Differential expression of HER-2/NEU receptor of invasive mammary carcinoma between Caucasian and African American patients in the Detroit metropolitan area. Correlation with overall survival and other prognostic factors.

GOALS: HER-2/neu overexpression in invasive mammary carcinoma is associated with more aggressive biologic behavior. Breast cancer in African American (AA) women has been associated with a shorter survival rate than that seen in Caucasians (C). This study evaluated the frequency of HER-2/neu overexpression in C compared to AA patients and the association of HER-2/neu expression with overall survival and other prognostic factors. METHODS: A retrospective review of the SEER data of Karmanos Cancer Institute for patients with invasive mammary carcinoma was conducted between 1998 and 2001. Pathology reports and pathology slides were obtained for those patients with missing data. Available data and material on 608 patients were found. The median follow-up interval was 35 months with a range of 1-91 months. 46.7% of the study population was C while 53.3% was AA. The differential of HER-2/neu expression in C and AA was evaluated. The association of HER-2/neu expression and other prognostic factors with overall survival was carried out by univariate and multivariable analyses using Cox's proportional hazards regression model. PRINCIPLE RESULTS: No statistically significant difference was found in HER-2/neu expression between C and AA patients. Overexpression of HER-2/neu did not correlate with decreased overall survival in this analysis. MAJOR CONCLUSIONS: Breast cancer HER-2/neu expression in AA patients is not statistically different from that of Caucasians. HER-2/neu expression is not associated with overall survival. Among the other prognostic factors analyzed, ER status and histologic grade were not statistically significant.

Genistein potentiates the radiation effect on prostate carcinoma cells.

We have shown previously that genistein, the major isoflavone in soybean, inhibited the growth of human prostate cancer cells in vitro by affecting the cell cycle and inducing apoptosis. To augment the effect of radiation for prostate carcinoma, we have now tested the combination of genistein with photon and neutron radiation on prostate carcinoma cells in vitro. The effects of photon or neutron radiation alone or genistein alone or both combined were evaluated on DNA synthesis, cell growth, and cell ability to form colonies. We found that neutrons were more effective than photons for the killing of prostate carcinoma cells in vitro, resulting in a relative biological effectiveness of 2.6 when compared with photons. Genistein at 15 microM caused a significant inhibition in DNA synthesis, cell growth, and colony formation in the range of 40-60% and potentiated the effect of low doses of 200-300 cGy photon or 100-150 cGy neutron radiation. The effect of the combined treatment was more pronounced than with genistein or radiation alone. Our data indicate that genistein combined with radiation inhibits DNA synthesis, resulting in inhibition of cell division and growth. Genistein can augment the effect of neutrons at doses approximately 2-fold lower than photon doses required to observe the same efficacy. These studies suggest a potential of combining genistein with radiation for the treatment of localized prostate carcinoma.

Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model.

We have shown that implantation of human prostate carcinoma PC-3 cells in the prostates of nude mice led to the formation of prostate tumors with metastases to para-aortic lymph nodes. We found that day 6 prostate tumors were responsive to systemic injections of interleukin 2 (IL-2) therapy. We have now investigated the combination of primary tumor irradiation and IL-2 for metastatic prostate cancer in this preclinical tumor model. The effect of neutron radiation was compared with that of photon radiation. Advanced prostate tumors (approximately 0.4 cm) were irradiated, and a day later, mice were treated with systemic IL-2 for three weekly cycles. In separate experiments, mice were either sacrificed on day 30 to assess prostate tumor size and tumor histology or followed for survival. A dose-dependent inhibition of prostate tumor growth was caused either by photons or neutrons, but neutrons were more effective than photons with a relative biological effectiveness of 2. The tumor inhibition obtained with 250 cGy neutrons and 500 cGy photons was significant (>75%) and was further increased (> or = 90%) by addition of IL-2 therapy. In survival studies, the combination of radiation and IL-2 showed a significant survival advantage compared with untreated mice (P < or = 0.005) or radiation alone (P < or = 0.003) and an increase in median survival compared with IL-2 alone. Histologically, the combined regimen resulted in a greater degree of tumor destruction, inflammatory response, and vascular damage than that observed with each modality alone. After this combined treatment, no tumor was histologically detected in the para-aortic lymph nodes of these mice, and the lymph nodes were significantly smaller. These findings showed that primary tumor irradiation, either with neutrons or photons, enhanced IL-2 therapeutic effect for the treatment of advanced prostate cancer. This combined modality induced an antitumor response that controlled the growth of prostate tumors and their metastases.

Dosimetric improvements following 3D planning of tangential breast irradiation.

PURPOSE: To evaluate the dosimetric difference between a simple radiation therapy plan utilizing a single contour and a more complex three-dimensional (3D) plan utilizing multiple contours, lung inhomogeneity correction, and dose-based compensators. METHODS AND MATERIALS: This is a study of the radiation therapy (RT) plans of 85 patients with early breast cancer. All patients were considered for breast-conserving management and treated by conventional tangential fields technique. Two plans were generated for each patient. The first RT plan was based on a single contour taken at the central axis and utilized two wedges. The second RT plan was generated by using the 3D planning system to design dose-based compensators after lung inhomogeneity correction had been made. The endpoints of the study were the comparison between the volumes receiving greater than 105% and greater than 110% of the reference dose, as well as the magnitude of the treated volume maximum dose. Dosimetric improvement was defined to be of significant value if the volume receiving > 105% of one plan was reduced by at least 50% with the absolute difference between the volumes being 5% or greater. The dosimetric improvements in 49 3D plans (58%) were considered of significant value. Patients' field separation and breast size did not predict the magnitude of improvement in dosimetry. CONCLUSION: Dose-based compensator plans significantly reduced the volumes receiving > 105%, >110%, and volume maximum dose.

The impact of race on biochemical disease-free survival in early-stage prostate cancer patients treated with surgery or radiation therapy.

PURPOSE: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy. METHODS: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2-70) for CM and 35 months (range 1-70) for AAM. RESULTS: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group (p = 0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM (p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM (p = NS). For patients with PSA < or =15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA >15 were 61% for CM and 64% for AAM (p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA (p = 0.0001) and Gleason score (p = 0.0001). CONCLUSION: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.

Association of prostate size with urinary morbidity following mixed conformal neutron and photon irradiation.

PURPOSE: This study was designed to characterize the relationship between the observed rate of postradiation genitourinary (GU) complications and the prostate gland size. METHODS AND MATERIALS: Two hundred seventy-three patients received conformal neutron and photon irradiation to the prostate seminal vesicles. Data on post-treatment urinary morbidity were collected and examined in relationship to a number of clinical and technical factors. RESULTS: With a median follow-up of 30 months (range 7-61), the 4-year rate of Grade 2 or higher GU complications was 21%. On univariate analysis, the risk of complications was significantly associated with prostate size and neutron beam arrangement. On multivariate analysis, only the prostate size was significantly associated with the risk of GU morbidity. Patients with a preradiation prostate volume more than 74 cc had a two and a half fold increase in the risk of complications compared to patients with smaller glands. CONCLUSION: Patients with an enlarged prostate have a significantly higher risk of chronic GU complications. Although these data were obtained for patients receiving combined neutron and photon irradiation, it is likely that these data would also be applicable for those patients receiving photon irradiation as well. These observations may add an additional rationale for the study of preirradiation hormonal treatment.

Development and clinical implementation of an enhanced display algorithm for use in networked electronic portal imaging.

PURPOSE: To introduce and clinically validate a preprocessing algorithm that allows clinical images from an electronic portal imaging device (EPID) to be displayed on any computer monitor, without loss of clinical usability. The introduction of such a system frees EPI systems from the constraints of fixed viewing workstations and increases mobility of the images in a department. METHODS AND MATERIALS: The preprocessing algorithm, together with its variable parameters is introduced. Clinically, the algorithm is tested using an observer study of 316 EPID images of the pelvic region in the framework of treatment of carcinoma of the cervix and endometrium. Both anterior-posterior (AP/PA) and latero-lateral (LAT) images were used. The images scored were taken from six different patients, five of whom were obese, female, and postmenopausal. The result is tentatively compared with results from other groups. The scoring system, based on the number of visible landmarks in the port, is proposed and validated. Validation was performed by having the observer panel score images with artificially induced noise levels. A comparative study was undertaken with a standard automatic window and leveling display technique. Finally, some case studies using different image sites and EPI detectors are presented. RESULTS: The image quality for all images in this study was deemed to be clinically useful (mean score >1). Most of the images received a score which was second highest (AP/PA landmarks > or =6 and LAT landmarks > or =5). Obesity, which has been an important factor determining the image quality, was not seen to be a factor here. Compared to standard techniques a highly significant improvement was determined with regard to clinical usefulness. The algorithm performs fast (less than 9 seconds) and needs no additional user interaction in most of the cases. The algorithm works well on both direct detection portal imagers and camera-based imagers whether analog or digital cameras. CONCLUSIONS: We have demonstrated that it is possible to preprocess EPIs in such a way that the clinically relevant landmarks are easily detected on a generic computer screen. The algorithm is system-independent and fast. This allows for the encoding of EPIs in more generalized commercial formats so that distribution of images is facilitated.

Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas.

PURPOSE: To date, numerous retrospective studies have suggested that the addition of brachytherapy to the conventional treatment of malignant gliomas (MG) (surgical resection followed by radiotherapy +/- chemotherapy) leads to improvements in survival. Two randomized trials have suggested either a positive or no survival benefit with implants. Critics of retrospective reports have suggested that the improvement in patient survival is due to selection bias. A recursive analysis by the RTOG of MG trials has stratified MG patients into 6 prognostically significant classes. We used the RTOG criteria to analyze the implant data at Wayne State University to determine the impact of selection bias. METHODS AND MATERIALS: Between July 1991 and January 1998, 75 patients were treated with a combination of surgery, radiotherapy, and stereotactic I-125 implant as primary MG management. Forty-one (54.7%) were male; 34 (45.3%) female. Median age was 52 years (range 4-79). Twenty-two (29.3%) had anaplastic astrocytoma (AA); 53 (70.7%), glioblastoma multiforme (GBM). Seventy-two patients had data making them eligible for stratification into the 6 RTOG prognostic classes (I-VI). Median Karnofsky performance status (KPS) was 90 (range 50-100). There were 14, 0, 14, 31, 12, and 1 patients in Classes I to VI, respectively. Median follow-up time for AA, GBM, and any surviving patient was 29, 12.5, and 35 months, respectively. RESULTS: At analysis, 29 (40.3%) patients were alive; 43 (59.7%), dead. For AA and GBM patients, 2-year and median survivals were: 58% and 40%; 38 and 17 months, respectively. For analysis purposes, Classes I and II, V and VI were merged. By class, the 2-year survival for implanted patients compared to the RTOG data base was: III--68% vs. I--76%; III--74% vs. 35%; IV--34% vs. 15%; V/VI--29% vs. V--6%. For implant patients, median survival by class was (in months): I/II--37; III--31; IV--16; V/VI--11. CONCLUSION: When applied to MG patients receiving permanent I-125 implant, the criteria of the RTOG recursive partitioning analysis are a valid tool to define prognostically distinct survival groups. As reflected in the RTOG study, a downward survival trend for the implant patients is seen from "best to worse" class patients. Compared to the RTOG database, median survival achieved by the addition of implant is improved most demonstrably for the poorer prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with I-125 implant and would contradict the notion that the patients most eligible for implant are those gaining the most benefit from the treatment. In light of the contradictory results from two randomized studies and given the present results, further randomized studies with effective stratification are required since the evidence for a survival benefit with brachytherapy (as seen in retrospective studies) is substantial.

Responsiveness of human prostate carcinoma bone tumors to interleukin-2 therapy in a mouse xenograft tumor model.

We have tested an immunotherapy approach for the treatment of metastatic prostate carcinoma using a bone tumor model. Human PC-3 prostate carcinoma tumor cells were heterotransplanted into the femur cavity of athymic Balb/c nude mice. Tumor cells replaced marrow cells in the bone cavity, invaded adjacent bone and muscle tissues, and formed a palpable tumor at the hip joint. PC-3/IF cell lines, generated from bone tumors by serial in vivo passages, grew with faster kinetics in the femur and metastasized to inguinal lymph nodes. Established tumors were treated with systemic interleukin-2 (IL-2) injections. IL-2 significantly inhibited the formation of palpable tumors and prolonged mouse survival at nontoxic low doses. Histologically IL-2 caused vascular damage and infiltration of polymorphonuclear cells and lymphocytes in the tumor as well as necrotic areas with apoptotic cells. These findings suggest destruction of tumor cells by systemic IL-2 therapy and IL-2 responsiveness of prostate carcinoma bone tumors.

Postneoadjuvant hormone PSA levels and prognosis in locally advanced prostate cancer.

OBJECTIVES: To determine whether the response to hormonal therapy before radiation predicts the rate of biochemical relapse in patients with locally advanced prostate cancer. METHODS: Between October 1991 and December 1997, 105 patients with locally advanced adenocarcinoma of the prostate received radiotherapy in two dose-escalation studies. Sixty-seven patients received neoadjuvant hormonal therapy. The mean and median duration of hormonal therapy before radiotherapy was 4 months each. All treatments were designed using three-dimensional conformal therapy. The total dose to the gross tumor volume ranged from 73 to 87 Gy in 2 Gy per fraction photon equivalent dose. The median follow-up time was 30 months (range 1 to 66). RESULTS: The median prostate-specific antigen (PSA) nadir after neoadjuvant hormonal therapy but before radiotherapy was 1.7 ng/mL (range less than 0.05 to 71.2). The median nadir after radiation for patients who did and did not receive neoadjuvant androgen deprivation was 0.25 ng/mL (range less than 0.05 to 6.2) and 1.35 ng/mL (range 0.08 to 10), respectively. Median time to achieve nadir was 6 months (range 1 to 42) with and 12 months (range 1 to 48) without hormonal therapy. There was no significant difference in the rate of biochemical failure for patients with a posthormone (before irradiation) PSA nadir less than 1 ng/mL versus 1 ng/mL or greater (overall P = 0.9). However, there was a significant difference in biochemical no evidence of disease rates between those with a PSA nadir less than 1 ng/mL and those with a PSA nadir of 1 ng/mL or greater after radiation (63% versus 22% at 3 years, overall P <0.001). CONCLUSIONS: Our data showed that the initial response to hormonal therapy before radiation, as indicated by the PSA level, did not impact on the rate of recurrence. However, the time to reach nadir and the absolute nadir level achieved were lower in patients who did receive hormonal therapy.

Value of radiation therapy in the management of chemoresistant intermediate grade non-Hodgkin's lymphoma.

The purpose of this study was to evaluate the probability and extent of response to radiation therapy in patients with chemotherapy-resistant intermediate grade non-Hodgkin's lymphoma. Thirty-five patients with chemotherapy-resistant non-Hodgkin's lymphoma received local radiation therapy after initial treatment with at least six cycles of systemic chemotherapy. There were 17 men and 18 women in our study. Ages ranged from 15 to 68 years, median age was 42 years. Chemotherapy resistance was defined as relapse after initial chemotherapy (11 patients) or failure to achieve complete remission (partial response in 18 patients, stable disease in 1 patient, and disease progression in 5 patients). Radiation doses were between 1,980-5,040 cGy (median dose of 3,200 cGy). Treatment outcome was evaluated with respect to any subsequent relapse either within or outside the irradiated region. The 2-year actuarial survival was 65%. The cumulative incidence of isolated local failure and any local failure at 2 years were 33% and 54%, respectively. Tumors that responded to initial chemotherapy had a better local control probability than tumors that did not respond. The 2-year actuarial local failure rates for these two groups were 51% and 83%, respectively (P = 0.01). There was a trend for improved local control with radiation doses > or = 3,960 cGy, suggesting the presence of a dose-control relationship. The rate of disease progression within an irradiated region in patients with intermediate grade non-Hodgkin's lymphoma that relapsed after or failed to respond completely to full course chemotherapy was substantially higher than the historical in-field failure rates when radiation therapy was used as the sole modality of treatment. Prior response to initial chemotherapy was a predicting factor for local control following radiation therapy.

Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model.

Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.

Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy.

OBJECTIVES: To evaluate the relationship between the postprostatectomy prostate-specific antigen (PSA) nadir and the outcome of patients treated with salvage radiotherapy. METHODS: Seventy-eight patients received definitive external beam radiation for recurrence following radical prostatectomy (RP). The PSA nadir was undetectable in 41 patients (less than 0.05 ng/mL). All patients received salvage radiotherapy (median dose 66 Gy) for a median of 19 months (range 2 to 149) following prostatectomy. The median follow-up time was 25 months (range 1 to 59) from the date of completion of radiation. RESULTS: Among patients having an undetectable or detectable postoperative PSA, 78% and 68% were free of disease, respectively, at the last follow-up. At 3 years, the disease-free survival rates were 65% and 60%, respectively (P = 0.6). Overall, the disease-free survival rate at 3 years was 78% in patients with a PSA level 2 ng/mL or less at the time of radiotherapy compared to 31% with a PSA greater than 2 ng/mL (P < 0.0001). CONCLUSIONS: Many patients who never achieve an undetectable postprostatectomy PSA level may still be salvaged with therapeutic radiotherapy. The best predictor of a favorable outcome is a low (2 ng/mL or less) PSA level at the time of radiation.

Increased risk and decreased morbidity of coronary artery bypass grafting between 1986 and 1994.

BACKGROUND: The collective impact of advances in medical, surgical, and anesthetic care on the characteristics and outcomes of patients who undergo coronary artery bypass grafting was assessed. METHODS: We compared the demographic and clinical characteristics, preoperative risk factors, morbidity, and mortality of two groups of patients who underwent coronary artery bypass grafting in isolation or in combination with other procedures between July 1, 1986, and June 30,1988 (group 1, n = 5,051), and between January 1, 1993, and March 31, 1994 (group 2, n = 2,793). The patients were stratified according to their preoperative risk level. Outcome measures consisted of changes in preoperative risk categories; hospital mortality rates; overall and risk-adjusted major cardiac, neurologic, pulmonary, renal, and septic morbidity rates; and intensive care unit length of stay. RESULTS: Changes in the distribution of risk categories, from a median of 2 to 4 on a 9-point scale (p < 0.001), indicated that patients in group 2 were at significantly higher risk than those in group 1. The risk-adjusted mortality rate did not change (2.8% to 2.9%; p = 0.15), but the risk-adjusted morbidity rate decreased significantly (14.5% to 8.8%; p < 0.001). CONCLUSIONS: At our institution, patients who undergo coronary artery bypass grafting are now at greater preoperative risk at the time of hospital admission. However, their morbidity rate is significantly lower and their mortality rate is unchanged, results that we attribute to the collective impact of changes in our medical and surgical procedures.