Survival of mice with metastatic osteosarcoma treated by cyclophosphamide or radiotherapy.

Dunn osteosarcoma cells injected i.v. into tumor-free isogeneic C3H/He mice resulted in artificial pulmonary metastases, which were treated by cyclophosphamide (100 mg/kg/day i.p. for 3 days) or single thoracic X-ray doses of 1500 rads either 1 or 14 days after tumor cell injection. Compared to untreated controls, reduction in lung colony number and increase in life-span for the 1-day metastases were 56 and 46% for radiated mice, and 100 and greater than 367% for cyclophosphamide-treated mice. Corresponding values for 14-day metastases were 42, 26, 85, and 98%, respectively. Nine of 44 mice bearing 1-day metastases treated by cyclophosphamide are surviving greater than 340 days after treatment. Both treatments resulted in the extension of life-span and reduction of the number of lung colonies, and, in both modalities, there was a reduced antitumor effectiveness when treatment was withheld until the disease was more advanced.

PSA for outcome prediction and posttreatment evaluation following radiation for prostate cancer: do we know how to use it?

Pretreatment prostate-specific antigen (PSA) has been shown to be a powerful predictor of expected outcome after radiation for prostate cancer. Additional measures such as recursive partitioning analysis and PSA Cancer Volume calculations are further refining this useful tool to provide the greatest degree of prognostic information. The post-treatment PSA level is also being used as a means to assess therapeutic efficacy rapidly and objectively. Although no single PSA value has been shown to equate to long-term clinical tumor control consistently, consensus has been reached regarding the value of a rising PSA level as an early surrogate for tumor recurrence. Since the first introduction of PSA as a tumor marker, we have become much more comfortable with what it means, the ways it can help us, and how to use it.

The effect of TURP on prognosis in prostatic carcinoma.

Of 553 patients definitively irradiated for biopsy proven prostatic adenocarcinoma from January 1976 to March 1986, 287 patients with a minimum follow-up of 4 years were studied. One hundred sixty-two patients had transurethral prostatic resection (TURP); one hundred twenty-five patients did not. When subdivided by stage and histologic grade, those patients with poorly differentiated tumors who underwent TURP had a noticeably higher, but not statistically different, incidence of bony metastasis as compared to those who did not have TURP. Survival at 5 years also appeared to be better in patients with poorly differentiated and stage C disease without TURP. However, local tumor recurrence in poorly differentiated tumor with TURP was 42% as compared to 20% in the NO TURP group, p = .04. Moreover, when the incidence of osseous metastasis was assessed by local tumor status, 20% of the TURP patients with local tumor control developed metastases as compared to 66% of those with local failure. Similarly, within the NO TURP group, the incidence of bony metastasis was 16% for those with local control and 50% for those with local recurrence, p = .005 in both cases. Survival was likewise affected by local tumor control, regardless of whether or not TURP was performed. In patients with local tumor control, survival was 80% at 5 years with TURP and 86% without TURP (p greater than 0.1). In contrast, only 14% of patients with local recurrence and TURP were alive at 5 years which was not statistically different from the 32% survival in those with local recurrence but NO TURP. It seems, therefore, that comparing prognosis by TURP alone overlooks the inherent characteristics of the tumor and the extent of the disease.

The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures.

Patients treated for prostate cancer from 1975-1982 were reviewed to assess if pre-irradiation transurethral resection of the prostate (TURP) predisposed to the formation of post treatment urethral strictures or bladder neck contractures. A total of 368 patients were treated with external beam irradiation delivered by a linear accelerator or 125I interstitial implants. Of the 253 patients treated by external beam, 138 patients had a history of at least one TURP before treatment. Implants were performed in 115 patients and 57 had a history of TURP before treatment. A total of 40 patients from both groups developed post treatment complications of urethral strictures or bladder neck contractures. Three patients developed both complications. An analysis of the 40 patients revealed that 29 (72.5%) patients had a TURP performed within a median time of 33 days prior to their initiation of radiation therapy. Of 195 patients in the prior TURP group, 29 (15%) developed one or both complications. Only 11 (6%) of the 173 patients in the non-TURP group developed one or both complications. This comparison was statistically significant with a p value of .025. Various factors analyzed including the treatment regimen, histologic grade, stage of disease, and volume of prostatic tissue removed at surgery did not show any positive correlation. Multiple TURP's were evaluated for greater distribution to the incidence of post treatment complications. The prior TURP group of 195 patients contained 60 with a history of at least two TURPs before radiation therapy. Eleven (18.3%) developed one or both complications. Of the 135 patients in the single TURP group, 18 (13.3%) developed complications. This was not statistically significant. Therefore, we concluded that the initial TURP was its mechanical description of mucosa and resultant scarring is a predisposing risk for development of urethral strictures or bladder neck contractures. Review of the literature concerning time sequence for healing of the urethra shows 4-6 weeks to be appropriate interval between surgery and radiation.

The significance of post-irradiation prostate biopsy with long-term follow-up.

Ninety-four patients, Stage A2-C, definitively irradiated for adenocarcinoma of the prostate from 1975 to 1981 underwent digitally directed transperineal needle biopsy of a clinically negative prostate gland at least 18 months post-therapy. Ten of 55 patients (18%) treated with Iodine-125 implantation and 7 of 39 patients (18%) externally irradiated were found to have positive biopsy specimens. Overall, clinical local failure occurred in 53% of patients with positive biopsy results but in only 18% with negative specimens, p = .006. The false negative biopsy rate in patients treated with I-125 was nearly three times that for external beam, 24% versus 9%, perhaps because of the greater possibility of inhomogeneous dose distribution with I-125, allowing for a higher degree of sampling error. Actuarial local failure at 5 years was 44% versus 8% with positive and negative biopsies, respectively, and 75% versus 24% at 10 years (p = .0001). The distant metastatic rate was twice as high in biopsy-positive as compared to biopsy-negative patients, 71% versus 35%, p = .015. Actuarially, only 19% of patients with a positive biopsy are NED at 10 years as compared to 62% of those with a negative biopsy (p = .0001). PSA values are supportive in those patients thought to be disease-free. The incidence of positive biopsy and associated local recurrence are in keeping with clinical treatment failure rates as reported in multiple studies to date.

Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer.

PURPOSE: This study was undertaken to assess the predictive value of pretreatment prostate-specific antigen (PSA) and the difference between clinical and PSA disease-free status in patients with long-term follow-up after irradiation for prostatic carcinoma. Comparison of the distribution of prognostic factors between surgical and radiation series was also made. METHODS AND MATERIALS: From 1975-1989, 652 patients with clinical Stage A2-C prostatic adenocarcinoma were definitively irradiated using external beam therapy. One hundred and fifty patients with banked serum and up to 14 years follow-up have pretreatment PSA levels and 355 patients with up to 17 years follow-up have posttreatment values. Treatment failure was analyzed by tumor stage, grade, and four pretreatment PSA categories. Disease-progression was evaluated by clinical and biochemical (PSA) endpoints. Prognostic factors were compared to two surgical series. RESULTS: A significant difference was seen in clinical and PSA disease-free (PSA < or = 4.0 ng/ml) status based on tumor grade, stage, and pretreatment PSA category. Although the expected clinical outcome has been well-documented previously, results based on posttreatment PSA levels show 5-year disease-free survivals reduced by 10-16% and 10-year survivals lessened by 15-39% depending upon the particular tumor grade and stage. The earlier stage, lower grade tumors showed the largest difference between clinical and biochemical recurrence rates at the longest interval from treatment. Even more notable were the differences in the clinical and PSA disease-free rates based on the pretreatment PSA level. Comparing the irradiated patients to two surgical series showed that the former had a larger percentage of more advanced stage tumors with more unfavorable PSA levels as compared to prostatectomy patients. CONCLUSION: With long-term follow-up, the pretreatment PSA level continues to be a powerful predictor of clinical and biochemical outcome in patients irradiated for apparently localized prostate cancer. Differences between clinical and PSA outcome can be considerable, but oftentimes clinically insignificant. The distribution of prognostic factors between radiation and prostatectomy series seems to favor the latter.

The latent period in clinical radiation myelopathy.

Seventy-seven papers containing data on more than 300 cases of radiation myelopathy have been analyzed. The data suggest that the latent periods are similar in the cervical and thoracic levels of the spinal cord and are bimodally distributed. Myelopathy of lumbar cord apparently has a shorter latent period. As in controlled animal experiments, the latent period decreases with increasing dose. Furthermore, the variation in latent periods also decreases with dose. It is also seen that retreated patients and pediatric or adolescent patients have greatly reduced latent periods. The implications of these findings as they compare with the animal data are discussed.

Nuclear roundness factor and local failure from definitive radiation therapy for prostatic carcinoma.

Of 375 patients with prostatic carcinoma treated definitively with radiation therapy at this institution with at least a 5 year follow-up, 23 patients failed locally only, 72 failed with distant metastasis only, 60 had both local and distant failure, while 220 showed no evidence of disease. In search for a possible marker for local failure following radiation therapy, we examined several nuclear morphometric parameters which have been shown to correlate with the biologic aggressiveness of this disease. The 23 locally failed only patients were matched with 23 no evidence of disease patients for stage, grade, treatment modality, prior surgery, age at diagnosis and race. Archival hematoxylin and eosin slides were obtained for 22 of the 23 matched pairs, and morphometric features, including nuclear roundness factor and nuclear area, as well as numbers of nucleoli were assessed using computer-assisted image analysis in both tumor cells and normal prostatic epithelium. Tumor nuclei from the locally failed only patients had significantly higher nuclear roundness factor values (p = 0.0089) compared with tumor cells from no evidence of disease patients. Analysis of these data by clinical stage demonstrated no significant differences between the locally failed only and no evidence of disease patients. Likewise, there were no significant differences in nuclear roundness factor values of locally failed only and no evidence of disease patients with poorly or moderately well-differentiated tumors. However, there was a highly significant difference (p = 0.0012) in the nuclear roundness factor values of locally failed only and no evidence of disease patients with well-differentiated tumors. Thus, there appears to be a subset of patients with well-differentiated adenocarcinoma of the prostate who have significantly more irregular tumor nuclei and who fail locally only following definitive radiation therapy.

Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation.

PURPOSE: To determine whether the expression of epidermal growth factor receptor (EGFR) protein was predictive of patient survival independently of other prognostic factors in astrocytic tumors. METHODS AND MATERIALS: Epidermal growth factor receptor protein expression was investigated immunohistochemically in formalin-fixed, paraffin-embedded surgical specimens of 55 glioblastoma multiforme, 14 anaplastic astrocytoma, and 2 astrocytomas given definitive irradiation. We evaluated the relationship of EGFR protein expression and tumor grade, histologic features, age at diagnosis, sex, patient survival, and recurrence-free survival. RESULTS: The percentage of tumor cells which were EGFR positive related to reduced survival by Cox regression analysis in both univariate (p = 0.0424) and multivariate analysis (p = 0.0016). Epidermal growth factor receptor positivity was the only 1 of 11 clinical and histological variables associated with decreased recurrence-free survival by either univariate (p = 0.0353) or multivariate (p=0.0182) analysis. Epidermal growth factor receptor protein expression was not related to patient age, sex, or histologic features. CONCLUSION: Epidermal growth factor receptor positivity was a significant and independent prognostic indicator for overall survival and recurrence-free survival for irradiated patients with astrocytic gliomas.

Triple course external beam radiotherapy for carcinoma of the prostate.

In 1976 we began using a triple-course technique of external beam irradiation for localized carcinoma of the prostate. The treatment consisted of 2 courses of 20 Gy in 2 weeks to the pelvis and a third course of 20-25 Gy in 2-2 1/2 weeks as a boost to the prostate. A 2 week rest followed the first and second courses. The results of this treatment technique are reported on the first 50 patients who had been followed for at least 3 years. Although 96% of these patients developed bladder and/or bowel reactions, the majority of the symptoms were in the very mild to mild category, with only 2% severe reactions referrable to each organ. The incidence of late complications in this series compared favorably to those reported by other authors. Clinical local control was 96% while post-treatment needle biopsy performed on 22/50 patients yielded a negative rate of 86%. Those with Stages A and B disease had a negative biopsy rate of 94%. Three-year uncorrected disease-free survival for the whole group was 54%. This study has shown that with triple course external beam irradiation, excellent control of localized carcinoma of the prostate can be achieved with minimal acute morbidity.

Detection of extravasation of antineoplastic drugs by microwave radiometry.

Microwave radiometry may be used as a non-invasive technique for subcutaneous thermal sensing. This technique was capable of demonstrating extravasation of small volumes of fluids, including the antineoplastic agent adriamycin, when these fluids were administered at room temperature in dogs. The rate of temperature drop upon extravasation was proportional to the flow rate. It is feasible that microwave radiometry may be useful as an alarm system to reduce serious complications which often accompany the extravasation of antineoplastic drugs.

Radioprotective effect of polyethylene glycol.

Polyethylene glycol of molecular weight 400 (PEG-400) had a radioprotective effect of about 20% against lethality when given ip 20 min prior to single or fractionated X-ray doses to the head and neck. Dose modification factors (DMF) based on LD50/15 values ranged from 1.14 to 1.24. A similar DMF of 1.12 based on LD50/30 values was obtained using single doses of whole-body X irradiation. Mice given head and neck irradiation had significantly reduced rectal temperatures (31.3 +/- 3.0 degrees C) 9 days post irradiation compared with unirradiated controls (35.4 +/- 0.6 degrees C). No such reduction was observed when PEG-400 was given with radiation (36.3 +/- 0.9 degrees C). PEG-400 also lessened, but not significantly, the frequency of shivering in irradiated animals. Histopathologic examination of the oral structures demonstrated only marginal protection by PEG-400. Estimation of the alpha/beta ratio from LD50 data on head and neck-irradiated mice yielded values of 4.4 +/- 1.9 (95% confidence limits) Gy without PEG-400 and 7.9 +/- 1.4 Gy with PEG-400. Since it is a non-thiol radioprotector, PEG-400 may be more useful when combined with more conventional thiol-containing radioprotectors.

Pelvic complications after definitive treatment of prostate cancer by interstitial or external beam radiation.

Radiation complications, after definitive treatment of localized prostatic carcinoma by either external beam or interstitial implantation with Iodine-125 seeds, are reviewed. Late serious complications to immediately adjacent structures of the anterior rectal wall, prostatic urethra, bladder neck, and external sphincter occurred with similar frequency in both treatment groups. However, late serious complications of the remotely adjacent structures of the bladder, urethra, distal ureters, and circumferential rectal wall occurred more frequently in the external beam treatment series, a reflection of the fact that larger tissue volumes were irradiated. Rectal ulceration, while occurring in both treatment groups, was amenable to surgical correction or underwent spontaneous healing only in the 125I group. At this point in our experience, morbidity from late radiation complications has been less among those patients having interstitial implantation for definitive treatment of localized prostatic carcinoma.

Disease-related effects of perioperative blood transfusions associated with 125I seed implantation for prostate carcinoma.

In some retrospective studies perioperative transfusions during oncologic surgery have been shown to decrease the time interval between surgery and local and/or distant recurrence of cancer. This study examines the disease-related effect, if any, of perioperative blood transfusions among 108 patients with localized carcinoma of the prostate treated by radioactive iodine-125 seed implantation of the prostate and lymphadenectomy. When all subjects were analyzed, there was no statistical difference of local and distant failure between the transfused and nontransfused groups. Patients with well-differentiated tumors had statistically fewer local recurrences (0% vs 22%, p = 0.036) if they were transfused perioperatively. However, the difference in distant metastases (0% vs 11%) was not statistically significant (p = 0.21). In contrast, patients with moderately and poorly differentiated disease receiving transfusions had more local recurrences and metastases, though this was not statistically significant. Our data suggest that there is no obvious evidence that perioperative blood transfusions have an adverse effect on local recurrence or distant metastases for iodine-125 seed implantation of carcinoma of the prostate.

Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma.

Of 495 patients definitively irradiated for prostatic carcinoma, 286 with a minimum follow-up of thirty-six months were studied. While tumor histology appeared to predict prognosis, the poorly differentiated tumors showing the highest incidence of distant metastasis and the lowest survival, local tumor control was an important factor within the poorly differentiated group. Of those with local recurrence, distant metastases developed in 68 per cent compared with 37 per cent of those with no local disease (p = 0.025). Survival was similarly affected with 86 per cent of those with locally controlled tumor who were alive at five years (not significantly different from the more well-differentiated tumors) versus a 56 per cent actuarial survival in those with locally recurrent disease (p less than 0.05).

Mortality in prostatic carcinoma.

One hundred forty-seven patients definitively irradiated for biopsy-proved adenocarcinoma of the prostate from December, 1975, to March, 1979, have either died after a median survival of forty-five months or have been followed up for a minimum of seven years. Seventy-six patients (52%) are currently alive, 62 of them with no evidence of disease. Seventy-one patients (48%) have died, 28 without disease. In addition, 12 patients died with prostatic carcinoma but of other causes. In assessing the characteristics of those patients who remain disease-free following treatment, a significant difference in disease control was seen based on tumor stage, histologic differentiation, pelvic lymph node status, and whether or not tumor was present microscopically at rebiopsy. Of those deceased patients with recurrent prostate cancer, more than one-half had distant metastasis only. In all, 61 percent of patients had no further evidence of prostatic carcinoma after definitive irradiation, 20 percent had distant metastasis alone, and only 18 percent had locally recurrent disease along with distant disease spread.

Prognostic value of poorly differentiated prostatic adenocarcinoma.

One hundred patients with prostatic adenocarcinoma surgically staged were evaluated. Their clinical stage and surgical findings were assessed especially with respect to their original histopathologic grading. It was found that patients with poorly differentiated adenocarcinoma of the prostate presented with advanced clinical stage and were at high risk of distant metastases developing within a short time after their initial diagnosis and treatment.

Prostate-specific antigen to determine progression-free survival after radiation therapy for localized carcinoma of prostate.

Prostate-specific antigen (PSA) levels after radiation therapy will more precisely and objectively identify the presence of persistent prostate carcinoma. We determined the impact of PSA marker levels on progression-free status for 123 patients treated by interstitial implantation (I-125) and 311 patients treated by external beam therapy (XRT) who have been followed for a median of 109 and 51 months, respectively. Actuarial progression-free survival curves were calculated, using standard clinical criteria, and then recalculated, using PSA marker criteria. Sera obtained twelve months or more after the initiation of XRT and twenty-four months or more after the date of I-125 were used for determination of PSA levels. Using normal PSA level (by Hybritech assay < or = 4.0 ng/mL) as the criterion for progression-free status for patients treated by XRT, 35 percent of patients with Stage A2, 20 percent of patients with Stage B1 or B2, and 10 percent of patients with Stage C tumor were progression-free at ten years. The progression-free survival by clinical criteria for Stage A2 and 65 percent, B1 was 40 percent, B2 was 35 percent, and C was 25 percent. Using undetectable PSA level (< or = 0.5 ng/mL) as the criterion, less than 10 percent of patients were progression-free at ten years, regardless of stage, grade; and treatment modality. This information should not be interpreted as indicating that radiation is ineffective therapy for prostate cancer, since clinical control of the disease among men in their eighth decade is a more practical goal than marker control. However, PSA monitoring after radiation therapy and after any local therapy for prostate cancer will provide more precise information on the success of that therapy in ablating disease.

Characteristics of spinal cord compression in adenocarcinoma of prostate.

Of 611 patients with biopsy-proved adenocarcinoma of the prostate, spinal cord compression developed in 41 (6.7%) at a median interval of twenty-four months after primary diagnosis. Spinal cord involvement most often occurred in the thoracic area, with 95 per cent of patients showing radiographic evidence of osseous vertebral metastasis at the level of cord compression. All lesions but one were located extradurally, and patients with Stage D2 disease, by virtue of bony metastases, were therefore at greatest risk for development of neurologically compressive disease. There was also a significant increase in the incidence of spinal cord involvement among the more poorly differentiated tumors, although tumor histology did not appear to influence the median interval between vertebral metastasis and cord compromise. Survival following spinal cord involvement was relatively poor and unrelated to tumor differentiation. Forty-six per cent of patients survived less than six months and 20 per cent less than two months. The two most noteworthy survivors are alive at thirty and ninety-seven months, the latter after combined treatment for an intradural lesion.

Brain metastases from transitional cell carcinoma of urinary bladder.

Of 293 patients with transitional cell carcinoma of the bladder seen at our institution between April 1977 and December 1987, 9 patients were found to have brain metastasis. Seven of 9 patients were found to have a solitary brain lesion, and in 4 of these, no other site of metastatic disease was identified. Five patients received palliative whole brain irradiation, 3,000 cGy in 10 fractions, due to the presence of multiple lesions of the central nervous system (CNS) or metastases to other sites. The average survival for this group was seven weeks. One patient with a solitary brain metastasis and no other documented metastatic site was hospitalized at another institution, and was managed expectantly receiving only parenteral steroid therapy and survived four weeks. Three patients with solitary lesions and no evidence of other metastatic sites were treated with a combined surgical and radiotherapeutic approach receiving 4,000-5,000 cGy to the lesion site postoperatively. The average survival of that group was twenty-nine months, with one five-year survivor and 1 patient with no evidence of disease fourteen months after treatment. It appears that survival is longer in those patients with solitary lesions, perhaps due, at least in part, to a more aggressive therapeutic approach.