p53 status and prognosis of locally advanced prostatic adenocarcinoma: a study based on RTOG 8610.

BACKGROUND: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. PURPOSE: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. METHODS: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ("a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy"). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. RESULTS: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). CONCLUSIONS: Determination of p53 protein expression status yield significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. IMPLICATIONS: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

Tumor size dependency in the radiation response of the Lewis lung carcinoma.

Tumor cell survival characteristics were assessed following 60Co gamma-irradiation of the Lewis lung carcinoma as 500-cu mm s.c. tumors or as 0.5-cu mm (1 mm in diameter) pulmonary metastases. Cells in the small pulmonary tumors were markedly more radiosensitive (D0 = 106 rads; hypoxic fraction less than 0.005) than were those in large s.c. tumors (final D0, 315 rads; hypoxic fraction, 0.36). When pulmonary metastases were excised and irradiated intact under well-oxygenated conditions in vitro, the hypoxic fraction rose to 0.30. This implies that, under normal in situ conditions, these nodules contain a microvascular system that achieves adequate oxygen supply to the great majority of tumor cells. Thus, the tumor cells within these small metastatic implants were more sensitive to irradiation, largely due to better oxygenation, and may be more sensitive to chemotherapy, due to better drug availability.

Repair of radiation damage in Lewis lung carcinoma cells following in situ treatment with fast neutrons and gamma-rays.

Lewis lung tumor cells were irradiated with 60Co gamma-rays or cyclotron-produced neutrons in situ as solid s.c. tumors or in vitro as single cell suspensions. Cell survival was assayed by colony formation both in vitro in soft agar and in the lungs of isogeneic recipient mice. Survival curve characteristics measured in vitro were: Do = 111 rads, Dq = 342 rads, n = 22 for gamma-rays, and Do = 61 rads, Dq = 46 rads, n = 2 for neutrons. In situ, the hypoxic fraction was 0.36. Irradiation in situ gave, for the hypoxic subpopulation, Do = 315 rads for gamma-rays and Do = 91 rads for neutrons. The oxygen-enhancement ratio for gamma-rays was 2.8 and for neutrons was 1.5. Using the split-dose technique, in which two equal doses were administered, separated by 4 hr chronically hypoxic tumor cells repaired sublethal damage, assayed by leaving tumor cells in situ up to 24 hr posttreatment, could not be detected after neutrons, but after gamma-rays it was observed as a 3- to 6-fold increase in survival. The repair of potentially lethal damage increased the relative biological effectiveness of neutrons from 3.7 at a survival level of 5% when assayed immediately after treatment to 4.7 when assayed 6 to 24 hr after treatment. These observations, primarily limited to the chronically hypoxic subpopulation of tumor cells, suggest that decreased repair of potentially lethal damage as well as sublethal damage may be an important radiobiological difference between the effects of high and low linear energy transfer radiation.

The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma.

We tested the efficacy of the hypoxic cell sensitizer misonidazole in conjunction with intraoperative electron beam radiation therapy (IORT) and external beam irradiation in patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas. Misonidazole was delivered intravenously (IV) at a dose of 3.5 g/m2 in conjunction with IORT of 1,500 to 2,000 cGy to the pancreas. Additional external beam radiation as administered to 4,960 cGy. The study was based on the premise that the effect of misonidazole would be maximized when a high dose of the drug was administered and, thus, high hypoxic cell sensitization could be obtained when using a high single dose of radiation where the hypoxic fraction would be expected to dominate in the survivors. In a nonrandomized study of 41 patients treated with misonidazole and 22 without, the 1-year local control was 67% and 55%, and 1-year survival was 50% and 77%, respectively. Although there was a bias towards larger tumors in the patients treated with the sensitizer, we were unable to demonstrate an advantage to misonidazole in this clinical situation.

Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy.

Clinical and pathologic factors were analyzed in 40 patients with localized muscle-invasive bladder carcinoma treated in a prospective bladder-preserving program consisting of transurethral tumor resection, neoadjuvant chemotherapy (methotrexate, cisplatin, and vinblastine [MCV]), and 4,000 cGy radiotherapy with concurrent cisplatin. Patients with biopsy-proven complete response after chemotherapy and 4,000 cGy radiation received full-dose radiotherapy (6,480 cGy) with cisplatin. Cystectomy was recommended to patients with residual disease. Distant metastasis rate was associated with tumor stage and size: 0% in T2 patients, 39% in T3-4 patients (P = .035), 6% for tumors less than 5 cm, and 59% for tumors greater than or equal to 5 cm (P = .002). Risk of bladder tumor recurrence was higher in patients with tumor-associated carcinoma in situ (CIS; 40%) than those without CIS (6%; P = .075). Papillary tumors and solid tumors both had similar treatment outcomes. By multivariate analysis, tumor stage T2 (P = .04) and absence of CIS (P = .03) were significant predictors of complete response; CIS was predictive of local bladder recurrence (P = .07); and tumor size (P = .03), response after chemoradiotherapy (P = .02), and vascular invasion (P = .08) were associated with distant metastasis. Six of eight local bladder tumor recurrences were superficial tumors. The low actuarial distant metastasis rate of T2 patients (0% at 3 years), the 3-year actuarial overall survival rates for T2 (89%) and T3-4 (50%) patients, and the similar treatment outcomes for papillary versus solid tumors are encouraging when compared with published historical controls. These results provide preliminary evidence (median follow-up, 30 months) that the current chemoradiotherapy regimen may have beneficial effects in the treatment of muscle-invasive bladder carcinoma. The true efficacy of neoadjuvant chemotherapy remains to be proven by ongoing randomized trials.

Bladder preservation by combined modality therapy for invasive bladder cancer.

PURPOSE: To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS: From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. CONCLUSION: Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92-02.

PURPOSE: The Ki-67 staining index (Ki67-SI) has been associated with prostate cancer patient outcome; however, few studies have involved radiotherapy (RT) -treated patients. The association of Ki67-SI to local failure (LF), biochemical failure (BF), distant metastasis (DM), cause-specific death (CSD) and overall death (OD) was determined in men randomly assigned to short term androgen deprivation (STAD) + RT or long-term androgen deprivation (LTAD) + RT. PATIENTS AND METHODS: There were 537 patients (35.5%) on Radiation Therapy Oncology Group (RTOG) 92-02 who had sufficient tissue for Ki67-SI analysis. Median follow-up was 96.3 months. Ki67-SI cut points of 3.5% and 7.1% were previously found to be related to patient outcome and were examined here in a Cox proportional hazards multivariate analysis (MVA). Ki67-SI was also tested as a continuous variable. Covariates were dichotomized in accordance with stratification and randomization criteria. RESULTS: Median Ki67-SI was 6.5% (range, 0% to 58.2%). There was no difference in the distribution of patients in the Ki-67 analysis cohort (n = 537) and the other patients in RTOG 92-02 (n = 977) by any of the covariates or end points tested. In MVAs, Ki67-SI (continuous) was associated with LF (P =.08), BF (P =.0445), DM (P <.0001), CSD (P <.0001), and OD (P =.0094). When categoric variables were used in MVAs, the 3.5% Ki67-SI cut point was not significant. The 7.1% cut point was related to BF (P =.09), DM (P =.0008), and CSD (P =.017). Ki67-SI was the most significant correlate of DM and CSD. A detailed analysis of the hazard rates for DM in all possible covariate combinations revealed subgroups of patients treated with STAD + RT that did not require LTAD. CONCLUSION: Ki67-SI was the most significant determinant of DM and CSD and was also associated with OD. The Ki67-SI should be considered for the stratification of patients in future trials.

Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31.

PURPOSE: Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated. MATERIALS AND METHODS: In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm. RESULTS: Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03). CONCLUSION: Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.

Prostate cancer DNA ploidy and response to salvage hormone therapy after radiotherapy with or without short-term total androgen blockade: an analysis of RTOG 8610.

PURPOSE: DNA ploidy has consistently been found to be a correlate of prostate cancer patient outcome. However, a minority of studies have used pretreatment diagnostic material and have involved radiotherapy (RT)-treated patients. In this retrospective study, the predictive value of DNA ploidy was evaluated in patients entered into Radiation Therapy Oncology Group protocol 8610. The protocol treatment randomization was RT alone versus RT plus short-course (approximately 4 months) neoadjuvant and concurrent total androgen blockade (RT+TAB). PATIENTS AND METHODS: The study population consisted of 149 patients, of whom 74 received RT alone and 75 received RT+TAB. DNA content was determined by image analysis of Feulgen stained tissue sections; 94 patients were diploid and 55 patients were nondiploid. Kaplan-Meier univariate survival, the cumulative incidence method, and Cox proportional hazards multivariate analyses were used to evaluate the relationship of DNA ploidy to distant metastasis and overall survival. RESULTS: DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tumors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RT+TAB and who had nondiploid tumors had reduced survival after salvage androgen ablation. CONCLUSIONS: Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.

Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Conservative surgery, patient selection, and chemoradiation as organ-preserving treatment for muscle-invading bladder cancer.

Multimodality organ-sparing treatment has, during the last decade, become the standard of care for many common malignancies. In appropriately selected patients with muscle-invading bladder cancer, bladder-preserving treatment combining surgical transurethral resection (TUR) with chemoradiation therapy offers a chance for long-term cure and survival equal to cystectomy, while also affording a 60% to 70% chance of maintaining a normally functioning bladder. Selection criteria helpful in determining appropriate patients for bladder preservation include such variables as small tumor size, that a visibly complete TUR is possible, the absence of hydronephrosis and that a complete response (CR) to induction chemoradiotherapy was achieved. Selecting patients based on response to induction therapy allows for prompt cystectomy if residual disease is found or for prompt consolidation chemoradiotherapy if a CR with induction therapy is achieved. Bladder-preserving treatment usually results in a normally functioning bladder without incontinence or hematuria for stage T2 and T3a patients. Stage T3b-T4 patients are locally controlled less frequently using these techniques. However, no data exist to suggest that patients with more advanced disease are in any way disadvantaged by preoperative chemoradiotherapy as an attempt at bladder conservation. Patients require close urological surveillance as do any patients with superficial bladder cancer who are being treated conservatively. As studies addressing the possibility of organ preservation continue to show positive results, more patients will become informed about and will be offered selective bladder-sparing approaches as one-treatment option.

A beam width improving device for a 25 MV X ray beam.

We have made a device that improves the dose distributions of X ray fields from a 25 MV accelerator by increasing the width of the 95% dose relative to the 50%. This device, called a beam width improving device, is a specially designed "compensator," consisting of two lead sheets taped onto a plastic blocking tray and is tailored for each field so that it can accommodate square fields, rectangular fields and fields with corner cuts. Comparison of profiles with and without this compensator indicates an increase in the width of the 95% dose of approximately 8 mm for small fields to approximately 14 mm for large fields.

Reduction of the scatter dose to the testicle outside the radiation treatment fields.

A technique is described to reduce the dose to the contralateral testicle of patients with testis tumors during retroperitoneal therapy with 10 MV X rays. When a conventional clam-shell shielding device was used, the dose to the testis from the photons scattered by the patient and the collimator jaws was found to be about 1.6% of the prescribed midplane dose. A more substantial gonadal shield made of low melting point Ostalloy, that reduced further the dose from internal scattered X rays, was therefore designed. A 10 cm thick lead scrotal block above the scrotum immediately outside the field is shown to reduce the external scattered radiation to negligible levels. Using the shield and the block, it is possible to reduce the dose to the testicle to one-tenth of one percent of the prescribed midplane dose.

The combination of cis-platin based chemotherapy and radiation in the treatment of muscle-invading transitional cell cancer of the bladder.

Radical cystectomy is the standard of care for patients with muscle-invading transitional cell carcinoma of the bladder. More limited surgery is only useful in highly selected patients and radiation therapy alone gives overall local-control rates under 40%. Phase II studies have shown that when radiation and trans-urethral surgery are combined with cis-platin based chemotherapy local-control rates increase such that the majority of patients preserve a tumor-free functional bladder. Up to 85% of patients selected for bladder sparing therapy on the basis of their initial response to chemo-radiation may keep their bladders. This figure could increase further when other powerful prognostic factors such as the presence of hydronephrosis, the presence of carcinoma in situ, and DNA ploidy are also taken into account in initial patient selection. The activity of cisplatin combinations in metastatic disease is not in doubt with up to 50% response rates generally reported. The hope that this will translate into the eradication of micrometastatic disease (known to be present in up to 40% of patients at diagnosis) has yet to be borne out. Those randomized trials so far reported have not shown any survival advantage when combined-modality therapy is compared to radiation alone. The addition of combination chemotherapy to radiation does not increase bladder morbidity but carries a considerable systemic penalty. Thus, despite promising Phase II studies, until local control and survival benefit is proven in a randomized trial it should continue to be regarded as experimental.

The long-term effect on PSA values of incidental prostatic irradiation in patients with pelvic malignancies other than prostate cancer.

PURPOSE: To determine the effect of external beam radiation therapy on serum prostate-specific antigen (PSA) production by the benign prostate. METHODS AND MATERIALS: We studied a cohort of 24 men receiving treatment for cancer of the bladder or rectum. The radiation fields in all cases encompassed the prostate gland, and none of the patients were known to have prostate cancer. All patients had 2 or more PSA estimations obtained in the years following their radiation treatment. A second group of 46 patients who had undergone radical external beam radiation therapy for prostate cancer and who were clinically disease free 8-22 years later were also observed, with a median of 5.8 years of PSA observations. RESULTS: Only 3 of the 24 patients in the first group showed a significant rise of > 0.2 ng/ml in their serum PSA levels, with a median of 3.3 years follow-up from the first PSA test. Seven of 24 showed progressive declines, and 14 of 24 showed steady levels. The median PSA for this group was < or = 0.5 ng/ml. Only 6 of the 46 in the second group showed a PSA rise of > 0.2 ng/ml. Thirty-four had stable values, and 6 had further declines. Again, the median PSA for the entire group was < or = 0.5 ng/ml. CONCLUSION: Recovery of prostatic secretory function is an uncommon event after external beam radiation. The concern that this might significantly confound new definitions of biochemical failure after radical radiation for prostate cancer that are based on progressively rising PSA values thus appears to be unfounded.

Adriamycin sensitivity following "ultra" low dose rate irradiation of Lewis lung carcinoma in vivo.

As an extension of recent study on the response of the Lewis lung tumor to low dose rate continuous irradiation (CI) at 15 cGy/hr, we have gone on to investigate the effects of such irradiation on the sensitivity of tumor cells to treatment with Adriamycin (Adr). Cells from untreated tumors gave an exponential dose response curve to Adr in vitro, the D10 of which increased (sensitivity decreased) with the size of tumor (0.05 g to 0.6 g) from which the cells were obtained. After previous in vivo CI to a total dose of 28 Gy (irradiation time--186 hr), this size dependence was abolished and the cells showed an exponential response to Adr in vitro (D10 = 0.4 microgram/ml). The enhancement was also observed after equivalent doses of fractionated irradiation, but not after acute irradiation. It was difficult to characterize the proliferative status of the cells surviving irradiation, but repopulation studies showed that only after CI was there any delay before repopulation commenced. LL was relatively insensitive to Adr in vivo, however, we did observe an increased effect after previous CI.

Preoperative irradiation, lymphadenectomy, and 125iodine implantation for patients with localized carcinoma of the prostate.

Fifty-four patients with clinically and surgically localized prostatic carcinoma were treated with low-dose preoperative irradiation (1,050 cGy), pelvic lymphadenectomy, and interstitial 125Iodine implantation. The follow-up range is 2 to 9 years with a median follow-up of 5 years. Overall local tumor control is 92%. Actuarial 5-year survival is 86% and the actuarial disease-free survival at 5 years is 73%. Patients with poorly differentiated tumors have a significantly worse actuarial survival (62%) at 5 years than patients with well (95%) or moderately well differentiated tumors (93%), p = 0.04. Disease-free survival at 5 years was influenced by grade: well (100%), moderate (60%), and poor (48%), p = 0.03. Multivariate regression analysis indicates that only the degree of differentiation (p = 0.05) significantly impacts on survival. Both degree of differentiation (p = 0.04) and nodal status (p = 0.03) significantly influence disease-free survival. Potency has been maintained in 71% of patients potent at the time of implantation. Late reactions have been acceptable to date: bladder outlet obstruction (13%), mild proctitis (13%), cystourethritis (6%), incontinence (2%), and prostatic calculi (2%).

Renal complications secondary to radiation treatment of upper abdominal malignancies.

A retrospective review of all patients undergoing radiotherapy for carcinoma of the colon, pancreas, stomach, small bowel and bile ducts, lymphomas of the stomach, and other GI sites and retroperitoneal sarcomas was completed to assess the effects of secondary irradiation on the kidney. Eighty-six adult patients were identified who were treated with curative intent, received greater than 50% unilateral kidney irradiation to doses of at least 2600 cGy and survived for 1 year or more. Following treatment, the clinical course, blood pressure, addition of anti-hypertensive medications, serum creatinine and creatinine clearance were determined. Creatinine clearance was calculated by the formula: creatinine clearance equals [(140-age) X (weight in kilograms)] divided by (72 X serum creatinine) which has a close correlation to creatinine clearances measured by 24 hr. urine measurements. The percent change in creatinine clearance from pre-treatment values was analyzed. Of the thirteen patients with pre-radiotherapy hypertension, four required an increase in the number of medications for control and nine required no change in medication. Two patients developed hypertension in follow-up, one controlled with medication and the other malignant hypertension. Acute or chronic renal failure was not observed in any patient. The serum creatinine for all 86 patients prior to radiation therapy was below 2 mg/100 ml; in follow-up it rose to between 2.2-2.9 mg/100 ml. in five patients. The mean creatinine clearance for all 86 patients prior to radiotherapy was 77 ml/minute and for 16 patients with at least 5 years of follow-up it was 62 ml/minute. The mean percent decrease in creatinine clearance appeared to correspond to the percentage of kidney irradiated: for 38 patients with only 50% of the kidney irradiated the mean percent decrease was 10%, whereas for 31 patients having 90 to 100% of the kidney treated the decrease was 24%. Although physiologic changes were seen in patients receiving 50% or more unilateral kidney irradiation, the development of significant clinical sequelae was limited to one patient.

Invasive bladder cancer: treatment strategies using transurethral surgery, chemotherapy and radiation therapy with selection for bladder conservation.

PURPOSE: Combined modality therapy has become the standard oncologic approach to achieve organ preservation in many malignancies. METHODS AND MATERIALS: Although radical cystectomy has been considered as standard treatment for invasive bladder carcinoma in the United States, good results have been recently reported from several centers using multimodality treatment, particularly in patients with clinical T2 and T3a disease who do not have a ureter obstructed by tumor. RESULTS: The components of the combined treatment are usually transurethral resection of the bladder tumor (TURBT) followed by concurrent chemotherapy and radiation therapy. Following an induction course of therapy a histologic response is evaluated by cystoscopy and rebiopsy. Clinical "complete responders" (tumor site rebiopsy negative and urine cytology with no tumor cells present) continue with a consolidation course of concurrent chemotherapy and radiation. Those patients not achieving a clinical complete response are recommended to have an immediate cystectomy. Individually the local monotherapies of radiation, TURBT, or multidrug chemotherapy each achieve a local control rate of the primary tumor of from 20 to 40%. When these are combined, clinical complete response rates of from 65 to 80% can be achieved. Seventy-five to 85% of the clinical complete responders will remain with bladders free of recurrence of an invasive tumor. CONCLUSIONS: Bladder conservation trials using combined modality treatment approaches with selection for organ conservation by response of the tumor to initial treatment report overall 5-year survival rates of approximately 50%, and a 40-45% 5-year survival rate with the bladder intact. These modern multimodality bladder conservation approaches offer survival rates similar to radical cystectomy for patients of similar clinical stage and age. Bladder-conserving therapy should be offered to patients with invasive bladder carcinoma as a realistic alternative to radical cystectomy by experienced multimodality teams of urologic oncologists.

Conformal irradiation of the prostate: estimating long-term rectal bleeding risk using dose-volume histograms.

PURPOSE: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes. It explores the dose-volume relationship for NTCP of the rectum, using long-term data on rectal wall bleeding following prostatic irradiation. METHODS AND MATERIALS: Previously published data were reviewed and updated on 41 patients with Stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost, including dose-volume histograms (DVHs) of each patient's anterior rectal wall and data on the occurrence of postirradiation rectal bleeding (minimum FU > 4 years). Logistic regression was used to test whether some individual combination of dose and volume irradiated might best separate the DVHs into categories of high or low risk for rectal bleeding. Further analysis explored whether a group of such dose-volume combinations might be superior in predicting complication risk. These results were compared with results of the "critical volume model," a mathematical model based on assumptions of underlying radiobiological interactions. RESULTS: Ten of the 128 tested dose-volume combinations proved to be "statistically significant combinations" (SSCs) distinguishing between bleeders (14 out of 41) and nonbleeders (27 out of 41), ranging contiguously between 60 CGE (Cobalt Gray Equivalent) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds ratios for each SSC were not significantly different across the individual SSCs; however, analysis combining SSCs allowed segregation of DVHs into three risk groups: low, moderate, and high. Estimates of probabilities of normal tissue complications (NTCPs) based on these risk groups correlated strongly with observed data (p = 0.003) and with biomathematical model-generated NTCPs. CONCLUSIONS: There is a dose-volume relationship for rectal mucosal bleeding in the region between 60 and 75 CGE; therefore, efforts to spare rectal wall volume using improved treatment planning and delivery techniques are important. Stratifying dose-volume histograms (DVHs) into risk groups, as done in this study, represents a useful means of analyzing empirical data as a function of hetereogeneous dose distributions. Modeling efforts may extend these results to more heterogeneous treatment techniques. Such analysis of DVH data may allow practicing clinicians to better assess the risk of various treatments, fields, or doses, when caring for an individual patient.