvant radiotherapy for patients with soft tissue sarcomas of the thigh, who receive external beam irradiation after limb-sparing surgery. When the target volume approximates the femur, it is often inevitable that a large segment of the femur will receive full prescription dose with conventional radiation techniques. We report the dosimetric feasibility of intensity- modulated radiation therapy (IMRT) techniques to achieve adequate target coverage and bone sparing. METHODS AND MATERIALS: Treatment planning was performed using both three-dimensional conformal radiotherapy (3D-CRT) and IMRT techniques for 10 patients with soft tissue sarcoma of the thigh with tumor approaching the femur. None of the patients had bony involvement. For all patients, the gross total volume (GTV) and the femur were contoured. The clinical target volume (CTV) was defined as the GTV with a 1.5-cm margin axially, except at the bone interface where the bone interface was used as CTV if the 1.5-cm axial margin extended beyond the bone interface. In the superior-inferior direction, the CTV margin placed around the GTV varied from 5 to 10 cm. The planning target volume (PTV) was defined as the CTV with 5-mm margin all around. The 3D conformal technique consisted primarily of two to three beams with wedges or partial transmission blocks as compensators. For the IMRT technique, five coplanar beams were used, chosen so as to spare much of the surrounding soft tissue and to clear the other extremity or groin areas. IMRT plans were designed to adequately treat the planning target volume and spare the femur as much as possible. RESULTS: Dose distributions and dose-volume histograms were analyzed. PTV coverage was comparable with both IMRT and 3D-CRT plans. Dose distributions were more conformal with IMRT, however, especially for patients with large variations of contours. The volume of the femur receiving at least full prescription (63 Gy) V100 decreased on average by approximately 57%, from 44.7 +/- 16.8% with 3D-CRT to 18.6 +/- 9.2% with IMRT (p < 0.01). For 3 patients with a GTV surrounding <50% of the circumference of the femur, the reduction in the V100 to the femur ranged from 61% to 79%. The hot spots in the femur, as measured by D05 (the dose encompassing 5% of volume), reduced on average from 67.2 +/- 1.8 Gy with 3D-CRT to 65.0 +/- 1.2 Gy with IMRT (p < 0.01). The mean dose to the femur was on average 38.5 +/- 11.5 Gy with IMRT, compared with 40.9 +/- 12.7 Gy with 3D-CRT. The volume of the surrounding soft tissues, defined as the ipsilateral limb excluding the PTV and the femur, receiving at least prescription dose (63 Gy) was reduced on average by about 78%, from 997 +/- 660 cc with 3D-CRT to 201 +/- 144 cc with IMRT (p < 0.01). The D05 to the surrounding soft tissues was on average 58.7 +/- 4.7 Gy with IMRT, compared to 67.8 +/- 1.3 Gy with 3D-CRT (p < 0.01), a reduction of approximately 13%. The mean dose to the surrounding soft tissues was comparable in both plans. The volume of the skin (from surface to 5 mm depth) receiving prescription dose (63 Gy) declined by roughly 45%, from 115 +/- 40 cc with 3D-CRT to 61 +/- 20 cc with IMRT (p < 0.01), with IMRT providing full skin dose coverage to scars. The hot spots in the skin decreased from 68.0 +/- 1.7 Gy with 3D-CRT to 65.2 +/- 1.2 Gy with IMRT (p < 0.01). The mean dose to the skin lessened from 51.5 +/- 4.7 Gy with 3D- CRT to 44.0 +/- 4.2 Gy with IMRT (p < 0.01), a reduction of 14%. CONCLUSIONS: Intensity-modulated radiation therapy techniques can reduce the dose to the femur without compromising target coverage by achieving concave dose distributions around the interface of the PTV and the femur. At the same time, IMRT can reduce the hot spots significantly in the surrounding soft tissues and skin. Whether such dosimetric improvements can translate into reduction of complications and/or improving local control needs to be investigated.

The prognostic significance of Gleason Grade in patients treated with permanent prostate brachytherapy.

PURPOSE: To assess the difference in biochemical freedom from relapse (BFR) between patients with clinically localized prostate cancer having Gleason Grade (GG) 3 + 4 vs. 4 + 3 disease treated with permanent prostate brachytherapy (PPB). METHODS AND MATERIALS: One thousand twenty-nine consecutive T1/T2 patients underwent PPB with Gleason sum 6, 7, or 8 adenocarcinoma of the prostate. Treatment consisted of transperineal ultrasound-guided implant as monotherapy or in combination with external beam radiation and/or neoadjuvant androgen ablation (NAAD). The Kattan modification of the ASTRO consensus definition that censors patients with rising follow-up PSA values early was used to measure BFR. Kaplan-Meier actuarial survival was calculated and compared using the log-rank test. Cox proportional hazards regression was performed to assess the role of Gleason grade, initial PSA value, stage, the addition of external beam radiotherapy, and the addition of NAAD. RESULTS: The median follow-up for all 1029 patients is 46 months (range: 3-108 months) with a BFR at 5 years of 78.2% and at 7 years of 76.2%. The 7-year BFR for patients with GG 3 + 3 was 81.8%, GG 3 + 4 was 78.4%, GG 4 + 3 was 56.7%, and GG 4 + 4 was 50.7% (p < 0.0001). Cox regression analysis identified that the Gleason grade (p < 0.0001), initial PSA value (p = 0.001), D90% (p < 0.0001), and clinical stage (p = 0.016) were associated with biochemical recurrence, whereas NAAD (p = 0.057) and external beam radiotherapy (p = 0.356) were not. CONCLUSIONS: Gleason sum 7 tumors in patients treated with PPB represent a heterogeneous group of patients based on the differentiation of Gleason Grade 3 + 4 tumors vs. 4 + 3 disease. This information confirms similar conclusions identified in patients treated with external beam radiation and is useful when determining prognosis after PPB.

Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.

PURPOSE: To analyze acute lung toxicity data of non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy in terms of dosimetric variables, location of dose within subvolumes of the lungs, and models of normal-tissue complication probability (NTCP). METHODS AND MATERIALS: Dose distributions of 49 non-small-cell lung cancer patients treated in a dose escalation protocol between 1992 and 1999 were analyzed (dose range: 57.6-81 Gy). Nine patients had RTOG Grade 3 or higher acute lung toxicity. Correlation with dosimetric and physical variables, as well as Lyman and parallel NTCP models, was assessed. Lungs were evaluated as a single structure, as superior and inferior halves (to assess significance of dose to upper and lower lungs), and as ipsilateral and contralateral lungs. RESULTS: For the whole lung, Grade 3 or higher pneumonitis was significantly correlated (p 0.5 for superior lung indices, and >0.1 for contralateral lung indices studied). CONCLUSIONS: For these patients, commonly used dosimetric and NTCP models are significantly correlated with >or= Grade 3 pneumonitis. Equivalently strong correlations are found in the lower portion of the lungs and the ipsilateral lung, but not in the upper portion or contralateral lung.

Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer.

PURPOSE: 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: 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.

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients.

PURPOSE: 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: 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.

Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer.

PURPOSE: It has been suggested that larger tumor volume is associated with poor survival in patients with non-small-cell lung cancer (NSCLC). We investigated whether high-dose radiation improved local control in patients with large-volume Stage III NSCLC. METHODS AND MATERIALS: Seventy-two patients with Stage III NSCLC and gross tumor volumes (GTV) of greater than 100 cc were treated with three-dimensional conformal radiotherapy (3D-CRT). Patients were divided into two groups: those treated to less than 64 Gy (37 patients) and those treated to 64 Gy or higher (35 patients). RESULTS: The 1-year and 2-year local failure rates were 27% and 47%, respectively, for Stage III patients treated to 64 Gy or higher, and 61% and 76%, respectively, for those treated to less than 64 Gy (p = 0.024). The median survival time for patients treated to 64 Gy or higher was 20 months vs. 15 months for those treated to less than 64 Gy (p = 0.068). Multivariate analysis revealed that dose and GTV are predictors of local failure-free survival. A 10 Gy increase in dose resulted in a 36.4% decreased risk of local failure. CONCLUSIONS: Our data suggest that administration of higher doses using 3D-CRT improves local control in Stage III NSCLC patients with large GTVs.

Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer.

BACKGROUND AND PURPOSE: 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: 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 (or=T2c), Gleason score (6), and pre-treatment prostate-specific antigen (PSA) (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.

Time trends in organ position and volume in patients receiving prostate three-dimensional conformal radiotherapy.

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.