Richard G. Evans

Patterns of failure after curative resection of pancreatic carcinoma

Thirty‐six patients underwent curative resection of a primary pancreatic carcinoma from January 1977 to September 1987; 26 had Whipple resections, seven had total pancreatectomies, and three had distal pancreatectomies. Twenty‐six patients manifested recurrent disease, four died of intercurrent disease, and six were apparently cured. Median survival was 11.5 months with actuarial survival at 2 and 5 years of 32% and 17%, respectively. of the eventual recurrences, 19% were local only (pancreatic bed, regional nodes, adjacent organs, and immediately adjacent peritoneum) and 73% had a component of local failure. All patients failing did so with a component in the intraabdominal cavity. Peritoneal (42%) and hepatic failures (62%) were common. Extraabdominal metastases were documented in only 27%, but never as a sole site. Fourteen patient and tumor characteristics were evaluated for any relationships with failure or survival. No single variable independently predicted for local failure. However, a group of three (age > 60 years, T2 or T3 stage, and location of tumor in the body or tail) was associated with a substantial local failure risk (85% of all patients with local failure). Multivariate analysis showed that low tumor grade (P = 0.002), female sex (P = 0.002), and adjuvant radiation (P = 0.02) were all independent predictors of prolonged survival. Ten patients were treated in an adjacent setting. Those given 55 Gy or greater had improved local control (50% versus 25%) and cure (33% versus none) when compared with patients treated to lower doses. The authors conclude that local failure after curative resection remains a significant problem and further efforts to improve local control are warranted. However, peritoneal and hepatic relapses occur frequently. Thus, adjuvant treatment strategies using wide‐field radiation techniques or intraperitoneal therapy, in combination with local tumor bed irradiation and chemotherapy, should be explored.

Management of advanced squamous cell carcinomas of the maxillary sinus

From 1970 to 1988, 41 cases of advanced maxillary sinus cancers were treated at the University of Kansas Medical Center. Local control for the 37 evaluable patients was achieved in 21 (57%). Local control by radiation therapy alone was achieved in ten of 19 (53%) patients compared with eight of 14 (57%) treated with a combination of surgery and radiation therapy. A dose greater than 6500 cGy correlated with better local control in patients treated with radiation therapy alone. Neck node failure occurred in three of 35 (8%) patients when not electively treated. Neck metastasis either at presentation or at a later stage reduced survival. The overall absolute survival for the entire group at 5 years was 35%. A combination of preoperative radiation therapy and surgery is recommended for patients with advanced‐stage maxillary sinus cancer. Radiation therapy is an equally good alternative for those who are not surgical candidates or refuse surgery.

Radiotherapeutic management of medulloblastoma in a pediatric patient with ataxia telangiectasia

Ataxia telangiectasia (AT) is a genetic disorder with a predisposition to malignancy. Cells from patients with AT demonstrate an increased sensitivity to ionizing radiation which creates a problem when these patients require treatment for their malignant disease. An eleven-year-old boy with a previous diagnosis of AT was seen in consultation following partial resection of medulloblastoma in the posterior fossa. To estimate how much the conventional radiation dose might have to be reduced, we compared the radiosensitivity of bone marrow myeloid progenitor cells from this patient to that of cells from the marrow of normal individuals, using colony formation in an agar culture assay system as the endpoint (CFU-Cs). Neither radiation dose-survival curve exhibited a shoulder--each displayed an extrapolation number of 0.99. The survival curve of normal cells displayed a steep slope with a D0 of 0.98 Gy (0.83-1.19 Gy, 95% confidence limits); the slope for the AT cells was considerably steeper with a value for D0 of 0.32 Gy (0.29-0.35 Gy). The ratio of D0s indicated that these AT cells were approximately 3X more radiosensitive than normal cells. Based on this, the daily dose was reduced from 1.8 to 0.6 Gy and the radiation was restricted to 25 treatments to the posterior fossa rather than the conventional cranio-spinal treatment. An additional 5 treatments at 1.0 Gy per day were given to the whole brain. The patients skin responded to these reduced fraction sizes and doses to a similar degree as normal patients skin following a standard schedule and the patient is doing well nine months after initiation of treatment.

Univariate and multivariate statistical analysis of high-grade gliomas: The relationship of radiation dose and other prognostic factors☆☆☆

Univariate and multivariate statistical analyses were used to examine the relationships between duration of survival and multiple variables in the presentation and treatment of 82 patients with high-grade gliomas (16 grade 3, 66 grade 4). The median survival time of the eight patients who received less than or equal to 40 Gy to the tumor bed was 16 weeks and was 17 weeks for the three who received between 40 and 50 Gy. Patients who received 50-60 Gy had a median survival time of 62 weeks, compared to 54 weeks in patients who received 60-70 Gy. These differences in median survival time were statistically significant between the extremes (p = 0.0001), as well as between the 40-50 Gy group and the 50-60 Gy group (p = 0.02). However, no significant difference could be detected between the groups receiving 50-60 Gy versus 60-70 Gy. Univariate analysis also identified preoperative performance status, age, histologic grade, extent of surgery, and seizure history as prognostic factors. Cox multivariate analysis was performed to identify variables that were significant in independently predicting duration of survival. Although contemporary studies have shown many variables to be significant in predicting survival, our analysis found that many of them were not independent predictors. The variables which independently predicted improved duration of survival were greater total radiation dose to the tumor bed (p less than 0.0001), superior preoperative performance status (p = 0.003), and grade 3 versus grade 4 (p = 0.04). Younger age at diagnosis was marginally significant (p = 0.07). In the group of 60 patients receiving greater than 50 Gy, a discriminant analysis was also performed. The patients were divided into two groups based on apparent clusters of survival times: greater than or equal to 60 weeks versus less than 60 weeks. The only variable that was found to be predictive of membership in the cluster with longer survival was the presence of seizure activity (p = 0.02). Although univariate and multivariate analyses both showed an apparent statistically significant improvement in survival with increasing total radiation dose to the tumor bed, no additional benefit could be demonstrated for doses greater than 60 Gy.

5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells

We evaluated conventional pulse exposure versus continuous exposure models of 5-fluorouracil (5-FU) radiosensitization in HT-29 (human colon adenocarcinoma) and DU-145 (human prostate cancer adenocarcinoma) cell lines. Cell survival following treatment with drug and/or radiation was determined by colony formation assays. Radiation was delivered either by itself, approximately midway through a 1-hr exposure to 5-FU (10 micrograms/ml), or at various times following initiation of exposure to 5-FU (0.5 microgram/ml) present throughout the entire period of incubation. Drug concentrations were selected to approximate those achieved in vivo in humans. HT-29 cells showed a plating efficiency of 87% and similar cytotoxicity (survival reduced to 0.57-0.71) for all 5-FU conditions. The Dos of the radiation survival curves were not different for 1 hr of 5-FU exposure versus radiation alone. However, continuous exposure conditions demonstrated statistically significantly different Dos from radiation alone and pulse 5-FU exposure. DU-145 cells displayed a plating efficiency of 17% and cytotoxicities of 0.10-0.91 for the 5-FU conditions. DU-145 cells showed different radiation 5-FU interactions: 5-FU produced statistically significant changes in Do well as the differences between cell lines insofar as their radiosensitization by 5-FU underscore the caution required in extrapolating these radiobiologic models to the clinical setting.

A phase I/II study of the use of Fluosol® as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors

The main objective of this study was to evaluate the safety and efficacy of a perfluorochemical emulsion, Fluosol, with short-term high inspired oxygen tension as an adjuvant to radiation therapy in the treatment of high-grade tumors of the brain. Radiation was delivered to the whole brain at 1.8 Gy per daily treatment for 5 weeks to a total dose of 45 Gy. The radiation portals were then reduced in size to encompass the known volume of tumor, as determined by the presurgical contrast-enhancing ring on computed tomography (CT), plus a 3-cm margin. An additional 10 treatments of 2 Gy each were given to the smaller volume, to bring the total tumor dose to 65 Gy in 7 weeks. This report describes the experience of the first 18 patients treated at the University of Kansas Medical Center on this study, whose median follow-up time from the date of surgery is 77 weeks (62-115 w). Immediately following Fluosol administration on a Monday, patients breathed 100% oxygen for at least 45 minutes prior to and throughout their radiation treatment. On each subsequent day of the weeks in which they received Fluosol, patients breathed 100% oxygen. Hematology and blood chemistries were also drawn prior to Fluosol treatment each Friday during treatment and at the 2-week, 3-month, and 6-month follow-up visits. The median age of the patients was 45 years (16-72); 13 patients were male and 15 carried the diagnosis of glioblastoma multiforme (3 had anaplastic astrocytoma). Two thirds of the patients had an initial allergic reaction to the Fluosol consisting of back pain, shortness of breath, and flushing, but all responded to 50-100 mg of Benadryl. During radiation therapy, all patients developed scalp erythema and complete alopecia by the end of 3 weeks, but no patient required a treatment rest. The serum levels of SGOT, SGPT, and alkaline phosphatase were examined before and throughout the Fluosol treatment and, by week 5, 11/18 of the patients had increased values of all three enzymes above the upper range of normal. These increases persisted through the end of treatment, but most values returned to essentially normal by the 3-month follow-up visit. We conclude that Fluosol, given in the manner described above, appears to be associated with minimal significant side effects and no changes could be detected in the white matter of any of the patients at the time of their magnetic resonance imaging study at 6 months follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)

Local recurrence of soft tissue sarcoma following brachytherapy

Twenty-five patients with soft tissue sarcomas were treated with Ir192 implants following wide local excision at our institution between 1982 and 1987. External beam radiotherapy was given in addition to the implant in a majority of patients. The median follow-up in these 25 patients is 36 months (12 to 75 months). Twenty patients have had no evidence of local recurrence following their primary treatment (FFR = 80%). A multivariate analysis using stepwise logistic regression was used to predict failure in 3 years or less. Potential predictors examined included age, sex, tumor location, primary versus recurrent disease, grade, histology, surgical margins, implant only versus implant plus external beam, and a ratio of the volume of tissue which received 65 Gy (TV65) to the tumor volume (TV), that is (TV65/TV). The single variable which was significantly associated with local failure by 3 years was a TV65/TV of less than one. Once this variable was entered into the analysis, no other factor proved statistically significant. Our data suggest that when attempting local control of soft tissue sarcomas with brachytherapy, the volume of tissue receiving 65 Gy (TV65) from both implant and external beam must exceed the volume of the excised lesion (TV). Since the volume of a tumor can be readily determined prior to surgical excision either by CT or MRI scanning, pre-planning of the implant volume could potentially reduce the rate of local failure.

Lack of complications in long-term survivors after treatment with fluosolR and oxygen as an adjuvant to radiation therapy for high-grade brain tumors☆

PURPOSEnA Phase I/II trial was initiated in 1987 to determine the toxicity/efficacy of the perfluorochemical emulsion Fluosol-DA 20% and 100% oxygen as an adjuvant to conventional radiation therapy for high-grade brain tumors.nnnMETHODS AND MATERIALSnThree grade 3 and 15 grade 4 patients received 1 Fluosol administration (8 mL/kg) per week with daily oxygen breathing prior to and during radiation therapy. Megavoltage radiation was delivered to the whole brain at 25 x 1.8 Gy, followed by 10 x 2 Gy to a boost volume, resulting in a total tumor bed dose of 65 Gy in 7 weeks.nnnRESULTSnOf the 18 patients, 10 (nine grade 4, one grade 3) survived more than 1 year postsurgery, six (all grade 4) lived more than 2 years, four of these patients lived more than 3 years, and three patients are alive at times ranging from 250 to 276 weeks. The median survival of the Fluosol group was 75 weeks, not statistically different from 54 weeks for a historical, matched control group. However, a Gehan-Wilcoxon test applied to those patients that survived > 1 year revealed a significant difference (p = 0.0013) in favor of the Fluosol group. Periodic clinical evaluations showed no evidence of any functional or neurological defects that could be attributed to radiation therapy and/or Fluosol. Radiographic studies (computed tomography and magnetic resonance imaging) revealed no structural alterations outside the original tumor volume, and changes within the tumor region were easily assignable to expected effects of tumor, surgery, or radiation alone.nnnCONCLUSIONnThese results indicate that, although Fluosol/oxygen added to conventional radiation therapy does not enhance survival of patients who succumb to their disease early, it does confer a significant benefit to patients that survive past 1 year. The minimal acute side effects and no long-term deleterious effects suggest that Fluosol/oxygen sensitizes only hypoxic cells, with no effect on well-oxygenated normal tissues within the brain. We have been impressed by the quality of life of the surviving patients following radiation therapy with adjuvant Fluosol+oxygen.

Combination of radiation therapy and intracranial bleomycin in the 9L rat brain tumor model

The rat 9L brain tumor model was used to investigate the therapeutic potential of a combined modality approach using intracranial Bleomycin and radiation therapy. Bolus Bleomycin was delivered intracranially into the tumor volume via cannula guides; for continuous infusions, osmotic mini-pumps were implanted subcutaneously between the scapulae with flexible tubing to deliver the drug directly into the tumor and brain. Two to six bolus injections of Bleomycin (1 unit/kg each) over 5-11 days produced modest (usually statistically significant, p less than 0.05) increases in the median survival time compared to controls. Continuous infusion of Bleomycin by osmotic pump (10 units/kg over 7 days or 15 units/kg over 14 days) was also effective at significantly increasing median survival times compared to that of controls. Radiation therapy schedules of 10 daily fractions in 12 days (2 weeks) or 10 twice-daily fractions in 5 days produced dose-dependent increases in median survival time. Multiple bolus injections of Bleomycin when combined with fractionated radiation therapy significantly increased the median survival time due to fractionated radiation therapy alone for low doses (40 or 50 Gy). However, at higher radiation doses, the addition of Bleomycin either had no effect on median survival time or actually shortened it. Continuous infusion of Bleomycin by osmotic pump was effective when added to low dose radiation therapy in several experiments, twice for a total radiation dose of 50 Gy and once for radiation therapy of 60 Gy. However, it was also observed (once for 60 Gy and twice for 70 Gy) that the addition of continuous infusion Bleomycin either had no effect or served to decrease the improvement of median survival time obtained by radiation therapy alone. Thus, we conclude that increases in normal tissue toxicity can prevent full attainment of improved therapeutic advantage from the addition of Bleomycin to fractionated radiation therapy in the rat 9L model. These results should be considered when attempts are made to combine radiation therapy and intracranial Bleomycin for the treatment of patients with primary malignant brain tumors.

Intracerebral chemotherapy in the 9L rat brain tumor model

SummaryWe have used the 9L rat brain tumor model to search for effective chemotherapeutic approaches to the management of brain tumors. Several antineoplastic agents which have been proposed or are currently being used for human brain tumors, including 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), bleomycin, aziridinylbenzoquinone (AZQ), cis-Platinum, and acivicin, were administered intravenously (iv), intraperitoneally (ip), or intracerebrally (ic) to rats burdened with the intracranial 9L gliosarcoma. The results confirm that BCNU is the most effective systemic agent among the chemotherapeutic agents tested as indicated by its ability to significantly increase the median survival time (MST) and life span of the tumor-burdened animals. Bleomycin is an effective agent against the intracranial 9L tumor when administered ic. While neither systemic single iv dose AZQ (0.5–2.5 mg/kg) nor multiple ip treatments (0.5–1.0 mg/kg × 5, q 6 h) were effective in prolonging the survival, single is dose AZQ (5–50 μg/rat) treatment significantly increased the MST of the treated animals (P < 0.05). Systemic AZQ treatments using higher doses produced a hematological toxicity, resulting in a decrease in MST of the treated animals. Cis-Platinum, either administered ip or ic, produced only a marginal effect on survival, although acute neurologic toxicity limited the dose of cis-Patinum that could be administered ic. Acivicin, either administered ip or ic, produced no effect on the survival of treated animals. Our results suggest that local treatment with certain antineoplastic agents may be an efficient therapy in the management of brain tumors.