Recursive partitioning identifies patients at high and low risk for ipsilateral tumor recurrence after breast-conserving surgery and radiation.

PURPOSE: Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer. PATIENTS AND METHODS: Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years. RESULTS: Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P =.03). For patients

Patterns-of-failure analysis of patients with high pretreatment prostate-specific antigen levels treated by radiation therapy: the need for improved systemic and locoregional treatment.

PURPOSE: The patterns of failure (local and/or regional v metastatic) have been determined for patients with prostate cancer and pretreatment prostate-specific antigen (PSA) levels > or = 20 ng/mL treated with radiation alone with the purpose to design appropriate multimodal treatments. MATERIALS AND METHODS: One hundred twenty patients with pretreatment PSA levels > or = 20 ng/mL were treated with external-beam radiation alone between February 1988 and October 1993. They were arbitrarily divided by PSA levels, 20 to 29.9 ng/mL, 30 to 49.9 ng/mL, and > or = 50 ng/mL, and analyzed in terms of freedom from any failure (no evidence of biochemical disease [bNED], and PSA level < 1.5 ngm/mL and not increasing), as well as freedom from imaging evidence of distant metastasis (fdm). RESULTS: There was no significant difference in short-term outcome by pretreatment PSA level, and thus all patients were pooled for analysis. At 4 years, 81% were fdm and 28% were free of any failure. This suggests that approximately 50% have recurred with local and/or regional disease or undetectable metastatic disease. Multivariate analysis indicated that low palpation stage and higher center of prostate dose were associated with better bNED survival. Multivariate analysis indicated that increasing stage and younger age are significantly associated with increasing distant metastasis. CONCLUSION: Patients with pretreatment PSA levels > or = 20 ng/mL are not optimally treated by irradiation alone. The pattern of failure suggests improvement may come from systemic treatment of metastatic disease and high-dose radiation to improve locoregional disease. To evaluate this, we have begun a multimodal trial of chemohormonal therapy followed by extended-field irradiation.

Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089.

PURPOSE: To determine the relationship, in patients with adenocarcinoma of the colon, between survival and the number of lymph nodes analyzed from surgical specimens. PATIENTS AND METHODS: Intergroup Trial INT-0089 is a mature trial of adjuvant chemotherapy for high-risk patients with stage II and stage III colon cancer. We performed a secondary analysis of this group with overall survival (OS) as the main end point. Cause-specific survival (CSS) and disease-free survival were secondary end points. Rates for these outcome measures were estimated using Kaplan-Meier methodology. Log-rank test was used to compare overall curves, and Cox proportional hazards regression was used to multivariately assess predictors of outcome. RESULTS: The median number of lymph nodes removed at colectomy was 11 (range, one to 87). Of the 3411 assessable patients, 648 had no evidence of lymph node metastasis. Multivariate analyses were performed on the node-positive and node-negative groups separately to ascertain the effect of lymph node removal. Survival decreased with increasing number of lymph node involvement (P =.0001 for all three survival end points). After controlling for the number of nodes involved, survival increased as more nodes were analyzed (P =.0001 for all three end points). Even when no nodes were involved, OS and CSS improved as more lymph nodes were analyzed (P =.0005 and P =.007, respectively). CONCLUSION: The number of lymph nodes analyzed for staging colon cancers is, itself, a prognostic variable on outcome. The impact of this variable is such that it may be an important variable to include in evaluating future trials.

Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx.

PURPOSE: A number of reports have documented the relationship between pretreatment hemoglobin level and local control and/or survival in the treatment of cervix, bladder, and advanced head and neck tumors. Consideration of correcting anemia before initiation of radiation therapy may prove increasingly important as clinical trials use intensive induction chemotherapy in the treatment of head and neck carcinomas. Neoadjuvant chemotherapy may produce anemia, which in turn may reduce the effectiveness of subsequent irradiation. MATERIALS AND METHODS: One hundred nine patients with T1-2N0 squamous cell carcinoma of the glottic larynx were treated with definitive radiotherapy at the Fox Chase Cancer Center between June 1980 and November 1990. Follow-up times ranged from 26 to 165 months (median, 82). RESULTS: The 2-year local control rate for patients who presented with a hemoglobin level < or = 13 g/dL was 66%, compared with 95% for patients with a hemoglobin level more than 13 g/dL (P = .0018). The 2-year survival rate for patients with a hemoglobin level < or = 13 g/dL was 46%, compared with 88% for patients with a hemoglobin level more than 13 g/dL (P < .001). Cox proportional hazards regression analysis showed that hemoglobin level (P = .0016) was the only variable that significantly influenced local control (P = .0016) and survival (P < .0001). CONCLUSION: Patients who presented with hemoglobin levels more than 13 g/dL had significantly higher local control and survival rates. The strong apparent correlation between hemoglobin level, local control, and survival supports consideration of correcting anemia before initiation of radiation therapy.

Scrutiny of the ASTRO consensus definition of biochemical failure in irradiated prostate cancer patients demonstrates its usefulness and robustness. American Society for Therapeutic Radiology and Oncology.

PURPOSE: The goals of this study are: (1) to establish the robustness of the Fox Chase Cancer Center (FCCC) and the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definitions of failure by comparing biochemical estimates under various modifications of the censoring and failure time components to their respective unaltered definitions; (2) to isolate the source of variation between the two definitions of failure; and (3) to describe the hazard of failure over time for each definition. METHODS: Between May 1989 and May 1997, 670 men were treated at Fox Chase Cancer Center for localized prostate cancer using three-dimensional conformal radiation therapy (3DCRT). These men were stratified into three groups for analysis: 111 men treated with adjuvant hormones; 204 men treated with radiation therapy alone and presenting with more favorable prognosis tumor characteristics; 255 men treated with radiation therapy alone and presenting with less favorable prognosis tumor characteristics. For each group, biochemical failure was estimated and compared using the FCCC and ASTRO definitions of failure. The robustness of each definition was evaluated by comparing estimates under the definition as stated to those under various modifications of the censoring and failure components. Analyses were also performed while excluding slow-progressing patients. To isolate the source of variation between the two failure definitions, estimates were compared for patients with agreement in failure status. Estimates of biochemical failure, and thus hazard rates, were made using Kaplan-Meier methodology. RESULTS: ASTRO biochemical failure estimates were higher than the FCCC failure estimates in the first 5 years post-treatment. Beyond 5 years, ASTRO estimates level off, while the FCCC failure estimates continued to increase. These failure patterns were similar in all patient groups; however, patients treated with adjuvant hormones had a much higher risk of failure immediately following treatment under the ASTRO definition. Modifying the censoring pattern had little effect on failure estimates in any patient group, regardless of definition used. The exclusion of patients with slow prostate-specific antigen (PSA) doubling time did not result in biochemical estimates that differed significantly from those for all patients. The analysis of patients with agreement in failure status continued to demonstrate significant differences in estimates between the two definitions, and thus differences may be attributed to the specification of time to failure. For all patient groups, hazard rates were dependent upon failure definition: under the FCCC failure definition, patients were at constant risk of failure over the observation period; under the ASTRO failure definition, patients were at risk of failure during the first 4 years following treatment, and then at low risk of failure beyond 5 years. CONCLUSIONS: Both FCCC and ASTRO failure definitions were robust to modifications in censoring and the inclusion of patients with long doubling times. The ASTRO failure definition was robust to specifying the time to failure at first rise, as opposed to midway between nadir and first rise. Similarities in estimates for all patients versus patients with agreeing failure status suggest that differences in failure definition lie in the specification of time to failure. The ASTRO definition of failure is more appropriate because it does not impose an empirical failure marker but is based on the initiation of biochemical rise. The use of the ASTRO consensus definition demonstrated little risk of biochemical failure 4 years beyond treatment. The ASTRO failure definition should be adopted in all research involving biochemical failure analysis of men treated with radiation therapy.

Quality of life study in prostate cancer patients treated with three-dimensional conformal radiation therapy: comparing late bowel and bladder quality of life symptoms to that of the normal population.

PURPOSE: The goals of this study were twofold. First, differences were quantified for symptoms that impact bowel and bladder quality of life (QOL) in prostate cancer patients treated with three-dimensional conformal radiotherapy (3DCRT) alone to the prostate vs. whole pelvis with prostate boost. Second, bowel and bladder QOL measures for these patients were compared to those of the normal population of men with a similar age distribution. MATERIAL AND METHODS: Two health status surveys evaluating bowel and bladder functioning, along with the AUA Symptom Problem Index and the BPH Impact Index, were mailed to 195 prostate cancer patients treated with 3DCRT between 12/92 and 11/95 at Fox Chase Cancer Center by a single clinician (GH). No patient received hormonal management as part of his treatment. Ninety-five patients had pretreatment PSA levels <10 ng/ml, T1/T2A tumors with Gleason scores 2-6, and no perineural invasion. They were treated to the prostate alone and are referred to as Group I. The remaining 100 patients had one or more of the following characteristics: pretreatment PSA levels > or =10 ng/ml, T2B/T3 tumors, Gleason scores 7-10, or perineural invasion. These patients were treated to the whole pelvis followed by a boost to the prostate and are referred to as Group II. Frequencies were tabulated, and differences in percentages for the two groups were evaluated using the two-tailed Fisher's Exact Test. Overall percentages were compared to those for equivalent measures reported by Litwin (1999) based on a normal population of men with a mean age of 73 years (range 47-86). Comparisons to the normal population were also evaluated using two-tailed Fisher's Exact p values. RESULTS: The mailing yielded a high response rate of 71% (n = 139, 66 in Group I and 73 in Group II). The mean age was 67 (range 49-82), and the median ICRU dose levels for Groups I and II were 73 and 76 Gy, respectively. Responses relating to bladder symptoms were similar for Groups I and II, except for the degree of bother associated with trouble in urination over the last month. Percentages for no bother at all were 66% and 56% for Groups I and II, respectively. Observed differences in bowel functioning related to rectal urgency over the past year (22% vs. 40% for Groups I and II, p = 0.03), the use of pads for protection against bowel incontinence (0% vs. 10% for Groups I and II, p = 0.01), and bowel satisfaction (88% vs. 72% for Groups I and II, p = 0.03). There was no significant difference in the degree of bother bladder symptoms cause men treated with radiotherapy as compared to men without cancer. Few patients reported bowel dysfunction bother as a big problem, but patients do tend to have more very small to moderate bother from bowel dysfunction than the normal population (55% vs. 33%, p < 0.001). CONCLUSION: This is the first long-term study of QOL in men treated with high-dose 3DCRT for prostate cancer. It demonstrates that these men enjoy QOL related to bladder function similar to that of the normal population. Few patients report bother from bowel symptoms as a big problem but tend to have more very small to moderate bother than the normal population. Treatment of prostate cancer patients to the whole pelvis may result in decreased QOL as defined by rectal urgency, the use of pads for bowel incontinence, and satisfaction with bowel functioning. However, regardless of field size, men are generally satisfied with their bowel and bladder functioning three to six years post treatment.

Early stage prostate cancer treated with radiation therapy: stratifying an intermediate risk group.

PURPOSE: This study identifies two early prostate cancer populations within the T1/T2AB, Gleason 2-7, pretreatment prostate specific antigen (PSA) 4-15 ng/ml grouping. By demonstrating different outcomes we may be able to more appropriately select a subgroup for whom adjuvant therapy trials or altered treatment techniques are indicated. MATERIALS AND METHODS: One hundred forty-six patients with T1/T2AB, Gleason score 2-7, PSA 4-15 ng/ml prostate cancer were treated with external beam radiotherapy alone from November 1987 to October 1993. The median pretreatment PSA was 8.6 and the mean 8.7. Minimum follow-up was 2 years with a median of 38 months (mean 42 months, range 24-87). The median age was 70 years (range 58-83) and the median central axis dose delivered was 7240 cGy (mean 7273, range 6541-7895 cGy). Eleven patients received conventional radiotherapy while 135 were treated using conformal techniques. As there is evidence that a low PSA nadir is an early marker for long term biochemical control, time to post treatment PSA < 1 ng/ml was actuarially analyzed by Gleason score, pretreatment PSA, radiation dose, stage, and the presence of perineural invasion. Pretreatment PSA was the only patient characteristic predictive of achieving a PSA level < 1.0 ng/ml. Biochemical relapse free (bNED) control (non rising PSA) was then compared for patients above and below the approximate median pretreatment PSA level of 8 ng/ml. bNED control rates and the time to PSA < 1.0 ng/ml were estimated using Kaplan-Meier methodology, and differences in bNED control and PSA < 1.0 ng/ml according to PSA level were evaluated using the log-rank test. RESULTS: Results from actuarial analysis revealed that pretreatment PSA was the only significant variable predictive of a PSA < 1.0 ng/ml. Ninety-eight percent of patients with pretreatment PSA < 8 achieved a PSA level < 1.0 ng/ml within 3 years compared to 78% for patients with a PSA > 8 ng/ml (p = 0.0003). bNED control for the two groups separated at a pretreatment PSA of 8 ng/ml confirms a favorable outcome, 88% bNED control at 5 years for < 8 ng/ml and 74% for a pretreatment PSA > or = 8 ng/ml (p = 0.007 for overall curve comparison). CONCLUSION: For early prostate cancer patients (T1/T2AB, Gleason 2-7, pretreatment PSA 4-15) there is a significant break in bNED control following external beam radiation at a pretreatment PSA level of 8 ng/ml. Patients with pretreatment PSA < 8 have a very favorable bNED response with radiation alone while those with a pretreatment PSA 8-15 have a significant decrease in bNED response. The 27% failure rate at 5 years in the PSA 8-15 ng/ml patients may justify altered treatment techniques or clinical trials of adjuvant androgen deprivation in this group.

Prostate cancer patient subsets showing improved bNED control with adjuvant androgen deprivation.

PURPOSE: Cooperative groups have investigated the outcome of androgen deprivation therapy combined with radiation therapy in prostate cancer patients with variable pretreatment prognostic indicators. This report describes an objective means of selecting patients for adjuvant hormonal therapy by a retrospective matched case/control comparison of outcome between patients with specific pretreatment characteristics who receive adjuvant hormones (RT+H) vs. patients with identical pretreatment characteristics treated with radiation therapy alone (RT). In addition, this report shows the 5-year bNED control for patients selected by this method for RT+H vs. RT alone. METHODS AND MATERIALS: From 10/88 to 12/93, 517 T1-T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase Cancer Center. Four hundred fifty-nine of those patients were treated with RT alone while 58 were treated with RT+H. The patients were categorized according to putative prognostic factors indicative of bNED control, which include the palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED control rates according to treatment group within each of the prognostic groups. In addition, we devised a retrospective matched case/control selection of RT patients for comparison with the RT+H group. Five-year bNED control was compared for the two treatment groups, excluding the best prognosis group, using 56 RT+H patients and 56 matched (by stage, grade, and pretreatment PSA level) controls randomly selected from the RT alone group. bNED control for the entire group of 517 patients was then analyzed multivariately using step-wise Cox regression to determine independent predictors of outcome. Covariates considered for entry into the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment PSA (0-15 vs. > 15), treatment (RT vs. RT+H), and center of prostate dose. bNED failure is defined as PSA > or = 1.5 ngm/ml and rising on two consecutive determinations. The median follow-up for the 112 matched case/control patients was 41 months. The median follow-up was 46 months for the RT (range 11-102 months) and 37 months for the RT+H group (range 6-82 months). RESULTS: Univariate analysis according to treatment for the prognostic factors of palpation stage, Gleason score, and pretreatment PSA demonstrates a significant improvement in 3-year bNED control with the addition of hormones for patients with T2C/T3, Gleason score 7-10, or pretreatment PSA > 15 ngm/ml. A comparison of bNED control according to treatment demonstrates improvement in 5-year bNED control of 55% for patients treated with RT+H vs. 31% for those patients treated with RT alone (p = 0.0088), although there is not a survival advantage. Multivariate analysis demonstrates that hormonal treatment is a highly significant independent predictor of bNED control (p = 0.0006) along with pretreatment PSA (p = 0.0001), palpation stage (p = 0.0001), grade (p = 0.0030), and dose (p = 0.0001). CONCLUSIONS: (1) Patients with specific adverse pretreatment prognostic factors (i.e., T2C/T3, Gleason score 7-10, pretreatment PSA > 15) benefit from adjuvant hormonal therapy. (2) Upon multivariate analysis, hormonal therapy is determined to be a highly significant predictor of bNED control, after adjusting for all other covariates. (3) The 5-year bNED control rates of 55% for RT+H vs. 31% for RT alone represents the magnitude of benefit from adjuvant hormone therapy. (4) The bNED control curves are separated by about 20 months, representing a delay in disease progression with adjuvant hormonal therapy, as there is no overall survival difference.

Diabetes mellitus: a predictor for late radiation morbidity.

PURPOSE: Given the high frequency of diabetes, as well as prostate cancer in the elderly population, we sought to determine whether diabetic patients treated with three-dimensional conformal external-beam radiotherapy (3DCRT) had an increased risk of late gastrointestinal (GI) or genitourinary (GU) complications. METHODS AND MATERIALS: Nine-hundred forty-four prostate cancer patients were treated between April 1989 and October 1996 using 3DCRT. Median patient age was 69 years (range 48-89), median center of prostate dose was 7211 cGy (range 6211-8074) and median follow-up was 36 months (range 2-99). Patients were evaluated every 6 months with digital rectal examinations, serum PSAs and symptom questionnaires. Radiation morbidity was quantified using Radiation Therapy Oncology Group (RTOG) and modified Late Effects Normal Tissue Task Force (LENT) scales. Patients with a preexisting history of either Type I or Type II diabetes mellitus were coded as diabetics. RESULTS: One hundred twenty-one patients had diabetes (13% of total). Rates of acute morbidity did not differ between diabetics and nondiabetics; however, diabetics experienced significantly more late grade 2 GI toxicity (28% vs. 17%, p = 0.011) and late grade 2 GU toxicity (14% vs. 6%, p = 0.001). There was a trend toward increased late grade 3 and 4 GI complications in diabetics, but not for late grade 3 and 4 GU complications; however, the total number of recorded events for these categories was small. Examining the onset of late toxicity, diabetics developed GU complications earlier than nondiabetics (median: 10 months vs. 24 months, p = 0.02). Considering age, dose, rectal blocking, field size, and history of diabetes in a stepwise multivariate regression model for late grade 2 GI toxicity, dose (p = 0.0001), diabetes (p = 0.0110), and rectal blocking (p = 0.0163) emerged independently predictive for complications. For late grade 2 GU toxicity, only the presence of diabetes remained independently significant (p = 0.0014). CONCLUSION: Diabetes mellitus is common in the elderly prostate cancer population. Diabetics are at a significant risk for the development of late grade 2 GI and GU complications after external-beam radiotherapy for prostate cancer. While diabetes, radiation dose, and rectal blocking predict for late GI complications, only the presence of diabetes influences late GU morbidity. Physicians may consider treatment modifications for diabetic patients, particularly those patients wishing to enter dose-escalation studies. Further study of the relationship between diabetes and late radiation complications is needed.

Is there an increased risk of second primaries following prostate irradiation?

PURPOSE: To assess the risk of developing a second primary cancer following prostate irradiation compared to the underlying risk in patients with prostate cancer. METHODS AND MATERIALS: The baseline rate of secondary cancers following prostate cancer was obtained from a study of 18,135 patients from the Connecticut Tumor Registry, of whom only 12.5% received radiotherapy. These patients, with a mean age of 72 and a mean follow-up of 3.9 years, were compared to a cohort of 543 patients (median age 70) with similar follow-up (median 3.9 years), all of whom were treated with definitive radiotherapy at Fox Chase Cancer Center. The possible association between various covariates (age, dose, palpation stage, field size, Gleason score, pretreatment PSA) and the development of a secondary cancer was assessed. RESULTS: 1,053 of 18,135 patients (5.8%) in the Connecticut Tumor Registry developed a second primary cancer compared with 31 of 543 (5.7%) patients treated with prostate radiation (p = 0.99). Although this risk increases gradually over time, it is not significantly different, at any time period, between the two groups of patients. Of the 31 secondary primaries in the irradiated group, 82% had a history of tobacco and/or alcohol use. Only melanomas were significantly increased compared to the expected rate in an age-matched population (p < 0.001). Five of the 31 secondary cancers occurred within the radiation field (four bladder, one colon), four within 3 years and only one occurred 9 years after radiotherapy. No association was found between age (<70 vs. > or =70 and as a continuous variable), dose (<74 vs. > or =74 Gy), palpation stage ( or =T2C), field size (prostate vs. pelvic), radiation technique (conventional vs. conformal), Gleason score (2-6 vs. 7-10), or pretreatment PSA (<15 vs. > or =15 and as a continuous variable) and the risk of developing a second primary. Although a lower radiation dose (as a continuous variable) correlated with an increased risk of developing a secondary cancer (p = 0.04), this phenomenon is likely due to differences in follow-up time. CONCLUSION: Up to at least 10 years, there is no increased risk of developing a second primary cancer following prostate irradiation compared to the baseline rate from prostate cancer itself. This risk is not higher in younger patients with localized disease (

The influence of lymphangiography on the development of hypothyroidism in patients irradiated for Hodgkin's disease.

PURPOSE: There is no consensus in the literature regarding the role of lymphangiography in promoting hypothyroidism in individuals with Hodgkin's disease irradiated with a mantle field. We sought to analyze the onset and rate of developing clinical or chemical hypothyroidism as well as possible factors related to its development in patients who received irradiation to the thyroid gland during treatment of Hodgkin's disease. METHODS AND MATERIALS: One hundred and forty-two patients with Hodgkin's disease were treated at the Fox Chase Cancer Center between June 1967 and October 1993. All patients were treated with curative intent with radiation therapy using a mantle field. After exclusion of patients without available thyroid function tests, < 200 days of follow-up, or no radiation to the thyroid, 104 patients were eligible for analysis. Follow-up ranged from 7-170 months (median: 43 months). Sixty-seven patients had a lymphangiogram. Seventy-three patients were treated with radiation alone and 31 with radiation plus chemotherapy. RESULTS: The actuarial 2-, and 5-year rates of biochemical hypothyroidism for all 104 patients were 18 and 37%, respectively. Forty patients developed hypothyroidism: 9 (23%) at < or = 1 year, 18 (45%) at < or = 2 years, and 33 (83%) at < or = 5 years. The actuarial 2-, and 5-year rates of biochemical hypothyroidism for patients who underwent a lymphangiogram were 23 and 42%, respectively, compared to 9 and 28%, respectively, for patients who received mantle irradiation without a lymphangiogram (p = 0.05). The effects of lymphangiogram, total thyroid dose, stage, chemotherapy, dose per fraction, energy, and age were evaluated for all patients by Cox proportional hazards regression analysis. The use of a lymphangiogram (p = 0.05) was the only variable that significantly influenced hypothyroidism. CONCLUSIONS: This paper demonstrates in a multivariate analysis accounting for other potentially important variables the significant effect of lymphangiography and subsequent radiation therapy on the development of hypothyroidism. This information must be balanced with the fact that lymphangiograms remain a useful aid in assessing lymph node involvement, staging patients, and planning treatment fields.

The value of setup portal films as an estimate of a patient's position throughout fractionated tangential breast irradiation: an on-line study.

PURPOSE: To determine if portal setup films are an accurate representation of a patient's position throughout the course of fractionated tangential breast irradiation. METHODS AND MATERIALS: Thirteen patients undergoing external beam irradiation for T1-T2 infiltrating ductal carcinoma of the breast following excisional biopsy and axillary dissection were imaged using an on-line portal imaging device attached to a 6 MV linear accelerator. Medial and lateral tangential fields were imaged and a total of 139 fractions, 225 portal fields, and 4450 images were obtained. Interfractional and intrafractional variations for anatomical parameters including the central lung distance (CLD), central flash distance (CFD), and inferior central margin (ICM) were calculated from these images. A pooled estimate of the random error associated with a given treatment was determined by adding the interfractional and intrafractional standard deviations in quadrature. A 95% confidence level assigned a value of two standard deviations of the random error estimate. Central lung distance, CFD, and ICM distances were then measured for all portal setup films. Significant differences were defined as occurring when the simulation-setup difference was greater than the 95% confidence value. RESULTS: Differences between setup portal and simulation films were less than their 95% confidence values in 70 instances indicating that in 90% of the time these differences are a result of random differences in daily treatment positioning. CONCLUSIONS: In 90% of cases tested, initial portal setup films are an accurate representation of a patients daily treatment setup.

Rectal bleeding after conformal 3D treatment of prostate cancer: time to occurrence, response to treatment and duration of morbidity.

PURPOSE: Rectal bleeding is the most common late sequelae of high-dose 3D conformal treatment (3DCRT) for prostate cancer and may limit attempts to improve local control by dose escalation. The clinical course of this complication is reported including time to onset, response to treatment, duration of morbidity, and multivariate analysis for predictors. METHODS AND MATERIALS: From March 1989 to June 1995, 670 patients with prostate cancer were treated with 3DCRT at Fox Chase Cancer Center. Eighty-nine patients developed Grade 2 or Grade 3 complications due to rectal bleeding and are analyzed. Multivariate analysis results for predictors of Grade 2 and 3 rectal bleeding are reported as well as time to development, response to initial and retreatment, and duration of morbidity. RESULTS: The median time to occurrence is not significantly different (p = 0.09) for Grade 2 (13 months, range 4-41 months) compared to Grade 3 rectal bleeding (18 months, range 4-40 months), while the corresponding median duration of symptoms was significantly different (p < 0.0001) being 1 month (range 1-12) vs. 10 months (1-34) for Grade 2 and Grade 3 bleeding, respectively. For Grade 2 bleeding, medication or coagulation was highly effective as initial or retreatment resolving 66 of 73 patients. For Grade 3 bleeding, three patients responded without medication following blood transfusion only, while with multiple coagulations and medication 12 of 16 patients improved to < or = Grade 1. Multivariate analysis demonstrates that dose is the only significant factor associated with Grade 2 (p = 0.01) or Grade 3 (p = 0.01) rectal bleeding. Of seven nonresponders to treatment for Grade 2 bleeding, three have died of intercurrent disease at 10, 19, and 26 months, while four are alive with continuing Grade 2 bleeding at 12, 14, 15, and 30 months after onset. The four nonresponders to treatment for Grade 3 bleeding continue to bleed 1, 9, 32, and 35 months after the third coagulation despite continuing care. CONCLUSIONS: Chronic rectal bleeding is a sequelae of high-dose conformal treatment of prostate cancer. Grade 2 morbidity responds to medication or limited coagulation (< or = 2) in 90% of patients. Grade 3 morbidity responds to medication and multiple coagulations (> or = 3) in 75% of patients. The chronicity of Grade 3 morbidity is illustrated by a 10-month median duration for response to treatment, with a range of response extending to 34 months. Nonresponders to treatment have continued to bleed up to 35 months after the third coagulation. Appropriate shielding of the rectal mucosa limiting dose to < 72 Gy is required to avoid a high incidence of these complications, as dose is the only significant variable associated with rectal bleeding.

Patterns and fate of PSA bouncing following 3D-CRT.

PURPOSE: The goals of this study were to quantify the frequency of post-treatment prostate-specific antigen (PSA)-level bouncing following three-dimensional conformal radiation therapy (3D-CRT) for prostate cancer and to identify any relationships that may exist between bouncing activity and biochemical control (bNED). METHODS: Between May 1989 and July 1995, 306 patients were treated with 3D-CRT alone. All patients had 6 or more post-treatment PSA levels and at least 5 years of PSA follow-up. The median total follow-up and total dose to the center of prostate was 79 months and 74 Gy, respectively. A bounce was defined by a minimum rise in PSA of 0.4 ng/mL over a 6-month period, followed by a drop in PSA of any magnitude. Estimates of bNED control rates were made using Kaplan-Meier methodology and comparisons were made using the log-rank test. Multivariate analysis of bNED control predictors was accomplished using a stepwise Cox proportional hazards model. RESULTS: Nearly one third of the patients experienced at least one bounce. Bouncers were found to present with higher pretreatment PSA levels and were treated with lower dose levels to the center of prostate. Five-year bNED control estimates for nonbouncers vs. bouncers were 69% and 52%, respectively (p = 0.0024). After controlling for dose and pretreatment PSA level, total number of bounces emerged as a significant predictor of bNED control (p = 0.02). CONCLUSIONS: Bouncing PSA levels occur in approximately one third of the patients treated with 3D-CRT alone, with bouncing occurring at a constant rate from 2 to 5 years post-treatment. Bouncing is associated with lower radiation dose levels, higher pretreatment PSA levels, and decreased bNED control. Nearly half of the bouncers are bNED controlled; thus, clinicians should not use bouncing as a sole indicator of relapse.

Defining the appropriate radiation dose for pretreatment PSA < or = 10 ng/mL prostate cancer.

PURPOSE: To investigate whether a dose response exists for biochemical no evidence of disease (bNED) control in prostate cancer patients with pretreatment prostate-specific antigen (PSA) < or = 10 ng/mL and to identify the patient subgroups affected. METHODS AND MATERIALS: Between 5/89 and 10/97, 488 T1-T3 NX-0 M0 prostate cancer patients with PSA < or = 10 ng/mL were treated with three-dimensional conformal radiation therapy (3D-CRT) alone. Median and mean pretreatment PSA values were 6.3 and 6.2, respectively. Gleason scores of 2-6 and 7-10 were noted in 386 and 102 men, respectively. AJCC 1992 palpation T1-T2AB tumors were noted in 415 patients. Perineural invasion (PNI) was noted in 60 men. Mean and median age was 67 and 68 years, respectively. Dose to the center of the prostate ranged from 6260 cGy to 8409 cGy with a mean and median of 7423 cGy and 7278 cGy, respectively. Patients were stratified into three groups according to dose: <7250 cGy, 7250-7599 cGy, and > or =7600 cGy. Median dose in these three groups was 7067 cGy, 7278 cGy, and 7734 cGy, respectively. Univariate analysis was performed to determine differences in bNED control (American Society for Therapeutic Radiology and Oncology [ASTRO] Consensus Guidelines definition of failure) by dose group for the entire cohort, for 310 good prognosis patients (T1-T2A, Gleason score 2-6, absence of PNI), and for 178 poor prognosis patients (T2B-T3 or Gleason score 7-10 or presence of PNI) (1). Multivariate analysis (MVA) was performed to determine if dose was an independent predictor of bNED control. Median follow-up was 36 months. RESULTS: A dose response was not demonstrated for the entire group of patients with pretreatment PSA < or =10 ng/mL. Doses of <7250 cGy, 7250-7599 cGy, and > or =7600 cGy were associated with 5-year bNED control rates of 73%, 86%, and 89%, respectively (p = 0.12). MVA demonstrated prognosis group (p = 0. 038) to be the only independent predictor of bNED control. Good prognosis patients had a 5-year bNED of 85% and no dose response was seen. The subgroup of poor prognosis patients demonstrated a 5-year bNED control rate of 81% and a dose response was seen for those receiving > or =7600 cGy, compared to the two lower dose groups (94% vs. 75% vs. 70%; p = 0.0062). MVA for the poor prognosis subset demonstrated dose (p = 0.01) to be the only independent predictor for improved bNED control. CONCLUSIONS: The poor prognosis subset of PSA < or =10 ng/mL prostate cancer patients benefit from dose escalation. A dose response is not demonstrated for prostate cancer patients with pretreatment PSA < or =10 ng/mL and other favorable features.

Perineural invasion and Gleason 7-10 tumors predict increased failure in prostate cancer patients with pretreatment PSA <10 ng/ml treated with conformal external beam radiation therapy.

PURPOSE: It has been well established that prostate cancer patients with pretreatment PSA <10 ng/ml enjoy excellent bNED control when treated with definitive external beam radiation therapy. This report identifies predictors of failure for patients with pretreatment PSA <10 ng/ml. These predictors are then used to define favorable and unfavorable prognostic subgroups of patients for which bNED control is compared. METHODS AND MATERIALS: Between 3/87 and 11/94, 266 patients with T1-T3NXM0 prostate cancer and pretreatment PSA values <10 ng/ml were treated with definitive external beam radiation therapy. Median central axis dose and median follow-up for the entire group was 72 Gy (63-79 Gy) and 48 months (2-120 months). Predictors of bNED control were evaluated univariately using Kaplan-Meier methodology and the log-rank test and multivariately using Cox proportional hazards modeling. Covariates considered were pretreatment PSA, palpation stage, Gleason score, presence of perineual invasion (PNI) and central axis dose. Independent predictors based on multivariate results were then used to stratify the patients into two prognostic groups for which bNED control was compared. bNED failure is defined as PSA > or = 1.5 ng/ml and rising on two consecutive determinations. RESULTS: Univariate analysis according to pretreatment and treatment factors for bNED control demonstrates a statistically significant improvement in 5-year bNED control for patients with Gleason score 2-6 vs. 7-10, patients without evidence of perineural invasion (PNI) vs. those with PNI, and patients with palpation stage T1/T2AB vs. T2C/T3. Multivariate analysis demonstrates that Gleason score (p = 0.0496), PNI (p = 0.0008) and palpation stage (p = 0.0153) are significant independent predictors of bNED control. Based on these factors, patients are stratified into a more favorable prognosis group (Gleason 2-6, no PNI, and stage T1/T2AB, n = 172) and a less favorable prognosis group (Gleason 7-10 or PNI or T2C/T3, n = 94). A comparison of the two groups reveals that bNED control is significantly lower in the less favorable prognosis group (74% vs. 91% at 5 years, p = 0.0024). CONCLUSIONS: (1) This report identifies Gleason 7-10 and the presence of PNI as well as palpation stage T2C/T3 as factors that predict worse bNED outcome for patients with pretreatment PSA <10 ng/ml who are treated with radiation therapy alone. (2) Patients with these pretreatment prognostic factors may benefit from adjuvant therapies or altered treatment programs. (3) In order to make fair comparisons between radiation therapy and prostatectomy series, the distribution of perineual invasion and Gleason 7-10 must be taken into account.

Young patients with prostate cancer have an outcome justifying their treatment with external beam radiation.

PURPOSE: The majority of young patients with early stage prostate cancer in the United States are treated with radical prostatectomy. To determine whether this preference for surgical care is justified, we analyzed by patient age the survival without biochemical evidence of disease (bNED) of men with clinically organ-confined prostate cancer treated with external beam irradiation. METHODS AND MATERIALS: One hundred and sixty-nine men with clinical stages T1-2 adenocarcinoma of the prostate received external beam radiation therapy alone at Fox Chase Cancer Center. All patients had serum prostate-specific antigen (PSA) values less than 10 ng/ml prior to initiation of treatment. Out of 169 patients, 167 had unstaged regional nodes (NX) and all had no evidence for distant metastasis (M0). The median age was 69 years. Criteria for bNED survival were posttreatment serum PSA < or = 1.5 ng/ml and not rising on two consecutive values. The median follow-up is 35 months. RESULTS: The actuarial 5-year bNED survival of all 169 patients was 85%. The bNED survival of patients less than 65 was not significantly different than that of patients 65 and older (89 vs. 84%, respectively). Patient age, American Joint Committee on Cancer (AJCC) stage, palpation stage, Gleason score, and dose to the center of the prostate were not found to be significant predictors of bNED survival on multivariate analysis. CONCLUSION: Our results using strict biochemical endpoints are comparable to reported series of similarly staged men treated with prostatectomy. In addition, the patient age of less than 65 is not a prognostic factor for worse outcome after radiation therapy. Young patients with clinically organ-confined prostate cancer who are fully informed of their treatment options can be appropriately accepted for external beam treatment.

Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: further evidence for a significant dose effect.

PURPOSE: Using conventional treatment methods for the treatment of clinically localized prostate cancer central axis doses must be limited to 65-70 Gray (Gy) to prevent significant damage to nearby normal tissues. A fundamental hypothesis of three-dimensional conformal radiation therapy (3DCRT) is that, by defining the target organ(s) accurately in three dimensions, it is possible to deliver higher doses to the target without a significant increase in normal tissue complications. This study examines whether this hypothesis holds true and whether a simple modification of treatment technique can reduce the incidence of late rectal morbidity in patients with prostate cancer treated with 3DCRT to minimum planning target volume (PTV) doses of 71-75 Gy. METHODS AND MATERIALS: The 257 patients with clinically localized prostate cancer who completed 3DCRT by December 31, 1993 and received a minimum PTV dose of 71-75 Gy are included in this report. The median follow-up time was 22 months (range: 4-67 months); 98% of patients had follow-up of longer than 12 months. The calculated dose at the center of the prostate was < 74 Gy in 19 patients, 74-76 Gy in 206 patients, and > 76 Gy in 32 patients. Late rectal morbidity was graded according to the Late Effects Normal Tissue (LENT) scoring system. Eighty-eight consecutive patients were treated with a rectal block added to the lateral fields. In these patients the posterior margin from the prostate to the block edge was reduced from the standard 15 to 5 mm for the final 10 Gy, which reduced the dose to portions of the anterior rectal wall by approximately 4-5 Gy. Estimates of rates for rectal morbidity were determined by Kaplan-Meier actuarial analysis. Differences in morbidity percentages were evaluated by the Pearson chi-square test. RESULTS: Grade 2-3 rectal morbidity developed in 46 out of 257 patients (18%) and in the majority of cases consisted of rectal bleeding. No patient has developed Grade 4 or 5 rectal morbidity. The actuarial rate of Grade 2-3 morbidity is 23% at 24 months and the median time to the development of Grade 2-3 complications is 15 months. A statistically significant dose effect is evident. The incidence of Grade 2-3 rectal morbidity increased as the dose at the center of the prostate increased (p = 0.05). In patients receiving minimum PTV doses of < or = 76 Gy the use of a rectal block significantly reduced the incidence of Grade 2-3 toxicity; 6 out of 88 (7%) with a block vs. 30 out of 137 (22%) without a block, (p = 0.003). CONCLUSION: The incidence of late rectal morbidity with 3DCRT to minimum PTV doses of 71-75 Gy is acceptable and to date no Grade 4-5 rectal morbidities have been observed. In our experience, higher doses to the center of the prostate are associated with an increased likelihood of developing Grade 2-3 rectal morbidity but treatment techniques that reduce the total dose to the anterior rectal wall have reduced the incidence of late rectal morbidity. If clinical studies indicate improved tumor control with minimum PTV doses above 71 Gy, then dose escalation above 76 Gy to the center of the prostate should be pursued cautiously with treatment techniques that limit the total dose to the anterior rectal wall.

Long-term results of treatment of cervical carcinoma in the United States in 1973, 1978, and 1983: Patterns of Care Study (PCS).

PURPOSE: To extend the observations of patients with carcinoma of the cervix treated in 1973 for over 15 years, in 1978 for over 10 years, and in 1983 for over 5 years for survival and local control to compare treatment times and outcome. METHODS AND MATERIALS: A nationwide survey of the patterns of practice in radiation therapy for patients with squamous carcinoma of the cervix collected pretreatment and treatment data using external surveyors who reviewed patients' records. Outcome information was updated for the three separate databases by mail survey. Overall survival, no evidence of disease (NED) survival, and local control curves by stage were plotted using the estimates derived by the Kaplan-Meier method. RESULTS: Total number of patients surveyed was 1686: 937 patients in 1973, 565 patients in 1978, and 184 patients in 1983. These are the results from changes in treatment policy, particularly the increasing use of brachytherapy. Of Stage III patients, the percentage receiving brachytherapy was 60.5% in 1973, 76.5% in 1978, and 87.9% in 1983 (p < 0.001 by linear trend test). Also, there was an increased proportion in use of higher energy for external pelvic irradiation during the more recent time period, e.g., 28% in the 1973 study, 60% in the 1978 study, and 87% in the 1983 study compared to the usage of cobalt-60 equipment. Comparison of results including overall survival, local control, and NED survival for the three different time periods showed improvement in outcome for Stage III in 1983, but not Stages I and II. The 5-year survival for Stage III increased from 25% in the 1973 survey to 47% in the 1983 survey, a linear trend that is statistically significant (p = 0.02). CONCLUSION: The long-term results of radiotherapy for patients with carcinoma of the cervix show improved outcome for Stage III patients, which probably results from improved treatment, including higher energy for pelvic irradiation and increase in use of brachytherapy contributing better local control and fewer complications.

Pretreatment prostate-specific antigen doubling times: clinical utility of this predictor of prostate cancer behavior.

PURPOSE: The distribution of pretreatment and posttreatment prostate specific antigen (PSA) doubling times (PSADT) varies widely. This report examines the pretreatment PSADT as an independent predictor of biochemical freedom from disease (bNED) and describes the clinical utility of PSADT. METHODS AND MATERIALS: Ninety-nine patients with T1-3 NX, M-0 prostate cancer treated between February 1989 and November 1993 have pretreatment PSADTs calculated from three or more PSA levels. Biochemical disease-free (bNED) survival (failure is PSA > or = 1.5 ngm/ml and rising) is evaluated by multivariate analysis of common prognostic indicators and PSADT. RESULTS: Prostate-specific antigen doubling time (PSADT) is a significant predictor of survival along with radiation dose. Patients with a pretreatment PSADT of < 12 months show 50% failure by 18 months, while those with a PSADT that is not increasing show only 3% failure at 3 years. CONCLUSIONS: Prostate-specific antigen doubling time (PSADT) is a predictor of bNED outcome in prostate cancer. Patients with PSADT < 12 months have aggressive disease, and should be considered for multimodal therapy. Slow PSADT (> or = 5 years) is observed in 57% of patients, and this end point may be considered in the decision to observe rather than to treat. After treatment failure, the PSADT may be used to determine which patients do not need immediate androgen deprivation.