Swallowing function and weight change observed in a phase I/II study of external-beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207).

BACKGROUND: A multi-institutional, prospective study was designed to determine the feasibility and tolerance of combined-modality chemotherapy, external-beam irradiation, and esophageal brachytherapy in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. Swallowing function and weight were assessed before and after treatment. MATERIALS AND METHODS: Planned treatment was with 50 Gy of external-beam irradiation (25 fractions/5 weeks) followed 2 weeks later by esophageal brachytherapy (either a high dose rate of 5 Gy at weeks 8, 9, and 10 for a total of 15 Gy or a low dose rate of 20 Gy at week 8). Chemotherapy was given weeks 1, 5, 8, and 11 with cisplatinum, 75 mg/m2, and 5-fluorouracil, 1,000 mg/m2/24 hours in a 96-hour infusion. Swallowing was graded from 0 (no dysphagia) to 4 (complete obstruction for solids and liquids). Weight "loss" or weight gain was defined as a change in 3-month post- to pretherapy weight of < or = 5% or > 5%, respectively. RESULTS: The estimated survival rate at 1 and 2 years was 49% and 31%, respectively, and the estimated median survival was 11 months. Swallowing before treatment was graded as grade 1 in 14 patients, grade 2 in 22 patients, grade 3 in nine patients, and grade 4 in four patients. Swallowing grade after treatment was reported as improved in 29 patients (59%), unchanged in 12 patients (24.5%), and worse in eight patients (16.5%). The bestimproved dysphagia score after treatment in the 29 patients reporting improvement was grade 0 in 19 patients, grade 1 in five patients, grade 2 in four patients, and grade 3 in one patient. A posttreatment weight in 42 evaluable patients was categorized as a loss in 29 patients (69%), a gain in four patients (9.5%), and stable in nine patients (21.5%). Weight loss was significantly correlated with high swallowing grade, low performance status, and absence of a feeding tube. CONCLUSIONS: Swallowing function after brachytherapy and concurrent chemoradiation therapy is satisfactory in most surviving patients. Ninety-two percent of patients were able to swallow at least liquids at some point after therapy. Future plans are to compare this with other cooperative group studies that utilized chemoradiation or surgery, without brachytherapy.

Plasma levels of IGF-1, IGF-2, and IGFBP-3 in white and African-American men at increased risk of prostate cancer.

OBJECTIVES: To further investigate the relationship between the plasma levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone, testosterone, and demographic factors, particularly race, within a group of men at increased risk of prostate cancer development. METHODS: Enzyme-linked immunosorbent assays or an immunosorbent assay was used to quantitate the plasma levels of IGF-1, IGF-2, IGFBP-3, growth hormone, and testosterone. The study group consisted of 169 men (85 African-American, 84 white) aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were African-American. The relationships between the plasma levels and the categorical covariates were assessed using the nonparametric Wilcoxon test and between the continuous variables using Spearman's correlation coefficient. RESULTS: The mean plasma levels of IGFBP-3 were significantly lower in African-American (2657 ng/mL) than in white (2965 ng/mL) men (P = 0.0062). The plasma levels of IGF-2 were also lower in the African-American (503.5 ng/mL) than in the white (549.1 ng/mL) men (P = 0.0084). Overall, the IGF-1 plasma levels correlated positively with the IGF-2, IGFBP-3, and growth hormone levels and the IGF-2 plasma levels correlated negatively with the testosterone levels. CONCLUSIONS: Our results demonstrate that lower plasma levels of IGFBP-3 and IGF-2 are associated with race in a population of men at increased risk of developing prostate cancer. The ability of these markers to predict earlier disease onset is currently under investigation.

Hypoxia in human prostate carcinoma: an Eppendorf PO2 study.

The purpose of this study was to characterize the extent of hypoxia in human prostate carcinoma using the Eppendorf PO2 microelectrode. Custom-made Eppendorf PO2 microelectrodes were used to obtain PO2 measurements from the pathologically involved region of the prostate (as determined by the pretreatment sextant biopsies), as well as from a region of normal muscle for comparison. Fifty-nine patients with localized prostate cancer were studied, all of whom received brachytherapy implants under spinal anesthesia. A multivariate mixed effects analysis for prediction of tumor oxygenation was performed including the following covariates: type of tissue (prostate versus muscle), prostatic-specific antigen, disease stage, patient age and race, tumor grade, volume, perineural invasion, and hormonal therapy. Because of differences in patient characteristics, control measurements were obtained from normal muscle in all patients. This internal comparison showed that the oxygen measurements from the pathologically involved portion of the prostate were significantly lower (average median PO2 = 2.4 mm Hg) compared with the measurements from normal muscle (average median PO2 = 30.0 mm Hg), p < 0.0001. A multivariate, linear, mixed analysis demonstrated that the only significant predictor of oxygenation was the type of tissue (prostate versus muscle). This study, using in vivo electrode oxygen measurements, suggests that hypoxia exists in human prostate carcinoma. More patients will be accrued to this study to ultimately correlate the oxygenation status in prostate carcinoma tumors with treatment outcome.

Defining the optimal radiation dose with three-dimensional conformal radiation therapy for patients with nonmetastatic prostate carcinoma by using recursive partitioning techniques.

BACKGROUND: The objective of this study was to determine the effect of dose and its interaction with known prognostic variables, including pretreatment prostate specific antigen (PSA), Gleason score (GS), and T classification, on patients with nonmetastatic prostate carcinoma treated with three-dimensional conformal radiation therapy (3DCRT) alone using recursive partitioning analysis. METHODS: Between November 1987 and November 1997, 939 patients with nonmetastatic prostate carcinoma were treated with 3DCRT alone at Fox Chase Cancer Center. Biochemical no evidence of disease (bNED) control was defined using the American Society of Therapeutic Radiology and Oncology Consensus definition. Recursive partitioning analysis was used to identify subgroups with similar risks of bNED failure. Prognostic factors used in the model included pretreatment PSA, GS, T classification, and radiation dose. The median follow-up was 47 months (range, 2-133 months). RESULTS: Twelve terminal nodes of the decision tree were merged to form four prognostic groups with similar bNED control rates. The 5-year actuarial rates of bNED control rates for Groups I, II, III, and IV were 84%, 41%, 16%, and 67%, respectively (P < 0.0001). Increasing the dose to greater than 7235 centigray (cGy) improved bNED control rates for patients with PSA levels of 10-19.9 ng/mL and T1/2a classification disease. Increasing the dose to greater than 7629 cGy improved bNED control rates for patients with T2b/3 classification disease with PSA levels less than 20 ng/mL. Patients with PSA levels greater than or equal to 20 ng/mL need high-dose 3DCRT. For those patients with GS 2-6 and T1/2a classification disease, treatment with greater than 7400 cGy resulted in 67% bNED control rate versus 16% at 5 years for treatment with less than 7400 cGy. High radiation dose (> 7700 cGy) improved bNED control rate from 16% to 41% for patients with high-risk disease (PSA > or = 20 ng/mL and GS 7-10) at 5 years. CONCLUSIONS: The authors showed that with recursive partitioning techniques radiation dose continues to be an important predictor of bNED control rate and that a radiation dose response for patients with clinically localized prostate carcinoma exists. Patients with one or more prognostic feature (PSA > 10 ng/mL, classification T2b/T3, GS 7-10, or the presence of perineural invasion) achieve similar rates of bNED control compared with those patients with lower volume disease when radiation dose is increased.

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.

To move or not to move: measurements of prostate motion by urethrography using MRI.

PURPOSE: Urethrography is commonly used to aid in definition of the prostate apex during CT simulation for prostate cancer. If the position of the prostate were altered by the urethrogram itself, then systematic error could be introduced into the patient's treatment. Sagittal MRI scans were acquired immediately before and after a localization urethrogram to determine the extent of displacement. METHODS AND MATERIALS: Thirteen patients underwent sagittal T2-weighted fast spin echo MRI scans. Patients were scanned supine in an alpha cradle cast in the treatment position. The prostate was contoured by 3 different observers to determine the apex location on the central sagittal MRI section and the center of mass relative to an immobile bony landmark. Statistical multivariate analysis was performed to establish if there was a net displacement of the prostate (systematic error), and to determine the margin required to cover the random prostate position within a 95% confidence interval. RESULTS: There was no significant systematic motion of either the prostate nor its apex in either the anterior-posterior or superior-inferior directions. The average motion of the prostate center of mass was 0.04 +/- 0.40 cm (1 SD) and 0.01 +/- 0.33 cm in the anterior-posterior and superior-inferior direction, respectively. The corresponding figures for location of the apex were 0.05 +/- 0.30 cm and 0.01 +/- 0.33 cm, respectively. The statistical analysis revealed that a margin of 2 mm is sufficient to cover any random motion of the prostate that could occur as a result of the urethrogram 95% of the time. CONCLUSION: Urethrography during CT simulation for prostate cancer does not cause significant prostate displacement or systematic error in planning and delivering external-beam radiation.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperitoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected whenever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P < 0.001), and number of previous operations, which was greater in group II (P < 0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher's exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

Trimodality therapy for advanced gallbladder cancer.

We conducted a retrospective review of all patients who underwent surgical extirpation for stage III, stage IV, or recurrent carcinoma of the gallbladder. Between 1991 and 1999 ten patients underwent surgical resection for advanced gallbladder cancer. All patients received adjuvant therapy either pre- or postoperatively. Radiotherapy was used in all patients and chemotherapy in 90 per cent of patients. Two patients subsequently underwent resection for locally recurrent disease. An additional patient with stage II disease initially was also treated surgically for a local recurrence. Surgical management involved cholecystectomy and resection of various amounts of liver surrounding the gallbladder bed and regional lymphadenectomy. Contiguously involved structures were resected en bloc. Resection of recurrent disease included excision of all gross tumor. The median overall survival excluding the one 30-day mortality was 53.6 months (range 8-73 months). Four patients have survived 4 or more years, and currently four patients are alive and disease free at 73, 49, 33, and 8 months. Median disease-free interval after each resection of recurrent disease was 13.8 months (range 4-28 months). We conclude that trimodality therapy in selected patients with stage III, IV, or recurrent carcinoma of the gallbladder is possible and may result in prolonged survival.

Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2) study.

BACKGROUND: The purpose of this study was to analyze the extent of hypoxia in prostate carcinoma tumors using the Eppendorf pO(2) microelectrode and correlate this with pretreatment characteristics and prognostic factors. METHODS: Custom-made Eppendorf pO(2) microelectrodes were used to obtain pO(2) measurements from the pathologically involved region of the prostate (as determined by the pretreatment sextant biopsies) as well as from a region of normal muscle for comparison. Each set of measurements comprised approximately 100 separate readings of pO(2), for a total of 10,804 individual measurements. Fifty-five patients with localized prostate carcinoma were studied: Forty-one patients received brachytherapy implants, and 14 patients underwent radical prostatectomy. The pO(2) measurements were obtained in the operating room by using a sterile technique under spinal anesthesia for the brachytherapy group and under general anesthesia for the surgery group. The Eppendorf histograms were recorded and described by the median pO(2), mean pO(2), and percentage < 5 mm Hg and < 10 mm Hg. A multivariate mixed-effects analysis for the prediction of tumor oxygenation was performed and included the following covariates: type of tissue (prostate vs. muscle), type of treatment (implant vs. surgery) and/or anesthesia (spinal vs. general), prostate specific antigen level, disease stage, patient age and race, tumor grade, tumor volume, perineural invasion, and hormonal therapy. RESULTS: Due to differences in patient characteristics and the anesthesia employed, control measurements were obtained from normal muscle (in all but two patients). This internal comparison showed that the oxygen measurements from the pathologically involved portion of the prostate were significantly lower (average median pO(2), 9.9 mm Hg) compared with the measurements normal muscle (average median pO(2), 28.6 mm Hg; P < 0.0001). A multivariate, linear, mixed analysis demonstrated that, among all of the patients, the significant predictors of oxygenation were tissue (prostate vs. muscle) and anesthesia (spinal vs. general) or treatment (implant vs. surgery). Among the brachytherapy (spinal anesthesia) patients, the significant predictors of pO(2) were tissue type, disease stage, and patient age. There were no significant predictors of oxygenation in the surgical (general anesthesia) group. CONCLUSIONS: This study, employing in vivo electrode oxygen measurements, demonstrated that hypoxia exists in prostate carcinoma tumors. A dramatic effect of anesthesia was observed, likely due to modulation of polarography in the presence of fluorine. Within the group of brachytherapy (spinal anesthesia) patients, increasing levels of hypoxia (within prostatic tissue) correlated significantly with increasing clinical stage and patient age. More patients will be accrued to this prospective study to further correlate the oxygenation status in prostate carcinoma tumors with known prognostic factors and, ultimately, treatment outcome.

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.

Dose selection for prostate cancer patients based on dose comparison and dose response studies.

PURPOSE: To better define the appropriate dose for individual prostate cancer patients treated with three-dimensional conformal radiation therapy (3D CRT). METHODS AND MATERIALS: Six hundred eighteen patients treated with 3D CRT between 4/89 and 4/97 with a median follow-up of 53 months are the subject of this study. The bNED outcomes were assessed by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. The patients were grouped into three groups by prostate-specific antigen (PSA) level (<10 ng/ml, 10-19.9 ng/ml, and 20+ ng/ml) and further subgrouped into six subgroups by favorable (T1, 2A and Gleason score < or =6 and no perineural invasion) and unfavorable characteristics (one or more of T2B, T3, Gleason 7-10, perineural invasion). Dose comparisons for bNED studies were made for each of the six subgroups by dividing patients at 76 Gy for all subgroups except the favorable <10 ng/ml subgroup, which was divided at 72.5 Gy. Five-year bNED rates were compared for the median dose of each dose comparison subgroup. Dose response functions were plotted based on 5-year bNED rates for the six patient groupings, with the data from each of the six subgroups divided into three dose groups. The 5-year bNED rate was also estimated using the dose response function and compares 73 Gy with 78 Gy. RESULTS: Dose comparisons show a significant difference in 5-year bNED rates for three of the six subgroups but not for the favorable <10 ng/ml, the favorable 10-19.9 ng/ml, or the unfavorable > or =20 ng/ml subgroups. The significant differences ranged from 22% to 40% improvement in 5-year bNED with higher dose. Dose response functions show significant differences in 5-year bNED rates comparing 73 Gy and 78 Gy for four of the six subgroups. Again, no difference was observed for the favorable <10 ng/ml group or the unfavorable > or =20 ng/ml group. The significant differences observed in 5-year bNED ranged from 15% to 43%. CONCLUSIONS: Dose response varies by patient subgroup, and appropriate dose can be estimated for up to six subdivisions of prostate cancer patients. The appropriate use of high dose with 3D CRT results in 5-year cure rates that equal or exceed other treatments. The national practice must be upgraded to allow the safe administration of 75-80 Gy with 3D CRT.

Outcome and predictive factors for patients with Gleason score 7 prostate carcinoma treated with three-dimensional conformal external beam radiation therapy.

BACKGROUND: The purpose of this study was to determine the biochemical outcome and factors predictive of outcome in prostate carcinoma patients with Gleason score 7 tumors who were treated with three-dimensional conformal radiation therapy (3DCRT). METHODS: Between August 1990 and October 1997, 163 T1-T3NXM0 prostate carcinoma patients with Gleason score 7 were treated with definitive 3DCRT alone. The median follow-up, International Commission on Radiological Units dose, and pretreatment prostate specific antigen (PSA) for the entire group were 50 months, 76 grays (Gy), and 11.4 ng/mL, respectively. Independent predictors based on multivariate results were used to stratify the patients into prognostic groups for which biochemical no evidence of disease (bNED) control was reported. Biochemical NED failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS: The 5-year bNED control for all patients was 66%. Stratified by pretreatment PSA, 5-year bNED control rates were 83%, 65%, and 21% for 0-9.9 ng/mL, 10-19.9 ng/mL, and > or =20 ng/mL, respectively. Dose to the central axis was found to be a significant treatment factor, with patients receiving > or =76 Gy experiencing 76% 5-year bNED control versus 54% when treated with <76 Gy to isocenter. Pretreatment PSA, dose, and palpation stage were significant independent predictors for bNED control upon multivariate analysis. Patients with a PSA <10 ng/mL who received a dose of > or =76 Gy had excellent 5-year bNED control of 100% compared with 50% bNED if patients had PSA >10 ng/mL or received radiation therapy doses of <76 Gy. CONCLUSIONS: Patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL and received doses of > or =76 Gy had excellent 5-year bNED control, emphasizing the importance of higher central axis doses in treating Gleason 7 tumors. Patients with intermediate PSA (10-19.9 ng/mL) also required doses > or =76 Gy. Pretreatment PSA > or = 20 ng/mL portends a very poor bNED outcome for Gleason 7 patients treated with radiation therapy alone, and thus efforts should be directed toward multimodal or long term hormonal treatment strategies.

Pancreatic cancer.

Optimal therapy for pancreatic adenocarcinoma requires surgical removal with tumor-free margins. Superior outcomes have been reported for high-volume centers incorporating a multidisciplinary approach. Postoperative ("adjuvant") chemotherapy and radiation should be considered in patients with successfully resected primary tumors. Combined modality treatment with chemotherapy and radiation should be considered for locally advanced, unresectable tumors. Gemcitabine can provide symptom relief and a modest improvement in survival for patients with metastatic disease. Strict attention to relief of symptoms such as pain, depression, anorexia/cachexia, and jaundice is essential in all patients with pancreatic cancer. All patients with pancreatic cancer should be encouraged to enter clinical trials of new therapies, given that long-term survival for all stages remains poor.

The cost effectiveness of 3D conformal radiation therapy compared with conventional techniques for patients with clinically localized prostate cancer.

BACKGROUND: We previously demonstrated the advantages of three-dimensional conformal radiation therapy (3DCRT) in improved rates of biochemical (bNED) control in certain subsets of patients with clinically localized prostate cancer. However, in this era of cost consciousness and limited resources, the cost effectiveness of 3DCRT compared with conventional external beam irradiation (CRT) remains unexamined. METHODS AND MATERIALS: Between October 1, 1987 and November 30, 1991, 193 patients with clinically localized prostate cancer received definitive external beam irradiation at Fox Chase Cancer Center. The 1998 Medicare fee schedule was used to determine treatment charges and to provide a reference for a national comparison. Complete charges for pretreatment work-up, treatment, and follow-up were tabulated for each patient. The mean total charges (MTC) using the Lin method of estimating medical costs was used to analyze and compare costs between groups. A matched case/control analysis was performed to further evaluate the effect of cost between techniques. The median follow-up was 72 months (range 3-118). RESULTS: The overall 5-year actuarial rate of bNED control was 41% and 53%, respectively, for the CRT and 3DCRT patients (p = 0.03). The MTC for the CRT patients was $10,544.53. For the 3DCRT patients, the MTC was $8,955.48. The sample mean of the total costs from the observed deaths for the two patient groups by follow-up interval ranged from $9,800.63 to $59,635.01 for the CRT patients to $17,259.00 to $24,250.38 for the 3DCRT patients. No statistically significant difference in cost was observed between groups using the matched case/control analysis. CONCLUSION: Initial work-up and treatment costs were greater for patients treated with 3DCRT compared with patients treated with conventional techniques. However, with longer follow-up, the mean total cost of treatment was not statistically different between the two treatment groups. Because of improved rates of bNED control for these patients and the increased costs associated with the treatment of a greater fraction of patients with recurrent disease following CRT, 3DCRT was cost effective for patients with clinically localized prostate cancer.

Is there a role for short-term hormone use in the treatment of nonmetastatic prostate cancer?

We reviewed our institution's experience treating patients with prostate cancer with 3-dimensional conformal radiation therapy (3DCRT) and short-term adjuvant hormonal therapy to determine biochemical no evidence of disease (bNED) and clinical outcome compared with patients treated with 3DCRT alone. Between 4/1/89 and 11/30/94, 558 patients with clinically localized prostate cancer received treatment at Fox Chase Cancer Center (Philadelphia, Pa.); 484 patients were treated with 3DCRT alone (Group I); 74 patients were treated with 3DCRT and hormones (Group II). Five-year actuarial rates of bNED control, distant metastasis-free survival (DMFS), cause-specific survival (CSS), and overall survival (OS) were calculated for pretreatment PSA, Gleason score, T stage, use of hormones, treatment field size, age, and dose. A matched case/control analysis was performed to further evaluate the effect of hormones on treatment with 3DCRT. Median follow-up was 47 months (range: 2-97 months). The 5-year actuarial rates of bNED control, DMFS, CSS, and OS were 66%, 93%, 98%, and 86%, respectively, for Group I patients and 68%, 93%, 98%, and 89%, respectively, for Group II patients. Multivariate analysis demonstrated that hormone use was an independent predictor of bNED control only. A significant difference in bNED control was observed between Group I and II (43% vs. 71%) using the matched case/control analysis (P = 0.02). A trend towards significance was observed for different rates of DMFS between Group I and II (79% vs. 94%, P = 0.09). Patients with clinically localized prostate cancer with poor prognostic features (pretreatment PSA > or = 10 ng/ml, Gleason score > or = 7, and/or T2c or greater palpation stage) show improved rates of bNED control and a trend towards improved DMFS when treated with 3DCRT and short-term adjuvant hormones compared with 3DCRT alone. Long-term observation will be necessary to see if improvements in bNED control will translate into improvements in overall survival.

Racial differences in insulin-like growth factor binding protein-3 in men at increased risk of prostate cancer.

OBJECTIVES: To determine the overall plasma levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in a group of men at higher risk of prostate cancer development and to investigate the relationships between demographics and these levels, particularly with regard to race. METHODS: An enzyme-linked immunosorbant assay was used to quantitate plasma levels of IGF-1 and IGFBP-3. The study group consisted of 105 men (63 African American [AA], 42 white), aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were AA. Differences in plasma levels and categorical covariates were assessed using the nonparametric Wilcoxon test. Associations between plasma levels and the continuous variables were quantified using the nonparametric Spearman correlation coefficient. RESULTS: The mean plasma level of IGF-1 was not significantly different between AA (162.3 ng/mL) and white (172.1 ng/mL) men (P = 0.415). However, the mean plasma level of IGFBP-3 was lower in AA (2789 ng/mL) than in white (3216 ng/mL) men, and this decrease was highly significant (P = 0.0045). No correlation between IGFBP-3 plasma level and age was detected in the group as a whole, but an inverse relationship between IGF-1 plasma level and age was evident (P = 0.0079). CONCLUSIONS: Our results demonstrate that IGFBP-3 plasma levels are lower in AA men than in white men. Since IGFBP-3 can control IGF-1 bioavailability, the lowered IGFBP-3 could explain in part the increased risk of prostate cancer in AA men.

Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy.

PURPOSE: The value of treating prostate cancer has been questioned, and some insist that a survival benefit is demonstrated to justify treatment. Prospective dose-escalation studies with three-dimensional conformal radiotherapy technique have demonstrated improvement in biochemical freedom from disease and local control. We report the outcomes of high-dose treatment with three-dimensional conformal radiotherapy compared with low-dose treatment for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival. PATIENTS AND METHODS: The study design was retrospective, involving pairs matched on independent prognostic variables in which each patient treated with low-dose radiotherapy was matched with a patient treated with high-dose radiotherapy. Outcomes were compared for two groups of patients: Group I: Three-dimensional conformal radiotherapy treatment--296 patients treated with more than 74 Gy matched on stage, grade, and prostate-specific antigen level, to 296 patients treated with less than 74 Gy. Group II: Three-dimensional conformal radiotherapy treatment--357 patients treated with more than 74 Gy matched on stage and grade to 357 patients treated with less than 74 Gy. RESULTS: Univariate analysis showed that dose is a significant predictor of biochemical freedom from disease, freedom from distant metastasis, and cause-specific survival for group I and biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival for group II. Multivariate analysis showed that dose is a significant independent predictor in group I for biochemical freedom from disease and freedom from distant metastasis and for biochemical freedom from disease, freedom from distant metastasis, cause-specific survival, and overall survival in group II. DISCUSSION: These data provide strong support for the definitive treatment of prostate cancer with high-dose (> 74 Gy) three-dimensional conformal radiotherapy. These doses can be safely delivered with three-dimensional conformal radiotherapy techniques. Various institutions and industry must collaborate to expand the technology allowing the use of high-dose three-dimensional conformal radiotherapy in the national practice beyond centers of technological excellence.

Is there a subset of patients with PSA > or = 20 ng/ml who do well after conformal beam radiotherapy?

To determine if there is a subgroup of patients with pretreatment PSA > or = 20 ng/ml with a favorable outcome after external beam radiation therapy. We analyzed retrospectively treatment outcomes of 129 patients with pretreatment PSA > or = 20 ng/ml treated in our department from 2/88-8/94. Median patient age was 70 years (range 51-89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients. Initial Gleason grade was < 7 in 82 and > or = 7 in 47 patients. Median PSA was 35 ng/ml (mean 45 ng/ml, range 20-191 ng/ml). Ninety-seven patients received four-field conformal external beam radiation therapy. No patient received surgery or hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68-79 Gy). Covariates considered in univariate and multivariate analyses included central axis dose, pretreatment PSA, presence of perineural invasion, Gleason score, palpable tumor stage and patient age. bNED failure was defined as a PSA > or = 1.5 and rising on two consecutive determinations. Median follow up was 50 months (range 3-100 months). Overall bNED control for the entire patient population was 22% at five years. Of the covariates analyzed, dose (P < 0.01), stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01) were significant on multivariate analysis. Based on these results, patients could be stratified into two distinct groups. Group I consisted of 19 patients with favorable features including T1/T2ab disease, Gleason Score 2-6, no perineural invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had at least one of the above poor prognostic features or were treated to central axis doses < 73 Gy. The bNED control was significantly higher for patients in Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a favorable subgroup of patients with PSA > or = 20 ng/ml where treating to doses over 73 Gy to the central axis is warranted (four-year bNED rate of 58%). However, because of the small patient numbers, these results will need to be validated with longer follow up.

Outcome evaluation of the 1997 American Joint Committee on Cancer staging system for prostate carcinoma treated by radiation therapy.

BACKGROUND: The 1997 American Joint Committee on Cancer (AJCC) staging system condensed unilobular tumors into one entity and continues the use of both imaging and biopsy to alter classification status in T2 and T3 carcinomas. This study analyzes the biochemical freedom from disease recurrence (bNED) outcome in a large database to determine whether these changes reflect outcome differences. METHODS: Five hundred and thirty-seven patients with adenocarcinoma of the prostate were treated with radiation therapy to a median dose of 7180 centigrays (cGy) (range, 6316-8074 cGy) between November 1987 and November 1994. The median age of the patients was 70 years and the median follow-up was 51 months. The median pretreatment prostate specific antigen (PSA) was 11.0 ng/mL. Patients were analyzed using 1992 AJCC stage comparing bNED outcome after radiation therapy for T2a versus T2b versus T2c tumors using Kaplan-Meier estimation and the log rank test. Patients then were analyzed multivariately using Cox regression with the known prognostic variables of dose, pretreatment PSA, palpation stage, and grade in addition to palpation plus imaging stage and palpation plus biopsy stage. The prognostic endpoint was bNED with failure as defined by the 1997 American Society for Therapeutic Radiology and Oncology Consensus Panel. RESULTS: The 1992 AJCC palpation classifications T2a versus T2b versus T2c have a significantly different (P = 0.02) bNED outcome. Prognostic significance is lost by pooling these three classifications in the 1997 AJCC staging system. Adding imaging information to palpation did not improve the ability of palpation alone to assess bNED status (P = 0.33). However, the addition of biopsy information to palpation significantly (P = 0.02) increased the accuracy of palpation stage alone to predict for bNED outcome for T2 and T3 tumors. CONCLUSIONS: The subdivision of T2 tumors in the 1992 AJCC classification (T2a, T2b, and T2c) should be used in the next revision of the 1997 AJCC staging system. The addition of imaging data does not discriminate bNED outcome any better than palpation stage alone in T2 and T3 tumors and should not be used. The addition of biopsy information to palpation stage did significantly improve the predicted outcome compared with palpation alone and should continue to be used.