Ida B. Scudder, 1900-1995.
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Biomedical subjects
Publications and source records attributed to C F von Essen.
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BACKGROUND: The treatment of bladder cancer with 60 converging pion beams was expected to have certain dose-distribution advantages with possibly fewer side effects than other high linear-energy-transfer (LET) radiation therapies, such as neutrons. RESULTS: Early results were promising: 20 of 24 (83%) evaluable patients with sessile invasive bladder carcinomas had clinically complete responses. However, only 3 of 10 (30%) evaluable patients with superficial bladder tumors had clinically complete responses. This article reports the long-term follow-up (6-8 years) of these patients with emphasis on the late side effects of pion radiation therapy. Thirty-eight of the 41 (93%) patients treated died after a median survival time of 17 months (range, 4-98 months). Seventeen (45%) died of metastatic disease (in two instances, this was combined with a local recurrence) 5-27 months after radiation therapy. Four (10%) died of locally progressive disease, and eight (21%) died of late side effects of radiation therapy 9-98 months after treatment. All these patients were treated with more than 33 pion Gy and had generally a symptom-free interval of 9-18 months. The observed side effects were severe, consisting of chronic inflammation and vascular damage in the pelvic region often followed by ulceration, fistulas, and perforations throughout the intestines. In 11 patients, cystectomy and urinary diversion was necessary because of excessive fibrosis and bladder shrinkage. In eight patients, a colostomy was required for stenotic inflammatory disease, necrosis, and perforations of the intestines. The remaining nine patients (24%) died of causes unrelated to the primary disease 4-60 months after radiation therapy. CONCLUSIONS: The results of the first Phase I/II trial using the Swiss piotron showed a high complete response rate in patients with sessile bladder cancers but also a high incidence of local recurrences and severe, in some instances lethal side effects. Although it is expected that these results will be the basis for future improvements, particularly regarding dosing and fractionation, this experience emphasizes the need for a sufficiently long observation period before reaching conclusions about any high LET treatment, such as neutron, pion, or heavy ion radiation therapy.
Clinical phase I/II studies have been performed at the Swiss Institute for Nuclear Research (SIN) since February 1982. Fifty-two out of 249 patients accepted for pion treatment by the end of 1986 were treated for malignant glioma with high dose pion irradiation. A substantial influence of their radioresistance was expected from increased radiation quality due to the contribution of high LET particles from pion capture, and by the possibility of target volume shaping and dose distribution related to the dynamic spot-scan conformation technique. The patients' treatment followed a dose escalation program with total doses from 2720-3420 cGy, fraction sizes from 170 to 205 cGy (90% isodose, minimum target dose), and treatment times from 4 to 5 weeks. 12/52 patients received an accelerated treatment with 3280 cGy in 14-22 days. 49/52 patients are eligible: 3 with astrocytoma of clinical aggressive behaviour, 14 with anaplastic astrocytoma (median age 42 years), and 32 patients with glioblastoma (median age 52 years). 8/49 patients had total/subtotal tumour resection, 19 patients a stereotactic biopsy. The patients were divided into three groups according to total dose, and a fourth group which received the accelerated treatment. There was no statistically significant difference in the median survival rate between the four groups, which was 13 months for the non-glioblastoma patients and 9 months for the glioblastoma patients. No radiation necrosis and no demyelination was found in 17 patients (6 recraniotomies, 11 autopsies). In 10/17 patients, clearly identifiable tumour cells were not demonstrated. NMR findings showed the tumour-surrounding oedema mostly stimulated by tumour necrosis and tumour progression. From these findings, further dose escalation programs, together with a shaping of the target volume close to the tumour, are not contraindicated.
Since November 1981, when pion irradiation was introduced for deep seated tumors at the Swiss Institute for Nuclear Research (SIN, now Paul Scherrer Institute, PSI) a dynamic, 3-dimensional spot scan treatment technique has been in use. To exploit this technique a special optimization treatment planning system has been designed. Of a total of 331 patients treated with pions from November 1981-December 1987, 35 were irradiated for unresectable soft tissue sarcomas. In 32/35 patients, tumor sites were retroperitoneal, pelvic or in the groin or thigh. Twenty-nine tumors had a maximum diameter of greater than 10 cm, 18 tumors of greater than 15 cm; 30 tumors had grade 2/3 and 32 Stage III B/IV A/IV B. Eight of 35 patients received a low pion total dose, 7-27 Gy. Twenty-seven patients received a total dose of 30-36 Gy, fraction size 150-170 cGy (90%-isodose), 20 fractions, 4 times per week. Of these 27 patients, severe late reactions appeared in five: 2/8 patients with extremity/groin sarcomas (1/2 caused by biopsy) and 3/19 patients with retroperitoneal/pelvic sarcomas (one a skin reaction after Actinomycin-D, one a small bowel reaction after 36 Gy, a dose no longer used). Seven of 27 patients had metastases at the beginning of irradiation. Three of 27 were treated with excisional biopsy, 9 with incisional biopsy or partial resection and in 15 patients biopsies were performed for histology only. The median follow-up of these 27 patients was 17 months (5-66). There was no progression in eight extremity/groin tumors but in 4 of 19 retroperitoneal/pelvic tumors. Three of these were marginal progressions. The actuarial 5-year rate of local tumor control is 64%; the actuarial 5-year survival rate of patients without metastases at the beginning of treatment is 58%. Dynamic spot scan pion irradiation proves to be a successful treatment technique for unresectable sarcomas with a high rate of tumor control and a very low rate of severe late reactions.
Two hundred twenty-eight patients were treated at the Los Alamos Meson Physics Facility (LAMPF) with negative pi-mesons (pions) between 1974 and 1981. Of these, 19 patients with metastatic disease were treated in pilot studies. Following the clinical determination of relative biological effectiveness (RBE) of pions, 209 patients were treated in site and dose searching studies beginning in 1977. Advanced but regionally localized cancers that were considered poorly responsive to conventional therapy were selected for treatment. A wide range of treatment fractions (22 to 45) and of total dose (1800 to 4200 cGy at the 80% isodose level) to the prescribed target volumes was explored. A follow-up observation period of between 4.5 and 9 years has been completed. The analysis focuses on 129 patients receiving pion therapy alone. Thirty-six (28%) had persisting local tumor control of which 12 (9%) suffered complications of treatment. The results varied among treatment sites, for example: prostate cancer, 18/21 (86%) locally controlled, 6/21 (29%) complications; head and neck, 8/31 (26%) locally controlled, 1/31 (3%) complications; and pancreas, none controlled and no complications. Analysis of dose-fraction response suggests a steep rising curve of complications beyond the dose level of 3750 cGy minimum, 4700 cGy maximum, in 38 fractions. The tumor control response has a broader and ill-defined curve possibly due to the heterogeneity of tumor types. The RBE for late effects in normal tissues appeared to be higher than that for acute effects although the mixture of tumor types, sites, dose, and fractionation made this estimate highly uncertain. No late secondary neoplastic changes in pion irradiated tissues were seen. It is concluded that pions can locally ablate some advanced cancers, often without significant sequelae, but that the optimum therapeutic range is critical. The Los Alamos data may be of use to ongoing pion studies in Canada and Switzerland.
Negative pi-meson (pion) therapy employing dynamic scanning with a focused spot of convergent beams has been in use since 1981 at SIN. Three-dimensional conformation of the treatment volume to the target volume can thus be achieved. Following previously reported Phase I and Ib clinical trials, a Phase II trial was initiated with the goal of treating primary deep-seated tumors in a dose optimization schedule which included stepwise increase of total pion dose and of target volume. Patients with multicentric superficial bladder tumors who were cystectomy candidates were initially selected. Since then, more invasive cases have been treated. A graded scoring of acute tissue reactions was employed. Follow-up periods were from 10 to 20 months. The pion dose escalation ranged from 3000 rad (minimum) to 3600 rad (minimum) in 20 fractions over 5 weeks. The treatment volumes encompassed 190 cc for local to 1,820 cc for extended volume therapy. Treatment reactions ranged from a faint erythema and increase of bladder frequency to dry desquamation, mild nausea, moderate dysuria, and moderate proctitis or diarrhea with mucus. These reactions were closely related to treatment volume and site. One severe late cystitis has occurred in a patient treated with 2 courses of pions (4475 rad). Mild to moderate late proctitis has been seen in 4 patients. Ten of 13 bladder cancer patients had local control of disease while all 3 pancreas or biliary tract cancer patients had microscopic residual disease locally at time of death from metastasis. A total of 11 of 17 patients are thus clinically or pathologically free of local tumor to time of last observation.
Negative pi mesons (pions) were used to treat 227 patients at the Los Alamos Meson Production Facility (LAMPF) between 1974 and 1981. Persisting local control values for 129 patients treated with pions alone in the following tumor sites were recorded at a minimum post-treatment observation interval of 2.5 years in the following tumor sites: cerebral gliomas 3/29; head and neck, 8/31; lung, 1/7; pancreas, 0/17; large bowel, 3/13; cervix, 2/45; bladder, 3/4; prostate, 18/20; miscellaneous sites, 0/4. Late severe sequelae ranged from none to 30% for major sites. A dose-response relationship was seen for late severe sequelae with a high probability following dose levels of 4750 cGy (max) in approximately 38 fractions. RBE values for pions appeared to lie in the range of 1.4-1.6 for both acute normal tissue reactions and late sequelae. At the Swiss Institute for Nuclear Research (SIN), 126 patients were treated in Phase I-II protocol studies between 1982 and 1984 with a new technique of scanning with a focused spot of pions. With minimum observation intervals of only 6 months, the local complete response values in 67 evaluable patients treated with pions alone to selected sites are gliomas 1/15 (9 months); pancreas, 3/11; cervix, 4/8; bladder, 18/26 (at 1 year, 9/22); sarcomas, 4/5; biliary tract, 3/4. Late severe sequelae ranged from none to 50% for major sites. A steep dose-response relationship is seen for late severe sequelae with high probability following doses exceeding 3800 cGy (max) in 20 fractions and very low probability with doses below 3500 cGy (max).
The results of neutron and neutron boost irradiation of 199 patients with soft tissue sarcomas treated between 1978 and 1983 are presented. The median follow-up period is 42 months. The recurrence free survival rates by last review are 93% for patients with T1 tumours (n = 14), 87% for T2 tumours (n = 84) and 73% for T3 tumours (n = 101). The actuarial survival rates at six years are 77% for T1, 63% for T2 and 34% for T3 tumours (p = 0.018). The actuarial survival rate for the group of patients irradiated after surgery without clinical evidence of residual tumour is 63.8% compared with 30.9% for the group of patients with measurable tumour volume at the beginning of radiotherapy (p = 0.002). The survival rates according to grading are 52% for patients with G1 tumours (n = 44), 54% for G2 tumours (n = 130) and 36% for G3 tumours (n = 25). The morbidity rate of 22% after full neutron irradiation was reduced to 15% by the introduction of a neutron boost. At the present time, the results of this modified treatment are not inferior to a full neutron course. The effectiveness of neutron or neutron boost irradiation in the postoperative treatment of soft tissue sarcomas will be evaluated in a forthcoming EORTC trial.
The experiences of the treatment of bladder carcinoma indicated the direction in which the dose optimization program of intraabdominal tumours can be carried out. Small intraabdominal target volumes seem to tolerate doses from 31 to 33 Gy applied in 20 fractions. The best results with local tumour control and low complication rates have so far been reached in carcinoma of the cervix. It has not so far been organizationally possible at SIN to treat with pions on more than four days per week. This restricts changes to the fractionation scheme in the treatment of highly malignant gliomas. An improvement of results could be possible on the basis of experience to date. The significance of a postbiopsy preoperative radiotherapy, of the increase of target volume and the increase of the total dose will be tested in a study by the SAKK (Swiss Group for Clinical Cancer Research).
The Brachytron has been used in the University of California at San Diego Medical Center since 1970 as one method of treating gynecological malignancies. This machine contains a high intensity cobalt 60 remote afterloading cycling source used for intracavitary brachytherapy. One hundred twenty-seven patients with epithelial carcinoma of the cervix are available for analysis of 5-year survival, and 176 are analyzed for treatment complications two years following therapy. Five year survival figures for FIGO-staged patients treated with external beam pelvic irradiation and intracavitary Brachytron treatments are as follows: Stage I, 89%; Stage II, 58%; Stage III, 33%, and two of five patients Stage IVa. Rectal complications graded moderate or severe (M, S) were dose-related and gradually decreased over the years as techniques improved. Complications from early results in 1970-1972 (24% M, 10% S) were reduced to lower levels in 1976-1979 (14% M, 4% S). The Brachytron offers the advantage of rapid dose delivery. Thus, patients can be treated in an outpatient setting, avoiding the cost of hospitalization and the risks of anesthesia. The Brachytron also offers virtually complete radiation safety to all attending medical personnel. With survival and complication figures similar to those reported for patients treated with conventional low-dose-rate brachytherapy, the Brachytron represents an effective alternate mode of therapy for uterine carcinoma.
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The prognosis of pancreatic adenocarcinoma is still very poor. Research activities have, however, been instituted recently in all fields. Epidemiologic studies indicate etiologic roles of diabetes mellitus, smoking, and meat and coffee consumption. Sonography of the pancreas is at present the best screening method. The significance of computerized tomography, endoscopic retrograde cholangiopancreatography (ERCP), arteriography and tumor markers is discussed. A TNM staging system and prognostic factors are presented. Resection is the treatment of choice for organ-limited pancreatic cancer. The development of new radiation modalities (e.g. pi-mesons) promises improved loco-regional tumor control. The most effective chemotherapy consists of combinations containing 5-fluorouracil, adriamycin and mitomycin-C. Intensive future research in the field of pancreatic cancer is essential if the prognosis of this devastating disease is to be improved.
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The PIOTRON is a large solid angle superconducting channel built for the use of negative pi-mesons in radiotherapy. The pions are produced by protons of 590 MeV striking a target of molybdenum or beryllium. The pions are divided into 60 channels and deflected twice to enter the treatment volume radially. The momentum and the momentum band for all 60 channels can be chosen and the beam spot of Bragg peak pions at the isocenter of the applicator is a few centimeters in each direction. Dynamic scanning can thus achieve 3-dimensionally shaped treatment volumes. Two different methods are available: the ring scan, using changes of pion range; and the spot scan, involving translation of the patient through the fixed beam spot. Dose distributions of individual and multiple beams were plotted in a cylindrical water phantom. Radiobiological experiments with mammalian cells in gel and with mouse feet were performed. A special beam geometry using a sector of 15 beams was selected for the first treatments of patients with metastatic skin nodules. Six patients were treated. Acute skin reactions were scored and compared with those from orthovoltage therapy with comparable beam geometry. The RBE for 10 fractions is between 1.4 and 1.5. The next step involved treatment of patients inside water-bolus rings in preparation for dynamic therapy. Patients were then treated with the spot scan dynamic mode in the water bolus. The initial responses and reactions are favorable and confirm the feasibility and accuracy of dynamic pion therapy.
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Forty-one patients with a total of 86 tumors were treated with negative pimesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) through December 31, 1977. An additional 30 tumors in the total patient population were treated with 100 kVp x-rays to assess comparative effects on skin nodules and 8 patients received additive photon or electron radiation to pion-treated portals. Of 52 evaluable tumors in 20 patients treated with pions only and followed for 3 to 22 months, 81% (42 tumors) completely regressed; 6% (3 tumors) partially regressed; and 13% (7 tumors) did not respond, although 5 of the 7 have shown no growth for 10 months. Of eight tumors in seven patients treated with a combination of pions and conventional radiation, three tumors showed complete response and five tumors showed partial response, though the resected specimens in two (one with complete and one with partial response) revealed no tumor microscopically. Reactions in normal tissues have been mild, with some patients exhibiting no normal tissue reaction, as compared with relatively marked tumor response.