The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate.
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Carcinoma↗
Biomedical subjects
Z Fuks
Publications and source records attributed to Z Fuks.
Localized carcinoma of the prostate (stages T1B, T1C, T2, and T3). Review of management with external beam radiation therapy.
BACKGROUND: Optimal treatment for patients with localized carcinoma of the prostate is controversial. Radiation therapy is an established modality in the management of these patients, and several reports indicate the results are comparable to those achieved with radical prostatectomy. Recently effectiveness of therapy for carcinoma of the prostate is being evaluated in light of post-treatment prostate-specific antigen (PSA) determinations. METHODS: A review was performed of multiple publications and data from selected institutions with large experience in the management of carcinoma of the prostate. Survival and clinical incidence of local recurrence and distant metastases were analyzed as well as preliminary data on postirradiation PSA levels. Factors that affect the outcome of therapy and relevant clinical trials are discussed. RESULTS: Reported differences in the age of patients treated with radical prostatectomy (59-63 years), irradiation (63-69 years), or observation (69-75.5 years) were identified. The effect of surgical staging on outcome of irradiation was significant. In multiple series of patients clinically and radiographically staged, the 5-year disease-free survival (DFS) with external irradiation was 95-100% for clinical stage T1a, 80-90% for Stage T1b,c, and 50-70% for clinical Stage T3. A correlation has been identified between the initial PSA levels and the probability from freedom of chemical failure (PSA elevation) after definitive irradiation. In five series comprising 814 patients with Stage T1c and T2 tumors, the DFS (end point chemical failure) was 95%, with initial PSA of less than 4 ng/ml, 83-92% with 4.1-10 ng/ml, 35-85% with 10.1-20 ng/ml, and 10-63% with PSA higher than 20 ng/ml. In the various series, follow-up ranged from a median of 1.5 years to a minimum of 4 years. In two series of 225 and 201 patients receiving doses of 7500-8000 cGy, less morbidity has been observed with three-dimensional treatment planning conformal radiation therapy than with conventional irradiation. New directions for future clinical trials are discussed, including dose escalation studies; use of high linear energy transfer to improve locoregional tumor control; and combination of irradiation and androgen suppression to enhance local tumor control, decrease distant metastasis, and improve survival. Preliminary results of a randomized study recently reported by RTOG strongly suggest that the use of goserelin acetate and flutamide decreases the incidence of clinical local recurrence (12.4% in 225 patients) compared with a control group treated with irradiation alone (25.2% in 230 patients) and enhances disease-free survival. CONCLUSIONS: Although modern approaches to the management of patients with localized carcinoma of the prostate with irradiation are effective, investigators must continue to critically assess policies of treatment, develop appropriately designed prospective clinical trials, and define the optimal management of patients with localized carcinoma of the prostate.
Carcinoma↗
The effect of setup uncertainties on the treatment of nasopharynx cancer.
PURPOSE: As radiation treatment techniques become more complicated, the need to understand the effect of uncertainties on dose distributions increases. This study investigates the effect of positional uncertainities for patients with nasopharynx carcinoma treated with a multiple field conformal boost technique. Three dimensional setup errors were measured for six patients and the effect on patient dose was evaluated using dose volume histograms. METHODS AND MATERIALS: A method is presented for determining 3-dimensional translational and rotational setup errors by identifying anatomical landmarks on two treatment field images and their corresponding simulation images. Measurements were made on a daily basis for six patients undergoing conformal treatment. RESULTS: The average magnitude of the translational errors was between 1.5 and 3 mm while the average distance between simulation and treatment isocenters was 5 mm. Both systematic and random setup errors were observed. Dose volume histograms incorporating these uncertainties for standard parallel opposed and conformal techniques were generated for patients experiencing random and systematic setup errors. CONCLUSION: The data imply that positional uncertainties effect the daily dose distributions for target and critical structures differently and that the effect may be treatment technique dependent. These results demonstrate the need to measure setup uncertainties for all sites and to develop techniques for incorporating dose uncertainties in treatment plans.
Calibration↗
Refining the predictive power of the prostate-specific antigen.
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Humans↗
Three-dimensional conformal radiation therapy may improve the therapeutic ratio of high dose radiation therapy for lung cancer.
PURPOSE: The specific aim of 3-dimensional conformal radiation therapy is to improve the target dose distribution while concomitantly reducing normal tissue dose. Such an approach should permit dose escalation until the limits of acceptable normal tissue toxicity are reached. To evaluate the feasibility of tumor dose escalation for nine patients with lung cancer, we determined the dose distribution to the target and normal tissues with 3-dimensional conformal radiation therapy and conventional planning. METHODS AND MATERIALS: Plans were compared to assess adequacy of dose delivery to target volumes, dose-volume histograms for normal tissue, and normal tissue complication probabilities (NTCP) for nine patients with lung tumors. RESULTS: The mean percentage of gross disease which received < or = 70.2 Gy with 3-dimensional conformal radiation therapy (3DCRT) was 40% of the mean percentage of gross disease which received < or = 70.2 Gy with conventional treatment planning (CTP). The mean NTCP for lung parenchyma with 3DCRT was 36% of the mean NTCP with CTP. The mean esophageal NTCP with 3DCRT was 88% of the mean NTCP with CTP. CONCLUSION: This preliminary analysis suggests that three dimensional conformal radiation therapy may provide superior delivery of high dose radiation with reduced risk to normal tissue, suggesting that this approach may have the potential to improve the therapeutic ratio of high dose radiation therapy for lung cancer.
Adenocarcinoma↗
Modeling the development of metastases from primary and locally recurrent tumors: comparison with a clinical data base for prostatic cancer.
For many types of cancer, patients who relapse locally following localized treatment such as surgery or radiation therapy are found to have a higher incidence of distant metastases than those who are locally controlled. In this study we developed a mathematical model to investigate whether the excess distant metastases arise mainly from the local recurrence or whether the primary tumors in this group of patients have an intrinsically higher metastatic potential than those of locally controlled patients of the same clinical stage. The parameters of the model were chosen to be representative of prostate cancer and the calculated results were compared with published clinical data for carcinoma of the prostate. The best agreement with the data was seen for parameters which imply somewhat more "aggressive" primary tumors for locally relapsing patients, yielding relatively high rates of micrometastatic dissemination prior to initial diagnosis. However, the model calculations indicate that more than half of the metastases in such patients originated in association with the development of a local recurrence. Therefore, achieving local control in this group of patients would be beneficial in improving long term survival.
Computer Simulation↗
Conventional external beam radiation therapy for prostatic cancer: where do we go from here?
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Adenocarcinoma↗
Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma. Results of a prospective randomized study.
BACKGROUND: In a prospective randomized manner, this study evaluated the effect of adjuvant chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP) in patients with Stage I non-Hodgkin lymphoma (NHL) who have achieved a complete response (CR) after radiation therapy (RT). METHODS: Forty-four patients with clinical or pathologic Stage I intermediate-grade or low-grade NHL were randomized to receive regional RT alone (median dose, 40 Gy) or regional RT followed by six cycles of CHOP chemotherapy. There were no differences in clinical and pathologic characteristics between the two treatment groups. RESULTS: The median follow-up was 7 years (range, 2-10 years). The actuarial relapse-free survival (RFS) rate for the RT plus CHOP group at 7 years was 83% compared with 47% (P < 0.03) for the RT-alone group. The overall survival (OS) for the two groups was 88% and 66%, respectively (P = 0.2). In patients with intermediate-grade NHL, the 7-year actuarial RFS for RT and CHOP was 86% compared with 20% for RT alone (P = 0.004). The corresponding actuarial survival rates were 92% and 47%, respectively (P = 0.08). In patients with low-grade histologic findings, the addition of adjuvant CHOP did not improve RFS (P = 0.6) or OS. All relapses in this study were at sites remote from the initially involved areas, and in 5 of 11 patients (45%), there were recurrences 5 years or longer after initial treatment. CONCLUSIONS: This study showed that adjuvant CHOP chemotherapy significantly improves RFS in patients with Stage I intermediate-grade NHL who achieve a CR after regional-field RT. The chemotherapeutic regimen favorably affected their probability of survival.
Adult↗
Short-term morbidity from CT-planned transperineal I-125 prostate implants.
PURPOSE: To summarize short-term morbidity and tumor response following transperineal CT-guided I-125 prostate implantation. METHODS AND MATERIALS: Twenty-one patients were treated with CT-based transperineal I-125 prostate implantation between June, 1988 and May, 1990. An average of 75 I-125 seeds were placed, with an average activity of .62 mCi/seed. Symptoms were quantified after interviewing each patient in detail. RESULTS: Nearly all patients developed substantial dysuria, nocturia and frequency from 2-24 weeks following implantation. Urinary symptoms usually resolved within 4-6 months of implantation. The one year actuarial potency rate among 18 patients who were potent prior to implantation was 94%. By 6 months after implantation, 14/17 patients (82%) with Stage B tumors had complete regression of palpable disease. Of 17 patients with Stage A or B tumors who presented with an elevated PSA, 76% returned to the normal range within 6 months of implantation. CONCLUSION: CT-guided transperineal prostate implants entail moderate, temporary urinary and rectral morbidity. Short-term tumor responses are encouraging.
Brachytherapy↗
The use of a multi-leaf collimator for conformal radiotherapy of carcinomas of the prostate and nasopharynx.
We investigate the use of a multi-leaf collimator for conformal radiation therapy of carcinomas of the prostate and of the nasopharynx. Following verification of dose calculation algorithms for multi-leaf collimated fields using film dosimetry, we compute dose distributions for multi-field conformal treatment using fields shaped with either the multi-leaf collimator or conventional cerrobend blocks. We compare the two sets of treatment plans using graphical isodose displays, tissue specific dose volume histograms, tumor control probabilities, and normal tissue complication probabilities. We also incorporate setup errors into the calculated dose distributions to assess the effect of treatment uncertainties on the various criteria. Based on these comparisons, we conclude that for multi-field conformal radiotherapy for these two disease sites, the use of multi-leaf collimation is equivalent to that of conventional cerrobend blocks.
Adenocarcinoma↗
Tumor control probability for permanent implants in prostate.
The tumor control probabilities (TCPs) for 11 transperineal permanent implants of the prostate with 125I seeds have been computed, based on target-specific volume-dose histogram data. Prostate dose-response of this modality is converted from that of external beam therapy based on biologically effective dose derived from the alpha beta model. The calculated TCPs for these transperineal prostate cases are compared with the results of 679 previous retropubic implants, providing interesting insight about these two techniques. Further refinement and validation of this model await long-term followup results of sufficient number of patients.
Brachytherapy↗
Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma.
Between March 1970 and December 1987, 1,078 patients with adenocarcinoma of the prostate were treated with pelvic lymph node dissection and permanent 125iodine implantation. Before implantation, 257 patients (27%) underwent transurethral resection of the prostate, while 702 (73%) did not and their diagnosis was established by needle biopsy. A total of 119 patients (10%) underwent hormonal therapy before implantation and they were excluded from the present analysis. Clinical stage and pathological grade were similar in both groups. A higher percentage of patients in the transurethral resection group had nodal metastases at implantation. Positive lymph nodes were found in 121 patients (47%) in the transurethral resection group versus 199 (26%) who did not undergo resection (p < 0.001). The actuarial 5, 10 and 15-year distant metastasis-free survival rates among the patients who underwent transurethral resection of the prostate were 79%, 42% and 16%, respectively, compared to 86%, 52% and 27%, respectively, in the group without transurethral resection (p < 0.0001). Similarly, the actuarial disease-free and local relapse-free survival rates were significantly inferior in the transurethral resection group. A negative impact of transurethral resection of the prostate could be demonstrated among patients with grade I/II tumors. However, when stratified for nodal status, no difference in outcome in any clinical parameter was noted between the groups with and without transurethral resection of the prostate. Specifically, distant metastasis-free survival among transurethral resection group patients with negative nodes was 78%, 57% and 47% at 5, 10 and 15 years, respectively, compared to 80%, 59% and 47%, respectively, among the patients with negative nodes who did not undergo transurethral resection of the prostate (p = 0.38). Similarly, the differences between the 2 groups among patients with positive lymph nodes were not significant. When stratified by the clinical stage, grade and nodal status, the negative impact of transurethral resection of the prostate could not be demonstrated in any combination. A multivariate analysis failed to demonstrate transurethral resection of the prostate to be an independent variable in predicting the metastatic, local control or disease-free survival outcome. In conclusion, the long-term results in these pathologically staged cases indicate that transurethral resection of the prostate does not impact negatively on the clinical outcome.
Actuarial Analysis↗
Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease.
PURPOSE: To evaluate the feasibility and therapeutic effect of accelerated hyperfractionated total-lymphoid irradiation (TLI), high-dose chemotherapy, and autologous bone marrow transplantation (AuBMT) in patients with relapsing or chemotherapy-resistant Hodgkin's disease (HD). PATIENTS AND METHODS: Forty-seven patients with HD who either relapsed after chemotherapy (n = 19), or failed to respond (n = 28) to at least two regimens of combination chemotherapy were studied. No patient received prior radiation therapy (RT). Treatment started with reinduction with standard-dose chemotherapy, followed by involved-field irradiation (15 Gy) to areas of relapsed or persistent disease and TLI (20.04 Gy given in 1.67 Gy fractions three times per day for 4 days). Subsequently, patients received etoposide and high-dose cyclophosphamide, followed by infusion of unpurged autologous bone marrow. All surviving patients had a minimum follow-up duration of 1 year. The median follow-up duration for survivors was 40+ months, and the maximum follow-up duration was 80+ months. RESULTS: Of the 47 patients treated, eight (17%) died of toxicity during the peritransplant period. Twenty-nine of the remaining 39 assessable patients (74%) attained a complete response (CR), while 10 remained with residual disease and progressed early after AuBMT. Four of the CR patients (14%) relapsed and 25 patients remained alive and free of disease. The actuarial disease-free survival (DFS) rate for the entire group at 6.5 years was 50%. Patients who received the protocol for relapsing HD had a significantly better DFS rate (79%) compared with patients treated for continuous refractory disease (DFS, 33%; P < .03). CONCLUSION: Previously unirradiated patients with relapsing or chemotherapy-resistant HD who have exhausted conventional chemotherapy may still respond to an aggressive therapeutic approach consisting of accelerated hyperfractionated TLI, high-dose chemotherapy, and AuBMT rescue. This program offers a potential for long-term DFS to approximately one half of patients who would otherwise have a dismal prognosis with standard-dose salvage therapy.
Adolescent↗
The role of cytokines in radiation oncology.
Cytokine induction following ionizing radiation exposure occurs through transcriptional activation in specific proteins studied to date. This process can be blocked by inhibition of radiation-induced signaling pathways, which may potentially modify certain deleterious effects of radiotherapy, e.g., effects related to production of TNF or TGF-beta. bFGF is another radiation-inducible protein that may participate in repair and protection of irradiated endothelial cells following a complex interaction with cellular receptors. The cytokines such as IL-6, TNF, and IL-1 may be useful to protect hematopoietic cells from radiation, while TNF may enhance the killing of tumor cells. Our understanding of cytokine/radiation interactions is only beginning to be understood, but knowledge of the biology of these interactions may prove clinically useful.
Animals↗
Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer.
BACKGROUND: It has been reported that 50%-70% of patients with bladder cancer experience recurrence after initial successful treatment and about 10%-20% of these patients die of the disease. Despite precise pathologic staging and grading, we are unable to predict clinical outcome in all patients. The retinoblastoma-susceptibility (RB) gene, a prototype of tumor suppressor genes, has recently been associated with development and/or progression of bladder cancer, as well as sarcoma and small-cell lung cancer. In transitional cell carcinomas of the bladder, we have observed altered expression of the Rb gene product--a nuclear phosphoprotein thought to function as a cell cycle regulator. PURPOSE: The aim of this study was to investigate the hypothesis that altered patterns of Rb expression correlate with prognosis in bladder cancer. METHODS: Expression of the RB gene was evaluated in specimens from 48 primary bladder tumors obtained by cystectomy or transurethral resection. Rb protein expression was correlated with disease outcome in these patients. Rb expression was examined by immunohistochemistry, using the mouse monoclonal antibody Rb-PMG3-245 on frozen tissue sections. Computerized image analysis was used to quantify the level of Rb protein in individual tumor cells. RESULTS: The overall 5-year disease-free survival was 66%, with a median follow-up of 42 months. Normal levels of Rb protein expression were found in 34 patients (Rb-positive group). A spectrum of altered patterns of expression from undetectable levels to heterogeneous expression, however, was observed in 14 patients (altered Rb group). Of the 38 patients with muscle-invasive tumors, 13 were categorized as having altered expression of Rb protein. Only one of 10 patients with superficial carcinomas had altered expression of Rb protein. The 5-year survival was significantly decreased in patients with altered Rb protein compared with the survival in patients with positive Rb expression (P less than .001). CONCLUSIONS: The results suggest that tumors exhibiting decreased expression of the RB gene-coded product (Rb protein) had a more aggressive biological behavior than those that expressed the Rb protein in the majority of their tumor cells. IMPLICATIONS: This study demonstrates that altered patterns of Rb protein expression may be an important prognostic variable in patients presenting with invasive bladder cancer.
Adult↗
Is local failure a cause of or a marker for metastatic dissemination in carcinoma of the uterine cervix?
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Female↗
A reappraisal of the role of prophylactic cranial irradiation in limited small cell lung cancer.
The use of prophylactic cranial irradiation in limited stage small cell lung cancer remains controversial. Prospective trials have demonstrated that PCI can reduce central nervous system relapse rates, but the impact on survival remains questionable except for the possible evidence of a beneficial effect for long term survivors. With higher rates of thoracic control now obtainable with hyperfractionated radiation and concomitant chemotherapy, it becomes important to analyze the benefit of PCI in that setting. Before 1982, we included PCI in the management of all patients with limited stage small cell lung cancer; thereafter, we discontinued its use. This report compares the outcome of the two treatment approaches and addresses the role of PCI among patients who achieve durable local control. There were 36 limited stage small cell lung cancer patients treated with PCI from 1979-1982 and 26 patients treated without PCI from 1985-1989. Induction chemotherapy was followed in both groups by thoracic irradiation (45 Gy). The PCI patients received 30 Gy to the whole brain in 10 fractions. Both groups received maintenance chemotherapy. Of complete responders, brain failure was the first failure in 18% (4/22) of PCI (+) versus 45% (10/22) of PCI (-) (p = .04). Survival at 2 years was 42% for PCI (+) versus 13% for PCI (-) (p less than .05). When the analysis was limited to those patients permanently controlled in the thorax; there were 25% (4/16) brain failures PCI (+) versus 70% (7/10) PCI (-) (p = .03). For this same subset the 2-year survival was 56% PCI (+) versus 14% PCI (-) (p less than .05). There were no 5 year survivors without PCI compared to 38% (6/16) with PCI. These data suggest that PCI appears to be effective in enhancing survival of patients who achieve durable thoracic control. Prospective trials are necessary to evaluate the use of PCI combined with therapeutic regimens with a documented ability to achieve high rates of sustained control of thoracic disease.
Brain↗
Radiation tolerance and the new biology: growth factor involvement in radiation injury to the lung.
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Animals↗