Search

To determine the incidence and factors associated with the development of arm edema in women who participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study B-04.Between 1971 and 1974, the NSABP protocol B-04 randomized 1,665 eligible patients with resectable breast cancer to either (1) the Halstead-type radical mastectomy; (2) total mastectomy and radiotherapy to the chest wall, axilla, supraclavicular region, and internal mammary nodes if by clinical examination axillary nodes were involved by tumor; and (3) for patients with a clinically uninvolved axilla, a third arm, total mastectomy alone. Measurements of the ipsilateral and contralateral arm circumferences were to be performed every 3 months.There was at least one recorded measurement of arm circumferences for 1,457 patients (87.5% of eligible patients). There were 674 women (46.3%) who experienced arm edema at some point during the period of follow-up until February 1976. For radical mastectomy patients, total mastectomy and radiotherapy patients, and total mastectomy patients alone, arm edema was recorded at least once in 58.1%, 38.2%, and 39.1% of patients, respectively (p.001) and at last recorded measurement in 30.7%, 14.8%, and 15.5%, respectively (p=or.001). Increasing body mass index (BMI) also showed a statistically significant correlation with arm edema at any time (p=.001) and at last assessment (p=.005).Patients who undergo mastectomy, including those whose treatment plans do not include axillary dissection or postoperative radiotherapy, suffer an appreciable incidence of arm edema.

Purpose: To determine whether excision of an in-breast tumor recurrence (IBTR) plus 5000 cGy in 25 fractions to the new operative area is both tolerated and effective as treatment for an IBTR after previous lumpectomy and whole breast irradiation. Methods and Materials: Thirty-nine women with an IBTR after lumpectomy and breast irradiation for invasive carcinoma (n = 31) or ductal carcinoma in situ (n = 8) were treated with excision of the IBTR and radiotherapy (RT), 5000 cGy in 25 fractions, to the operative area using electrons of appropriate energy. The interval from completion of the first course of RT to diagnosis of the IBTR ranged from 16 to 291 months (median 63). Results: The repeat course of RT to the new operative area was well tolerated in all patients, and no late sequelae occurred other than skin pigmentation changes. Eight patients, including 2 with suspicious bone scans at the time of IBTR, developed distant metastases, and 7 died 21–71 months (median 48) after retreatment. One patient was alive with distant metastases at 27 months after retreatment. Four of the 8 patients who developed distant metastases also had a second IBTR, and 3 died with persistent disease in the breast. An additional 4 patients, for a total of 8, had a second IBTR. Three were alive and free of disease after mastectomy, and 1 was alive and free of disease after mastectomy and additional RT for chest wall recurrence. An additional patient developed recurrence in the axilla 9 months after reirradiation and was treated with surgery; she died free of disease at 63 months. One patient underwent mastectomy for suspected persistent disease 2 months after completion of repeat RT; no evidence of recurrent tumor was found in the removed breast. Thus, 30 women (76.9%) had an intact breast free of tumor at death or at last follow-up 1–180 months (median 51.5) after reirradiation. Using the Kaplan-Meier life table analysis, the estimated overall and disease-free 5-year survival rate for the 39 patients was 77.9% and 68.5%, respectively. Conclusion: For select patients with an IBTR after lumpectomy and breast irradiation, excision of the IBTR followed by repeat external beam RT to the operative area may be an acceptable alternative to mastectomy.

Difluoromethylornithine (DFMO) depletes endogenous putrescine and enhances the uptake of and retention of [3H] putrescine in vitro. To determine if DFMO also enhances uptake of [3H] putrescine in vivo, DFMO and trace doses of [3H] putrescine, dissolved in artificial CSF, were infused into growing (6-9 day) 9L brain tumors by means of osmotic pumps. When 7-day osmotic pumps were loaded with 1 microCi [3H] putrescine, with or without 10 or 100 mM DFMO, pumped at 1 microl/h, the mean uptake after 3 days was 168 +/- 62 cpm/mg tumor (17 rats) without DFMO, 300 +/- 197 cpm/mg tumor (11 rats) with 10 mM DFMO and 1088 +/- 421 cpm/mg tumor (11 rats) with 100 mM DFMO (por = 0.05 vs. control). Significantly less radioactivity was detected in the contralateral brain and in nonbrain tissues (0.5 +/- 0.1 to 14 +/- 5 cpm/mg). To measure the extent of [3H] putrescine distribution in the tumor, the same dose of drugs was delivered for a longer period of time, using 14-day pumps to allow tumors to become large enough to be divided into 1.4 mm thick transections. The mean radioactivity in the sections from eight control rats receiving [3H] putrescine without DFMO were not significantly different between the sections (174 +/- 61 cpm/mg tumor for sections containing the cannulas, 273 +/- 61 and 259 +/- 91 cpm/mg for adjacent sections). In the six rats given 100 mM DFMO there was a significant increase in mean radioactivity in the cannula containing section (2251 +/- 919 cpm/mg tumor). Mean counts from adjacent sections in these rats were 97 +/- 44 and 33 +/- 13 cpm/mg. Values for contralateral corpus striatum and nonbrain tissues ranged from 0.7 +/- 0.3 to 4.3 +/- 1.5 cpm/mg tissue. When DFMO was delivered directly to the tumors while [3H] putrescine was infused intraperitoneally, the uptake in the tumor slices was low (5-10 cpm/mg in different slices). These results demonstrate that infusion of DFMO directly into growing 9L brain tumors can selectively enhance the uptake of exogenous [3H] putrescine by rapidly dividing cells which are within a 1.4 mm diameter area at the cannula tip. Although these studies used [3H] putrescine at trace doses, it is estimated that infusion of higher doses of [3H] putrescine plus DFMO will selectively kill tumor cells.

Purpose : This study explored the possible use of D,L-α-difluoromethylornithine (DFMO) to enhance the uptake of [3H] putrescine in order to selectively kill brain tumor cells. Methods and Materials : Gliosarcoma cells (9L) were grown for 4 or 20 day periods in monolayer cultures with or without [3H] putrescine and/or DFMO. Cells in culture incubated for 20 days were replated at 4-day intervals. Cells were counted on a Coulter Electronic Particle Counter and percent viability was determined by eosin dye exclusion. Survival of cells with proliferative capacity was assayed by their colony forming ability and surviving fraction was calculated. The radioactive counts due to [3H] putrescine were measured in 9L cells and in medium and expressed as cpm/100 cells or cpm/ml, respectively. Results : As previously reported (15), DFMO treatment resulted in termination of cell proliferation that was reversible by the addition of exogenous putrescine. Specifically, after 4 days in culture, cell counts in groups exposed to 10 mM DFMO were 55% of those in control groups and addition of 3 mM putrescine reversed the DFMO effects. Uptake of [3H] putrescine into untreated cells increased in proportion to the amount of exogenous putrescine present during 4 days of culture (range 0.01 nmol to 100 nmol) and the presence of DFMO in the medium enhanced the uptake 9 fold throughout these ranges. At activities greater than 100 cpm/100 cells the cell count was reduced to 23 to 48% of control after 4 days in culture. Extending the treatment to 20 days of incubation increased the killing of 9L cells. During the 20-day incubation, control cells increased from 5 × 105 to 13 × 1012 of which 90% were colony forming cells. Treatment with either 25 μCi[3H] putrescine or 1 mM DFMO for 4 days followed by removal of these agents and incubation for an additional 16 days for a total of 20 days resulted in 31 × 108 or 18 × 107 colony forming cells, respectively. Combining [3H] putrescine and DFMO treatments during the first 4 days of the 20 day incubation reduced the colony forming cells to 21 × 105 (surviving fraction to 67%). When the DFMO treatment was present during the entire 20 days, it became cytotoxic since the colony forming cells were reduced to 35 X 103 (surviving fraction was 17%). The combination of the 4-day [3H] putrescine and the 20 day DFMO treatments resulted in only 1200 surviving colony forming cells (surviving fraction was only 2%). Conclusion : DFMO treatment of 9L cells for 20 days resulted in increased uptake of [3H] putrescine, a 1010 fold inhibition of colony forming cells and extensive 9L cell killing relative to untreated controls.

From 1971 to 1985, 21 patients received megavoltage external beam radiation therapy at the University of Pittsburgh for control of craniopharyngioma. Minimum tumor doses prescribed to the 95% isodose volume ranged between 51.3 to 70.0 Gy. Median total dose was 60.00 Gy and median dose per fraction was 1.83 Gy. Three deaths occurred from intercurrent disease and no deaths from tumor progression. Actuarial overall survival was 89% and 82% at 5 and 10 years. Actuarial local control was 95% at 5 and 10 years. Radiation related complications included one patient with optic neuropathy, one with brain necrosis, and one that developed optic neuropathy followed by brain necrosis. The high dose group of patients who received a NSD or Neuret equivalent of greater than 60 Gy at 1.8 Gy per fraction had a significantly greater risk of radiation complications (p = .024). The actuarial risk at 5 years for optic neuropathy was 30% and brain necrosis was 12.5% in the high dose group. Tumor control in the high dose group was not shown to be significantly better. Any possible benefit in tumor control in treating patients with craniopharyngioma with doses above 60 Gy at 1.8 Gy per fraction appears to be offset by the increased risk of radiation injury.

Twelve children with cerebral metastases from non-lymphomatous primary tumors are reviewed. Eleven were treated with radiotherapy and four are alive without clinical or radiographic evidence of intracranial tumor 2-7 1/2 years later. Three of the four survivors are free of neurologic impairments. Eight patients died within two months of detection of cerebral metastases. There were no obvious differences between those patients who survived and those who did not, concerning the primary tumor, age at diagnosis, duration of symptoms or the interval from the primary to the cerebral metastases. All survivors are male.

From 1965 to 1984, ten patients with suprasellar or pituitary tumors received repeat courses of radiation therapy at the Joint Radiation Oncology Center of the University of Pittsburgh. The radiation doses varied between 36.00 to 53.65 Gy for the first treatment course and from 35.00 to 49.60 Gy for retreatment. Six patients were treated for pituitary tumors, two for germinoma, one for optic glioma, and one for craniopharyngioma. One died of disease progression 19 years after a second course of radiation. Two patients were dead of intercurrent disease 0.2 and 1.5 years after repeat radiation. The remainder are free of disease progression 1.6 to 20.5 years after repeat irradiation. Optic neuropathy developed in one patient 1.3 years following a second course of treatment to 40 Gy in 20 fractions administered 7.5 years after initial treatment to 46 Gy in 23 fractions. Neither the Nominal Standard Dose nor the Neuret formula provided an adequate estimate of the repair of radiation. An estimation that 40% of the original radiation dose effect is still present appears to be a reasonable “rule of thumb” guideline to account for prior radiotherapy.

In Brain Tumor Cooperative Group Study 77-02, eleven institutions randomized 603 adult patients with supratentorial malignant glioma to one of four treatment groups following surgery: conventional radiotherapy (6000 cGy in 30–35 fractions) + BCNU, conventional radiotherapy + streptozotocin, hyperfractionated (twice daily) radiotherapy (6600 cGy in 60 fractions) + BCNU, and conventional radiotherapy with misonidazole followed by BCNU. Data were analyzed for the total randomized population and for the 557 patients (86% with glioblastoma multiforme) who met protocol eligibility specifications (including confirmed histopathology on central review). Median survival was approximately 10 months following randomization. Overall there was no statistically significant difference in survival among the four groups. Among non-glioblastoma patients, the misonidazole group appeared to have poor survival. Peripheral neuropathy was a dose-limiting toxicity with misonidazole. It is concluded that neither the addition of misonidazole nor hyperfractionated radiotherapy as given in this protocol offered any advantage over conventional radiotherapy plus either BCNU or streptozotocin for treatment of malignant glioma.

Eight of 22 children with newly diagnosed medulloblastoma had asymptomatic spinal cord involvement detected by myelography. Two additional patients had demonstrable spinal cord lesions at the time of relapse in the posterior fossa. Cerebral spinal fluid (CSF) cytology results were inaccurate in predicting cord involvement. Seven patients have relapsed 9–69 months from completion of radiotherapy. Three had initial cord involvement and also bad subsequent cord involvement at the time of intracranial relapse or afterwards. Frontal lobe involvement as the initial site of relapse occurred-in 3 patients. Computerized tomography has been valuable in the early detection of intracranial relapse. Three children are alive and well 10, 18, and 19 months respectively from time of relapse. All were retreated with radiotherapy in conjunction with misonidazole and subsequent chemotherapy.

The present investigation reaffirms our observation that removal of a C3H mouse mammary adenocarcinoma results in a perturbation of tumor cells in a metastatic focus. An increase occurs in the proportion of cells undergoing DNA synthesis (labeling index, LI), and a decrease occurs in the proportion demonstrating estrogen receptor (ER index; ERI). The changes are transient but of sufficient duration and magnitude to produce an increase in the size of a distant tumor. This study was conducted to determine whether cytoreduction of a primary tumor by irradiation would produce a similar change in metastatic tumor cells and whether preoperative radiation would obtund the effect of primary tumor removal. The administration of a maximum tolerated dose of radiation (50 Gy) to a primary tumor produced a significant (p less than 0.001) increase in LI and decrease in ERI of a lesser magnitude than that observed following surgical removal of the primary tumor, but still sufficient to enhance the growth of a metastatic focus. Whereas, there was almost a 50% increase in LI in a metastasis 1 and 3 days following removal of a primary tumor the increase was only 13% three days after radiation. There was a 20% decrease in ERI 3 days following radiation and a 37% decrease at that time following tumor removal. Preoperative irradiation of a primary tumor 1, 3, or 5 days prior to tumor removal, obtunds the increase in LI and decrease in ERI following operation. Radiation the day before surgery was most effective because the changes in a distant focus occurring as a result of the radiation and of the surgery were prevented. The clinical relevance of these observations deserves further consideration.