The activation profile of tumour-associated reactive T-cells differs in the nodular and diffuse patterns of lymphocyte predominant Hodgkin's disease.

AIMS: To compare the activation profile of T-cells in reactive lymphoid follicles with that of tumour-associated T-cells in lymphocyte predominant Hodgkin's disease (LPHD) with a nodular pattern (n = 21), LPHD with partial diffuse growth pattern (n = 11) and T-cell-rich large B-cell lymphoma (TCRLBCL, n = 8). METHODS AND RESULTS: Reactive germinal centres showed sparse numbers of T-cells positive for CD134, a transient/early T-cell activation marker, and only scattered T-cells in the interfollicular areas positive for CD38, a marker of persistent activation. Lymphoid follicles showing progressive transformation of germinal centres (PTGC) had more numerous CD134+ T-cells which were negative for CD38. Tumour-associated T-cells in nodular LPHD were frequently positive for CD134 (15 of 16 cases, 94%), but negative or only focally positive for CD38 (three of 21 cases, 14%). LPHD with diffuse areas, however, showed increased CD38+ T-cells in the diffuse component in 10 of 11 (90%) cases, with CD134+ T-cells being more prominent in the nodular tumour component. TCRLBCL showed strong, uniform CD38 expression in T-cells and histiocytes in eight cases. CONCLUSIONS: T-cells in nodular LPHD express markers of transient/early T-cell activation. By contrast, T-cells in the diffuse form of LPHD, similar to those in TCRLBCL, have an immunostaining profile consistent with persistent cellular activation. T-cell activation may precede or accompany histological progression in nodular LPHD and immunostaining for these markers, in small samples or in difficult cases, may be useful in highlighting those cases of LPHD undergoing histological progression.

Long-term results with radiotherapy for Stage I-II follicular lymphomas.

PURPOSE: To analyze the long-term results with radiotherapy (RT) for early-stage, low-grade follicular lymphomas. METHODS AND MATERIALS: From 1960 to 1988, 80 patients with Stage I (n = 33) or II (n = 47), World Health Organization Grade 1 (n = 50) or 2 (n = 30) follicular lymphoma were treated with RT. The lymph nodes or spleen were involved in 97% of cases. The maximal tumor sizes ranged from 0.5 to 11.0 cm (median 2.0). The RT fields encompassed only the involved Ann Arbor nodal region (involved-field RT) in 9% of the patients. The fields also included 1-3 adjacent, grossly uninvolved nodal regions (regional RT) in 54% of patients but were smaller than mantle or whole abdominopelvic fields. Mantle or whole abdominopelvic fields encompassing up to 6 grossly uninvolved regions (extended-field RT) were used in the remaining 37% of patients. The total RT doses ranged from 26.2 to 50.0 Gy given in daily 1.0-3.0-Gy fractions. RESULTS: The follow-up of the surviving patients ranged from 3.5 to 28.7 years (median 19.0). No recurrences were found >17.0 years after RT, with 13 patients free of disease at their last follow-up visit 17.6-25.0 years after treatment. In 58% of cases, death was not from follicular lymphoma. The 15-year local control rate was 100% for 44 lymphomas <3.0 cm treated with only 27.8-30.8 Gy (median 30.0 in 20 fractions). Progression-free survival was affected by the maximal tumor size at the start of RT (15-year rate 49% vs. 29% for lymphomas <3.0 cm vs. > or =3.0 cm, respectively, p = 0.04) and Ann Arbor stage (15-year rate 66% vs. 26% for Stages I and II, respectively, p = 0.006). Ann Arbor stage also affected the cause-specific survival (15-year rate 87% vs. 54% for Stages I and II, respectively, p = 0.01). No significant difference was found in overall survival between those treated with extended-field RT and those treated with involved-field RT or regional RT (15-year rate 49% and 40%, respectively, p = 0.51). The 15-year incidence rate of Grade 3 or greater late complications according to the Subjective, Objective, Management, and Analytical scale in patients treated with 26.2-30.8 Gy vs. 30.9-50.0 Gy was 0% and 6%, respectively. CONCLUSIONS: RT can cure approximately one half of Stage I and one quarter of Stage II, World Health Organization Grade 1 or 2 follicular lymphomas. Follicular lymphomas <3.0 cm can be controlled locally with doses of 27.8-30.8 Gy, and there is a trend toward a higher incidence of late complications with doses of >30.8 Gy. Doses of 25-30 Gy delivered in 15-20 fractions should be examined prospectively in patients with follicular lymphomas of <3.0 cm.

Recent advances in radiotherapy for head and neck cancers.

Advancements in surgery have made it possible to resect cancers that had previously been regarded as incurable. Similarly, new developments in radiation oncology have helped improve the outlook for patients with locally advanced or recurrent head and neck cancers. Among these advancements are refinements in altered fractionation, three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, stereotactic radiosurgery and fractionated stereotactic radiotherapy, neutron-beam radiotherapy, charged-particle radiotherapy, and intraoperative radiotherapy. These recent developments have allowed radiation oncologists to escalate the dose of radiation delivered to tumors while minimizing the dose delivered to surrounding normal tissue. Additionally, more continues to be learned about the optimum delivery of chemotherapy. This article provides an update on the status of these new developments in the treatment of head and neck cancers.

Hematologic recovery after central lymphatic irradiation for patients with stage I-III follicular lymphoma.

BACKGROUND: The authors previously reported that central lymphatic irradiation (CLI) can induce molecular remission in patients with Stage I-III follicular lymphoma, as measured by polymerase chain reaction analysis for t(14;18) (q32;q21). Hematologic toxicity has been considered a major consequence of CLI. This study was undertaken to analyze the patterns of hematologic recovery after CLI. METHODS: Thirty-three patients with Stage I-III follicular lymphoma were treated with CLI between January 1993 and February 1998. CLI consisted of irradiation to mantle, upper two-thirds of abdomen, and pelvic fields. Each field was treated to 30.0-30.6 grays (Gy) at 1.5-1.8 Gy per fraction, with a boost to 36.0-39.6 Gy at the same rate to the sites of macroscopic disease. A break of approximately 4 weeks was given after treatment of each field. Twenty-four patients who were followed for a minimum of 1 year from the end of CLI form the basis of this analysis. Fourteen patients were male. Three patients had Stage I disease, 6 patients had Stage II disease, and 15 patients had Stage III disease. The International Prognostic Index (IPI) for malignant lymphoma was 0 for 5 patients, 1 for 13 patients, and 2 for 6 patients. The Eastern Cooperative Oncology Group performance status was 0 for 21 patients and 1 for 3 patients. The median values for their pretreatment characteristics were as follows: age, 60 years (range, 34-73 years); height, 173 cm (range, 155-193 cm); weight, 79 kg (range, 57-107 kg); body surface area (BSA), 1.95 m(2) (range, 1.61-2.31 m(2)); bone marrow cellularity, 27%(range, 2-75%), platelet count, 233,000/mm(3) (range, 139,000-339,000/mm(3)), white blood cell (WBC) counts, 6400/mm(3) (range, 4200-10,900/mm(3)); and hemoglobin, 14.5 mg/dL (range, 11.8 -16.6 mg/dL). The median duration of CLI was 159 days (range, 137-345 days). Ten patients had cardiovascular disease. The number of sites receiving a boost dose of > or = 36.0 Gy was 0 sites in 1 patient, 1 site in 6 patients, 2 sites in 11 patients, 3 sites in 5 patients, and 4 sites in 1 patient. The platelet, hemoglobin, and WBC counts were followed every 3 months after completion of CLI. These counts were normalized to the pretreatment counts for statistical analyses. Univariate and multivariate analyses were performed to investigate the correlations between patient factors and hematologic status at 1 year posttreatment. Pearson correlation analysis was used for the continuous factors (patient age, height, weight, BSA, bone marrow cellularity, and duration of CLI), and the Mann-Whitney test was used for categoric factors (IPI, gender, performance status, stage, number of sites receiving > or = 36.0 Gy, and presence or absence of cardiovascular disease). RESULTS: There was continued recovery, essentially approaching the pretreatment levels, over 3 years for platelet, WBC, and hemoglobin counts. Factors that were associated significantly with normalized platelet counts at 1 year by univariate analyses were age (P = 0.015) and cardiovascular disease (P = 0.041). Age was the only significant factor by multivariate analyses, with older patients having lower platelet counts at 1 year posttreatment. No factors were found that were associated significantly with 1-year normalized WBC or hemoglobin levels by either univariate or multivariate analyses. CONCLUSIONS: All three of the hematologic components (platelets, WBC, and hemoglobin) essentially recover after patients undergo CLI over a 3-year period. Older age was the only significant adverse factor that affected the platelet recovery, as detected by multivariate analysis. (c) 2001 American Cancer Society.

Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy.

BACKGROUND: Although surgery is considered standard therapy for unicentric Castleman disease, favorable responses to radiotherapy also have been documented. The authors undertook this study to analyze the clinical factors, treatment approaches, and outcomes of patients with unicentric or multicentric Castleman disease, and to report the outcomes of patients with unicentric Castleman disease treated with radiotherapy. METHODS: The authors reviewed the medical records of 22 patients who had received a histologic diagnosis of Castleman disease at the University of Texas M. D. Anderson Cancer Center between 1988 and 1999. One patient with a concurrent histopathologic diagnosis of nonsecretory multiple myeloma was excluded from the study. In all patients, the diagnosis of Castleman disease was based on the results of lymph node biopsies. Disease was categorized as being either unicentric or multicentric and further subdivided into hyaline vascular, plasma cell, or mixed variant histologic types. Clinical variables and outcomes were analyzed according to treatment, which consisted of surgery, chemotherapy, or radiotherapy. RESULTS: Records from 21 patients were analyzed: 12 had unicentric disease, and 9 had multicentric disease. The mean follow-up time for the entire series was 51 months (median, 40 months). Four patients with unicentric disease were treated with radiotherapy alone: 2 remain alive and symptom free, 2 died of causes unrelated to Castleman disease and had no evidence of disease at last follow-up. Eight patients with unicentric disease were treated with complete or partial surgical resection, and all are alive and asymptomatic. All nine patients with multicentric disease were treated with combination chemotherapy: five are alive with no evidence of disease, and four are alive with progressive disease. CONCLUSIONS: Surgery results in excellent rates of cure in patients with unicentric Castleman disease; radiotherapy can also achieve clinical response and cure in selected patients. Multicentric Castleman disease is a more aggressive clinical entity and is most effectively treated with combination chemotherapy, whereas the role of radiotherapy in its treatment remains unclear.

Radiation therapy after a partial response to CHOP chemotherapy for aggressive lymphomas.

PURPOSE: To analyze the results with involved-field radiotherapy after aggressive lymphomas had decreased in size by 50-99% in response to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. METHODS AND MATERIALS: From 1988 through 1996, 294 previously untreated patients with Working Formulation intermediate-grade or large-cell immunoblastic lymphomas underwent CHOP-based chemotherapy on 2 consecutive protocols at the M. D. Anderson Cancer Center. Forty-four (15%) of these patients achieved, based on international working group guidelines, a partial (50-75%) response (n = 25), or unconfirmed complete (76-99%) response (n = 19) to a median of 6 cycles of chemotherapy. These patients were treated with salvage involved-field radiotherapy (n = 32) or chemotherapy (n = 12), e.g., MINE-ESHAP, without autologous stem-cell rescue (ASCR). RESULTS: Median follow-up was 43 months. Partial responders experienced similar outcomes to unconfirmed complete responders. Local control (4-year rates: 86% vs. 53%, p = 0.009) and progression-free survival (4-year rates: 67% vs. 8%, p < 0.0001), but not overall survival (4-year rates: 70% vs. 50%, p = 0.067) were significantly better in those who received salvage radiotherapy, which was well tolerated. CONCLUSION: Progression-free and overall survival in aggressive lymphoma patients who underwent salvage radiotherapy were similar to results reported for high-dose chemotherapy with ASCR. The role of salvage radiotherapy in partial and unconfirmed complete responders to CHOP chemotherapy justifies examination in a large, cooperative group trial.

Bulky disease is an adverse prognostic factor in patients treated with chemotherapy comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy for aggressive lymphoma.

BACKGROUND: In the current study, the authors analyzed prognostic factors in patients with aggressive lymphoma treated with a chemotherapy regimen comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without radiotherapy. METHODS: Between September 1988 and December 1996, 294 patients with newly diagnosed, clinical Ann Arbor Stage I-IV, aggressive lymphoma were enrolled on 2 protocols at The University of Texas M. D. Anderson Cancer Center. Patients on these studies had a relatively favorable prognosis; 100% had M. D. Anderson tumor scores 1 extranodal site of disease (P < 0.001), bulky disease (>or= 7 cm) (P = 0.005), and an at least 10% elevation in the serum lactate dehydrogenase (LDH) level (P = 0.007). Patient age > 60 years (P = 0.001), bulky disease (P = 0.016), and an at least 10% elevation in the serum LDH level (P = 0.040) also were found to be independent prognostic factors for overall survival. CONCLUSIONS: The independent prognostic factors in the current study suggest that either the M. D. Anderson tumor score system or the IPI can be used to select which aggressive lymphoma patients are at high risk for disease recurrence based on their having more than two adverse factors and who consequently are candidates for more intensive frontline therapy. Involved-field radiotherapy should be considered in those patients with bulky lymphomas.

Clinical stage IEA-IIEA orbital lymphomas: outcomes in the era of modern staging and treatment.

BACKGROUND AND PURPOSE: The present study examines outcomes in patients with primary orbital lymphomas who underwent complete staging. MATERIALS AND METHODS: From 1978 to 1997, 21 adult patients at the M.D. Anderson Cancer Center had stage IEA-IIEA orbital non-Hodgkin's lymphomas based on staging that included computed tomography scans. Sixteen (76%) patients had working formulation low-grade lymphomas, and five (24%) had aggressive lymphomas. Fourteen of 16 (88%) patients with low-grade lymphomas were treated with radiotherapy alone, and four of five (80%) patients with aggressive lymphomas were treated using combination chemotherapy with or without radiotherapy. Total radiotherapy doses ranged from 30.0 to 40.0 Gy using daily 1.5-2.0 Gy fractions. RESULTS: The median follow-up was 84 months. For the low-grade lymphomas, the 5-year local control, progression-free survival, and overall survival rates were 100, 100, and 92%, respectively. For the seven low-grade lymphomas treated with radiotherapy alone to 30.0 Gy in 20 fractions, the 5-year local control, progression-free, and overall survival rates were 100, 100, and 75%, respectively. The 5-year incidence of complications, which were typically mild, in eyes irradiated to 30 Gy in 20 fractions versus higher biologically effective doses were 25 and 38%, respectively (P = 0.62). Of the five patients with aggressive lymphomas, none of the four who underwent chemotherapy with or without radiotherapy relapsed (all four remain alive), whereas the one treated with radiotherapy alone for stage IEA disease experienced a distant relapse. CONCLUSIONS: In patients with low-grade lymphomas, a good therapeutic ratio was obtained with low-dose radiotherapy alone. In patients with aggressive lymphomas, chemotherapy with or without radiotherapy resulted in excellent local control, progression-free survival, and overall survival; however, the statistical power was limited.

Localized non-Hodgkin lymphoma involving the thyroid gland.

BACKGROUND: The current study was undertaken to define the natural history and patterns of failure of localized non-Hodgkin lymphoma (NHL) involving the thyroid gland. METHODS: A retrospective review of 51 patients with Ann Arbor Stage I or II NHL involving the thyroid gland was performed. The median age of the patients was 59 years. There were 33 females. There were 21 patients with Stage I disease and 30 patients with Stage II disease. The International Prognostic Index (IPI) was known for 43 patients (it was 0 in 16 patients and > or = 1 in 27 patients). Fifteen patients had mediastinal involvement. Four patients underwent thyroidectomy, 18 patients received radiation therapy, 5 patients received chemotherapy, and 24 patients received combined modality therapy (CMT) with chemotherapy and radiation therapy. Treatment modality, patient gender, IPI, disease stage, and mediastinal involvement were examined for significance with regard to overall survival (OS) and failure free survival (FFS). RESULTS: The 5-year OS and FFS rates were 64% and 76%, respectively. The 5-year FFS rates by treatment regimen were 76% for radiation therapy, 50% for chemotherapy, and 91% for CMT (P = 0.15). IPI was found to be the only significant predictor of OS. The 5-year OS rates were 86% and 50%, respectively, for IPIs of 0 and > or = 1 (P = 0.02). None of the 5 variables were found to correlate significantly with FFS, although the 5-year FFS rates were 93% and 68%, respectively, for IPIs of 0 and > or = 1 (P = 0.08). Eleven patients failed treatment. Nine patients had a component of distant failure across the diaphragm. CONCLUSIONS: The prognosis of patients with localized NHL involving the thyroid gland appears to be very good, especially when CMT is used. Distant recurrences appear to account for the majority of treatment failures. The IPI was found to be a significant prognostic factor for OS and a marginal one for FFS.

Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy.

PURPOSE: To test the hypothesis that prechemotherapy tumor size affects the dose of radiation that should be delivered to intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based induction chemotherapy. METHODS AND MATERIALS: From September 1988 through December 1996, 294 patients with newly diagnosed, Stage I-IV, intermediate-grade or large-cell immunoblastic lymphomas were enrolled on 2 prospective protocols at the M. D. Anderson Cancer Center. Treatment consisted of CHOP-based chemotherapy with or without involved field radiotherapy. One hundred seventy-two patients, with 178 nodal sites and 87 nonbony, extranodal sites of disease achieved a complete response to 2-6 cycles of chemotherapy and underwent involved field radiotherapy. Total radiation doses ranged from 30.0 to 50.4 Gy (mean +/- standard deviation: 39.7 +/- 2.5 Gy) over 22-49 days using a daily fraction size of 1.3-2.3 Gy. Because various fraction sizes were delivered, the linear-quadratic model was used to convert total radiation doses to biologically equivalent doses given at 1.8 Gy per fraction (D1.8). An alpha/beta ratio of 10 Gy was used for the lymphomas, resulting in D1.8 ranging from 29.1 to 50.8 Gy. Regression tree analysis was performed on nodal sites of disease to determine which of the following factors were predictive of local control: age, tumor size, D1.8, total radiation dose, and duration of radiotherapy. Based on the results of the regression tree analysis, Kaplan-Meier analysis was used to determine the probability of local control per site as a function of tumor size and D1.8. Regression tree analysis was also performed on patients with nonbony disease who received D1.8 = 29.1-39.1 Gy to determine if small lymphomas could be locally controlled with relatively low doses of radiation. The log-rank test was used to compare local control curves. RESULTS: The median length of follow-up among survivors was 63 months. Regression tree analysis of nodal sites identified 3 distinct groups: (a) lymphomas < or = 10 cm and D1.8 = 29.1-39.1 Gy; (b) lymphomas < or = 10 cm and D1.8 = 39.2-50.8 Gy; and (c) lymphomas > 10 cm. For nonbony lymphomas that measured < 3.5 cm, low doses of radiation resulted in excellent local control (5-year rates: 96% vs. 97% for D1.8 = 29.1-39.1 Gy vs. D1.8 = 39.2-50.8 Gy; p = 0.610). For 3.5-10.0 cm lymphomas, higher doses of radiation resulted in better local control (5-year rates: 40% versus 98% for D1.8 = 29.1-39.1 Gy versus D1.8 = 39.2-50.8 Gy, p < 0.0001). A narrow dose range (D1.8 = 39.2-40.7 Gy) was delivered to the 8 lymphomas measuring > 10 cm that completely responded to 6 cycles of chemotherapy, resulting in a 5-year local control rate of only 70%. There was no difference in local control for nodal versus nonbony, extranodal sites of disease. CONCLUSION: D1.8 ranging from 29.1 to 39.1 Gy yielded excellent local control for nonbony lymphomas measuring < 3.5 cm that had completely responded to a median of 3 cycles of CHOP-based chemotherapy. D1.8 ranging from 39.2 to 50.8 Gy yielded excellent local control for nonbony lymphomas measuring 3.5-10.0 cm that completely responded to either 3 or 6 cycles of chemotherapy. For nonbony lymphomas measuring > 10 cm that completely responded to 6 cycles of chemotherapy, D1.8 ranging from 39.2 to 40.7 Gy yielded suboptimal local control, suggesting that higher doses of radiation are indicated.

Impact of involved field radiotherapy after CHOP-based chemotherapy on stage III-IV, intermediate grade and large-cell immunoblastic lymphomas.

PURPOSE: To analyze the impact of involved field radiotherapy on local control, freedom from progression, and overall survival in patients with clinical Stage III-IV, intermediate grade, or large-cell immunoblastic lymphomas that responded to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based induction chemotherapy. METHODS AND MATERIALS: From July 1989 through October 1996, 32 patients with clinical Stage III and 27 patients with clinical Stage IV, intermediate grade, or large-cell immunoblastic lymphomas were prospectively enrolled on two protocols at The University of Texas M. D. Anderson Cancer Center. None had previously undergone treatment for lymphoma. The median patient age was 54 years (range: 26-85 years). There were a total of 172 involved sites of disease at presentation. All 59 patients received CHOP-based chemotherapy. At least six cycles of chemotherapy were delivered to 92% of the patients. Involved field radiotherapy (39.6-40.0 Gy in 20-22 fractions in 74% of cases) was administered to 28/59 (47%) patients beginning 3-4 weeks after chemotherapy. Sites were irradiated at the discretion of the treating physician. Irradiated and nonirradiated groups were compared in terms of maximum pre-chemotherapy tumor size and University of Texas M. D. Anderson Cancer Center tumor score. Kaplan-Meier estimates of local control per patient, freedom from progression, and overall survival for the irradiated and nonirradiated groups were calculated in terms of the stage of disease and treatment delivered. The resulting curves were compared using the log-rank test. The Cox proportional hazards model was used to assess the prognostic significance of tumor size, tumor score, treatment delivered, and stage. RESULTS: The median length of follow-up for all patients was 53 months (range: 4-96 months). The median tumor size at the start of chemotherapy in irradiated patients was 4.5 cm (range: 0-15 cm) versus 3 cm (range: 0-7 cm) in nonirradiated patients (p = 0.004). The irradiated and nonirradiated groups were not significantly different in terms of tumor scores. Radiotherapy improved (p = 0.001) local control (5-year rates: 89% versus 52%) for Stages III and IV combined. This benefit was due to the dramatic improvement (p = 0.0009) in local control for patients with lymphomas measuring > or =4 cm at the start of chemotherapy (5-year rates: 89% for irradiated patients versus 33% for nonirradiated patients). Radiotherapy also improved (p = 0.003) freedom from progression (5-year rates: 85% for irradiated patients versus 51% for nonirradiated patients) for Stages III and IV combined. On multivariate analysis, radiotherapy was the most significant factor affecting local control and freedom from progression. Overall survival was not significantly different (p = 0. 620) between irradiated and nonirradiated patients (5-year rates: 87% versus 81%, respectively). When Stages III and IV were analyzed separately, radiotherapy improved local control and freedom from progression but not overall survival. Radiotherapy was tolerated reasonably well, with the main toxicity being moderate myelosuppression. Eleven out of 12 (92%) patients with recurrent disease at the time of their last follow-up visit were treated initially with chemotherapy alone. CONCLUSION: Involved field radiotherapy improved local control and freedom from progression in patients with > or = 4 cm Stage III-IV, intermediate grade, or large-cell immunoblastic lymphomas that responded to CHOP-based induction chemotherapy. Involved field radiotherapy was tolerated reasonably well.

Potency preservation after three-dimensional conformal radiotherapy for prostate cancer: preliminary results.

We sought to assess potency preservation after three-dimensional conformal radiotherapy (3D-CRT) in prostate cancer patients eligible for radical prostatectomy, conventional radiotherapy, 3D-CRT, or transperineal prostate implantation. Patients with more advanced disease are commonly treated with hormonal therapy, which can cause impotence, and were consequently excluded from the analysis. Between December 1991 and June 1998, 198 prostate cancer patients were treated with 3D-CRT at the University of California, Davis Medical Center. Fifty-two of these patients had a pretreatment prostate-specific antigen (PSA) level of 10.0 ng/ml or less, a Gleason score of 6 or less, and a 1997 AJCC clinical stage T1bN0M0 to T2bN0M0. One patient was not evaluable. None of the 51 evaluable patients had diabetes mellitus. In 40 patients, the prostate gland only was irradiated to a total dose of 66 to 79.2 Gy by using daily 1.8-Gy fractions. In 11 patients, the prostate and seminal vesicles were treated to 44 to 55.8 Gy. Lymph nodes were not included in the clinical target volume. The median age was 68 years, and the median length of follow-up was 15 months. Potency in this study is defined as an erection sufficient for vaginal penetration. Kaplan-Meier analysis was used to describe potency as a function of time after 3D-CRT. Of the 51 evaluable patients, 35 (69%) were potent, 15 were impotent, and 1 was sexually inactive before 3D-CRT. Kaplan-Meier estimates of the potency preservation rates 1, 2, and 3 years after 3D-CRT are 100%, 83%, and 63%, respectively. On multivariate analysis, age, total radiation dose, and a history of transurethral resection of the prostate did not significantly affect potency preservation rates. Three (43%) of 7 patients who became impotent after 3D-CRT and used sildenafil were subsequently able to achieve erections sufficient for vaginal penetration. The preliminary results reported herein suggest that approximately two thirds of prostate cancer patients will retain their potency 3 years after 3D-CRT. Further follow-up is necessary to assess long-term potency after 3D-CRT. Sildenafil should be considered in patients who develop radiation-induced impotence.

Preliminary results of three-dimensional conformal radiotherapy as salvage treatment for a rising prostate-specific antigen level postprostatectomy.

The purpose of this study is to determine the effectiveness of three-dimensional conformal radiotherapy delivered to the fossa of the prostate and seminal vesicles as salvage treatment for a prostate-specific antigen (PSA) level that becomes undetectable and subsequently begins to rise postprostatectomy. Between August 1994 and December 1997, 14 patients with prostate cancer whose PSA became undetectable after a radical prostatectomy subsequently developed a rising PSA, had no evidence of metastatic disease, and were treated with three-dimensional conformal radiotherapy at the University of California, Davis Cancer Center. Gleason scores ranged from 4 to 9 (29% of the patients had a Gleason score > or =8). The seminal vesicles were involved in three (21%) cases and the surgical margins were involved in seven (50%) cases. PSA values ranged from 0.3 to 6.7 (median: 0.7) ng/ml at the start of radiotherapy. Daily 1.8-2.0-Gy fractions were administered to total doses at isocenter ranging from 60.6 to 74.2 (median: 64.9) Gy. None of the patients received hormonal therapy. Follow-up ranged from 13 to 36 (median: 22) months. For patients with a preradiotherapy Hybritech PSA < or = 1.0 ng/ml, the Kaplan-Meier estimate of the 2-year biochemical disease-free survival rate is 67%, whereas for patients with a preradiotherapy PSA more than 1.0 ng/ml, the 2-year biochemical disease-free survival rate is 20% (p = 0.17). Because of the small number of patients, the difference is not statistically significant. A positive microscopic margin had no impact on the results obtained with salvage radiotherapy. Only one of four patients with a poorly differentiated adenocarcinoma remains free of disease. Acute toxicity was mild and did not require medication (Radiation Therapy Oncology Group grade I): four (29%) patients experienced genitourinary morbidity and three (21%) patients experienced gastrointestinal morbidity. With regard to late toxicity, one (7%) patient developed a urethral stricture requiring dilatation (Radiation Therapy Oncology Group grade III). All five patients who were potent at the start of radiotherapy remain potent. Medicare's median reimbursement for salvage three-dimensional conformal radiotherapy in this study ($7,512 in 1999 U.S. dollars) is equivalent to its reimbursement for a 17-month course of goserelin hormonal therapy. Patients with prostate cancer who develop an undetectable followed by a rising PSA postprostatectomy should be referred for salvage treatment with radiotherapy when their PSA is still less than or equal to 1.0 ng/ml. Salvage three-dimensional conformal radiotherapy is well tolerated and is less expensive than more than 17 months of goserelin.

Acute toxicity of three-dimensional conformal radiotherapy in prostate cancer patients eligible for implant monotherapy.

PURPOSE: To assess the acute toxicity of three-dimensional conformal radiotherapy (3D-CRT) in prostate cancer patients eligible for implant monotherapy. METHODS AND MATERIALS: Between December 1991 and June 1998, 198 prostate cancer patients were treated with 3D-CRT at the University of California Davis Medical Center. Fifty-two of these patients had a prostate-specific antigen (PSA) level /= Grade 3, e.g., hourly nocturia, gross hematuria, diarrhea requiring parenteral support, narcotics for pain control, or catheterization for acute urinary retention, was observed. CONCLUSION: Although relatively high doses of radiation are delivered to prostate cancers with 3D-CRT compared with conventional radiotherapy, 3D-CRT is surprisingly well-tolerated. No patients in the cohort eligible for implant monotherapy experienced acute toxicity >/= Grade 3.

Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406.

PURPOSE: A prospective Phase I dose escalation study was conducted to determine the maximally-tolerated radiation dose in men treated with three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. This is a preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study. METHODS AND MATERIALS: Each participating institution was required to implement data exchange with the RTOG 3D quality assurance (QA) center at Washington University in St. Louis. 3D CRT capabilities were strictly defined within the study protocol. Patients were registered according to three stratification groups: Group 1 patients had clinically organ-confined disease (T1,2) with a calculated risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2 disease with risk of SV invasion > or = 15%. Group 3 (G3) patients had clinical local extension of tumor beyond the prostate capsule (T3). All patients were treated with 3D techniques with minimum doses prescribed to the planning target volume (PTV). The PTV margins were 5-10 mm around the prostate for patients in Group 1 and 5-10 mm around the prostate and SV for Group 2. After 55.8 Gy, the PTV was reduced in Group 2 patients to 5-10 mm around the prostate only. Minimum prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level II) and subsequently to 79.2 Gy (level III). This report describes the acute and late toxicity encountered in Group 1 and 2 patients treated to the first two study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the expected probability of observing a > or = grade 3 late effect more than 120 days after the start of treatment. RTOG toxicity scores were used. RESULTS: Between August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288 cases were analyzable for toxicity. Acute toxicity was low, with 53-54% of Group 1 patients having either no or grade 1 toxicity at dose levels I and II, respectively. Sixty-two percent of Group 2 patients had either none or grade 1 toxicity at either dose level. Few patients (0-3%) experienced a grade 3 acute bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late toxicity was very low in all patient groups. The majority (81-85%) had either no or mild grade 1 late toxicity at dose level I and II, respectively. A single late grade 3 bladder toxicity in a Group 2 patient treated to dose level II was recorded. There were no grade 4 or 5 late effects in any patient. Compared to historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or greater late effects were observed in Group 1 and Group 2 patients when 9.1 and 4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level II, there were no grade 3 or greater toxicities in Group 1 patients and a single grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p = 0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the relative risk of developing acute bladder toxicity was 2.13 if the percentage of the bladder receiving > or = 65 Gy was more than 30% (p = 0.013) and 2.01 if patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of developing late bladder complications also increased as the percentage of the bladder receiving > or = 65 Gy increased (p = 0.026). Unexpectedly, there was a lower risk of late bladder complications as the mean dose to the bladder and prescription dose level increased. This probably reflects improvement in conformal techniques as the study matured. There was a 2.1 relative risk of developing a late bowel complication if the total rectal volume on the planning CT scan exceeded 100 cc (p = 0.019). CONCLUSION: Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality assurance standards and review, 3D CRT can be safely studied in a co

Impact of collimator leaf width on stereotactic radiosurgery and 3D conformal radiotherapy treatment plans.

PURPOSE: The authors undertook a study to analyze the impact of collimator leaf width on stereotactic radiosurgery and 3D conformal radiotherapy treatment plans. METHODS AND MATERIALS: Twelve cases involving primary brain tumors, metastases, or arteriovenous malformations that had been planned with BrainLAB's conventional circular collimator-based radiosurgery system were re-planned using a beta-version of BrainLAB's treatment planning software that is compatible with MRC Systems' and BrainLAB's micro-multileaf collimators. These collimators have a minimum leaf width of 1.7 mm and 3.0 mm, respectively, at isocenter. The clinical target volumes ranged from 2.7-26.1 cc and the number of static fields ranged from 3-5. In addition, for 4 prostate cancer cases, 2 separate clinical target volumes were planned using MRC Systems' and BrainLAB's micro-multileaf collimators and Varian's multileaf collimator: the smaller clinical target volume consisted of the prostate gland and the larger clinical target volume consisted of the prostate and seminal vesicles. For the prostate cancer cases, treatment plans were generated using either 6 or 7 static fields. A "PITV ratio," which the Radiation Therapy Oncology Group defines as the volume encompassed by the prescription isodose surface divided by the clinical target volume, was used as a measure of the quality of treatment plans (a PITV ratio of 1.0-2.0 is desirable). Bladder and rectal volumes encompassed by the prescription isodose surface, isodose distributions and dose volume histograms were also analyzed for the prostate cancer patients. RESULTS: In 75% of the cases treated with radiosurgery, a PITV ratio between 1.0-2.0 could be achieved using a micro-multileaf collimator with a leaf width of 1.7-3.0 mm at isocenter and 3-5 static fields. When the clinical target volume consisted of the prostate gland, the micro-multileaf collimator with a minimum leaf width of 3.0 mm allowed one to decrease the median volume of bladder and rectum within the prescription isodose surface by 26% and 17%, respectively, compared to the multileaf collimator with a leaf width of 10 mm. Use of the 1.7 mm leaf width micro-multileaf collimator allowed one to decrease the median volume of bladder and rectum within the prescription isodose surface by 48% and 39%, respectively, compared to the multileaf collimator with a leaf width of 10 mm. CONCLUSIONS: For most lesions treated with radiosurgery, the use of a micro-multileaf collimator with a leaf width of 1.7-3.0 mm at isocenter and 3-5 static fields allows one to meet the Radiation Therapy Oncology Group guidelines for treatment planning. Both planning and treatment are relatively straightforward with a micro-multileaf collimator, allowing for efficient treatment of non-spherical targets with either stereotactic radiosurgery or fractionated stereotactic radiotherapy. When the clinical target volume consists of the prostate gland, micro-multileaf collimators with a minimum leaf width of 1.7-3.0 mm allow one to spare more bladder and rectum than one can with a multileaf collimator that has a 10-mm leaf width based on an analysis of PITV ratios, isodose distributions, and dose volume histograms.

A preliminary cell kinetics model of thrombocytopenia after radioimmunotherapy.

UNLABELLED: Thrombocytopenia is often the dose-limiting toxicity for radionuclide therapy. Prediction of platelet counts after therapy is important for treatment planning. Simple prediction methods based on linear correlation between radiation dose and blood count nadir have been insufficient because they have not considered time, because of the complicated hierarchical structure of the hematopoietic system in which platelets are not directly injured by low dose rate radiation and because of changing radiation dose rates to marrow with time. This study addresses these problems using a cell kinetics model. METHODS: The model consists of compartments for progenitor cells, megakaryocytes, platelets and stromal cells. A linear quadratic formula was used for progenitor cell survival. Stromal cells were described by a model based on a maximum likelihood estimate for cellular damage, repair and proliferation. Reported values for murine cellular turnover rates and radiosensitivity of progenitor cells were used in the model calculations. Experimental mice received 4 Gy of external beam radiation for tumor implantation and 12.4-23.3 MBq 67Cu-2-iminothiolane-BAT-Lym-1 (BAT = 6-[p-(bromoacetamido) benzyl]-1,4,8,11-tetra-azacyclotetradecane-N,N',N'',N'''-tetraacet ic acid) 19-30 days later. Blood counts were measured three times each week. RESULTS: The model predicted the severity of thrombocytopenia, and the time of the nadir corresponded to measured values in mice. For a dose of 14.2 MBq 67Cu-2-iminothiolane-BAT-Lym-1 that induced a platelet nadir of 20% of baseline (Grade II), the model predicted that at least 20 days were needed before a second 14.2-MBq injection if a subsequent nadir of <10% of baseline (Grade IV) was to be avoided. CONCLUSION: The nadir and duration of thrombocytopenia predicted by the model were similar to those observed in the mice. Predicted information could be useful for planning the dose and timing of fractionated radionuclide therapy. This model provides a stepping stone for future development of a predictive model for patients.

Candidates for prostate radioactive seed implantation treated by external beam radiotherapy.

PURPOSE: We report the prostate-specific antigen-based freedom from biochemical failure after conventional and three-dimensional conformal external beam radiotherapy for patients who would have been candidates for 125I implantation monotherapy. MATERIALS AND METHODS: Patients included in the study were required to have prostate-specific antigen values < or = 20, T stage < or = 2b, and Gleason score sum of 2 to 6. All patients underwent external beam irradiation with curative intent and a minimum follow-up from completion of treatment of at least 1 year. In addition, all patients had to have pretreatment and follow-up prostate-specific antigen measurements and no history of hormonal manipulation, orchiectomy, or radical prostatectomy. A total of 187 patients meeting these criteria were treated between March 1988 and June 1995, and they form the study group for this analysis. Freedom from biochemical failure was defined as prostate-specific antigen value that failed to be maintained at 1 ng/mL or less or an increase in prostate-specific antigen value of 0.5 ng/mL or more in 1 year even if prostate-specific antigen value was less than 1 ng/mL. RESULTS: Among the 187 patients, the median pretreatment prostate-specific antigen value was 7.4 ng/mL (0.3-19.9 ng/mL). The median follow-up was 34 months. Twenty-three percent of patients had a Gleason score sum of 2 to 4, and 77% had a Gleason score sum of 5 to 6. Clinical stages were T1 in 33% and T2 in 67%. One hundred twenty-five patients were treated by conventional external beam radiotherapy with a median dose of 69.5 Gy (60-71 Gy), and 62 patients were treated by three-dimensional conformal external beam radiotherapy with a median dose of 76.4 Gy (71.6-87 Gy). The overall freedom from biochemical failure was 75% at 4 years. Rates of freedom from biochemical failure by pretreatment prostate-specific antigen levels were 91% for prostate-specific antigen value < or = 4 ng/mL, 65% for prostate-specific antigen value > 4 but < or = 10 ng/mL, and 30% for prostate-specific antigen value > 10 ng/mL. Pretreatment prostate-specific antigen value was a statistically significant prognosticator, with lower values associated with favorable freedom from biochemical failure outcome in univariate and multivariate analyses. Conventional versus three-dimensional treatment, T1 versus T2 stage, and Gleason score sum 2 to 4 versus 5 to 6 did not show statistically significant difference in freedom from biochemical failure. CONCLUSIONS: Although our overall results after external beam radiotherapy for early-stage prostate cancer patients are less favorable than the best results published for 125I implantation monotherapy, our results are comparable to those in most other studies with implantation monotherapy. This most likely results from selection bias as well as our stricter definition of freedom from biochemical failure. In addition, for our subset of patients, there was no statistically significant improvement in the 4-year freedom from biochemical failure with the use of higher doses.