Total body irradiation for myasthenia gravis: a long-term follow-up.

Total body irradiation (TBI) produces prolonged immunosuppression with rare side effects. We studied 12 thymectomized patients affected with chronic generalized severe myasthenia gravis. All patients had been totally or partially refractory to prolonged oral treatment with immunosuppressive drugs, and most had contra-indications for these drugs. Low-dose (1.8- to 2.3-Gy total dose) TBI was administered in single, 0.1-Gy doses, two to three times per week. TBI was well tolerated and was associated with objective clinical improvement in six patients, lasting more than 2 years in five. In addition, TBI produced a long-lasting lymphopenia with a pronounced decrease of T CD4+ lymphocytes; T CD8+ lymphocytes were almost unchanged over the 2 years of the study. CD16+ and CD20+ lymphocytes, after an initial decrease, increased above baseline. TBI was also associated with decreased anti-AChR antibody titer. The decrease of lymphocyte count and of anti-AChR antibody titer was more pronounced in the patients who improved, suggesting that lymphopenia and immunosuppression may have contributed to clinical improvement.

Thyroid dysfunction as a late effect in childhood medulloblastoma: a comparison of hyperfractionated versus conventionally fractionated craniospinal radiotherapy.

PURPOSE: Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of childhood medulloblastoma. Due to the strong radiobiologic rationale, hyperfractionation can reduce the delayed effects of radiation injury. METHODS AND MATERIALS: The authors compared the incidence of thyroid dysfunction after conventionally fractionated radiotherapy (Group A, n = 20 patients) vs. hyperfractionated radiotherapy (Group B, n = 12 patients) in a group of pediatric patients with posterior fossa primitive neuroectodermal tumor (PNET). RESULTS: The mean age at the time of tumor diagnosis was 7.4 years in Group A and 8.4 years in Group B. Thyroid function was evaluated yearly, with ultrasonographic examination every 2 years. The patients were followed after diagnosis for a mean of 10.8 years for Group A and 6.0 years for Group B. Approximately 80% of the Group A (16/20) and 33.3% of the Group B (4/12) patients developed primary hypothyroidism within a similar period after irradiation (4.2 vs. 3.5 years, respectively). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (p < 0.05). Ultrasonography showed reduced thyroid volume in 7 Group A patients and structural changes in 21 patients (17 Group A, 4 Group B cases); a thyroid benign nodule was detected in 2 Group A patients. CONCLUSIONS: The current study findings suggest that the use of hyperfractionated craniospinal radiotherapy in the treatment of childhood medulloblastoma is associated with a lower risk of these patients' developing late thyroid dysfunction.

Role of radiation therapy in locally advanced thymoma.

The records of all patients treated for thymoma in the Department of Radiotherapy of the University of Torino between 1970 and 1988 were reviewed. There were 77 patients in stage III or IVa (59 in stage III and 18 in stage IVa); 74 patients were operated upon before radiotherapy and 3 had a pre-operative irradiation followed by surgery and post-operative boost. Complete resection was possible in 55.9% of cases with stage III and in none with stage IVa. Subtotal resection was done in 35.6% of patients in stage III and 83.3% in stage IVa. 8 patients had only a biopsy: 5 in stage III (8.5%) and 3 in stage IVa (16.6%). Post-operative radiation doses ranged between 39.6 and 46 Gy to the whole mediastinum followed by a 10-16 Gy boost on smaller fields in cases presenting residual disease after surgery. The pre-operative dose was 30 Gy followed by a post-operative boost of 16-24 Gy. Conventional fraction sizes of 1.8-2 Gy were always used. The 10 years survival rate was 58.3%. There was a significant difference between stage III (70.9%) and stage IVa (26.3%) (p less than 0.0004). Survival of patients in stage III was not significantly affected by the type of surgery. No significant difference in survival or recurrence rate was observed in patients with different histologies and in patients with or without myasthenia. Thoracic relapses occurred in 15.2% of patients in stage III and in 50% of patients in stage IVa (p less than 0.01). Only 7 relapses (9.1%) were within the limits of the radiation field.(ABSTRACT TRUNCATED AT 250 WORDS)

Technique, dosimetry and results of total body irradiation in preparation to ABMT in Torino.

Twenty-five patients with haematologic malignancies received total body irradiation (TBI) as part of their conditioning regimen prior to autologous bone marrow transplantation (ABMT). TBI was delivered with an 18 MeV photon beam through AP-PA ports; the total dose was 13.2 Gy/8 fractions over 4 days; shields were used to limit the total dose to the lung to 8-10 Gy. Five relapses were observed; among 14 patients with ALL or advanced lymphoblastic lymphoma, 10 patients are currently alive and free of disease. Acute and late morbidity of TBI were low.

Aggressive treatment of intrathoracic recurrences of thymoma.

Between 1974 and 1988, 21 patients with intrathoracic recurrences of thymoma received radiotherapy with radical intent; surgery was always attempted when considered feasible: 11 patients were partially (6 cases) or totally (5 cases) resected before irradiation, while in the other 10 radiotherapy was the only treatment. In 7 cases the recurrence was confined to the anterior mediastinum, 9 had pleural nodules without mediastinal lesions and 5 had both mediastinal and pleural lesions. Mediastinal recurrences were treated by opposed parallel mediastinal fields with 2/3 of the dose delivered through the anterior port: doses ranged between 38 and 44 Gy; a boost of 10-16 Gy was given in patients not radically resected. Pleural nodules were treated with a variety of techniques according to the extent of the lesions. The 7-year survival of the whole group was 70%; 5 patients died: 4 with intrathoracic progression and one with distant metastases. The survival was 74% in the 11 patients having received surgery, either radical or subtotal, and 65% in the 10 patients treated with radiotherapy alone: the difference is not significant. Patients with Karnofsky index greater than 70 had a significantly better survival (100%, versus 28%, p = 0.0015). This is a selected series of patients presenting recurrences still amenable to a radical treatment either by surgery and radiotherapy or by radiotherapy alone: the results confirm that an aggressive approach is warranted in patients in good general conditions with recurrences confined to the mediastinum and/or 1 hemithorax.

Biological predictors of response to radiotherapy in cervical carcinomas.

On 21 patients with T1b-T3b tumours subjected to external radiotherapy and brachytherapy, the expression of P53 and glutathione S-transferase pi [GST-pi], immunohistochemically detected, the S-phase cells fraction (H-3-thymidine labeling index, TLI) and DNA content evaluated by image analysis were determined on biopsies before and after the first 10 Gy. P53 accumulation was reduced in 60% of P53-overexpressing tumours and not induced in P53-negative tumours, GST-pi was induced in about 40% of pretreatment GST-pi-negative cases, TLI was reduced in 70% of the cases regardless of pretreatment values, and DNA profiles remained unchanged in two-thirds of the cases. P53 accumulation was a predictor of 3-year relapse-free survival after radiotherapy, followed by GST-pi expression, whereas TLI did not influence prognosis.

Daily low-dose carboplatin and standard radiotherapy in unresectable head and neck and lung cancers: a pilot study.

A total of 14 patients with locally advanced and unresectable head and neck (SCCHN) or non small cell lung cancer were treated with a definitive course of radiation therapy with conventional fractionation and 30 mg/m2 carboplatin (CBDCA) given daily as an i.v. infusion during the 1st, 3rd, 5th and 7th weeks of the combined treatment. The planned tumor dose of at least 7000 cGy was reached in all SCCHN patients except 1 (6600 cGy). The 2 NSCLC patients received 6320 and 5980 cGy, respectively. The planned total CBDCA-dose of 600 mg/m2 was administered in all patients. No treatment delays were required in 10 patients. Interruptions for severe mucositis or myelosuppression occurred in 4 patients (28.6%), but in no case did the delay exceed 1 week. Complete response was obtained in 8 patients (57.1%); 7 of the 12 with SCCHN and 1 of the 2 with NSCLC. The other 6 patients achieved a partial response. Granulocytopenia of WHO grade 3 occurred in 1 patient; apart from vomiting and mucositis, toxicities above grade 2 were not observed.

[Mantle irradiation with 18 MeV photons. Measurement and calculation of dose distribution]. / L'irradiazione a mantellina con fotoni da 18 MeV. Misura e calcolo della distribuzione della dose.

Dose distribution in mantle fields irradiated with 18 MeV photons has been studied in an Alderson-Rando phantom with thermoluminescent dosimeters. The treatment was also simulated on an RT-plan 7000 computer; calculated and measured doses in anatomical sites of major interest were compared. Doses in all significant points were within +/- 7% of the doses at the reference point. Calculated and measured doses agreed within +/- 5% except points situated near unhomogeneous tissues. The authors discuss their results and present conclusions about algorithms for computer dose calculation in irregular field treatments.

[Total skin therapy with electron beams. I. Physical and geometric factors]. / Terapia cutanea totale con fasci di elettroni. Parte I. Fattori fisici e geometrici.

The study pf physical and geometrical factors influencing dose distribution is necessary in performing the Total Skin Electron Therapy. The authors examined some aspects. Photographic emulsions in humanoid phantom were used for dosimetry. The techniques uses 6 dual fields at 320 cm treatment distance, with a degrading lucite filter 100 x 200 x 0.6 cm3 at 20 cm from the patient. Absorbed dose and energy were determined according TG 30 and 21 AAPM. The position of degrading filter was recognized to be the main factor influencing dose rate, penetration depth and dose homogeneity.

[Total skin therapy with electron beams. II. Clinical results in mycosis fungoides]. / Terapia cutanea totale con fasci di elettroni. Parte II. Risultati clinici nella micosi fungoide.

Between 1985 and 1989, 19 patients with mycosis fungoides were treated by Total Skin Electron Therapy (TSET). Overall and disease-free survival at 3 years were 72% and 40%. The complete remission (CR) rate was 100% in patients with plaque and 33.3% in those with tumor masses; patients with negative nodes had a 90% CR rate whereas in those with adenopathy the rate was 55%. Overall and disease free survivals were also correlated with these factors.

[Total cutaneous irradiation with low energy electrons and mycosis fungoides. Technic and dosimetry]. / Irradiazione cutanea totale con elettroni di bassa energia e micosi fungoide. Tecnica e dosimetria.

Mycosis fungoides initially involves the epidermis and the superficial layers of derma at a depth of about 1 cm. Wide field irradiation with low energy electrons is therefore the treatment of choice in the initial stages of the disease. In our Institute, total skin electron beam irradiation is delivered with Therac 20 linear accelerator: the lowest available energy is 6 MeV. A lucite sheet of 0.6 cm thickness is used to decrease the energy of the beam. We used film dosimetry to evaluate the homogeneity of dose distribution in an Alderson-Rando phantom with different arrangements of the fields and the lucite sheet: 4 and 6 fields techniques have been compared with different positions of the lucite filter, near the phantom and near the collimator. Six fields yield a better dose distribution: homogeneity is within +/- 3.7%, while with four fields it is within +/- 6%. X-rays contamination is less than 2%. "In vivo" dosimetry has been performed using thermoluminescent dosimeters: homogeneity is within +/- 15%.

[Technic and dosimetry in total body irradiation with 18 MeV photons]. / Tecnica e dosimetria nell'irradiazione corporea totale con fotoni da 18 MeV.

Total body irradiation (TBI) is used in our Institution in the conditioning regimen for bone marrow transplantation. The fractionation pattern consists of two daily fractions of 1.65 Gy repeated for 4 days (total dose 13.20 Gy in 8 fractions). Lung dose is reduced by means of lead custom shaped shields directly strapped to the patient surface. TBI is delivered by a THERAC 20 linear accelerator with two opposing AP-PA photon beams with a maximum energy of 18 MeV. Treatment distance is 340 cm and the patient is treated in a semi-standing position. Dosimetry studies in a homogeneous phantom were performed in the treatment geometry and consisted in the determination of: tissue maximum ratios (TMR) at different depths, absorbed dose along the median axis and the diagonal of the field, variation of the absorbed dose in the prescription point with different volumes of scattering material, and transmission of shielding and compensating material. A semi-empiric formula for the calculation of absorbed dose in a point has been obtained. A subsequent study in a Rando phantom with termoluminescent dosimeters (TLD) has shown a +/- 5% agreement between calculated and measured values and a +/- 7% homogeneity.

Lateral high abdominal ovariopexy: an original surgical technique for protection of the ovaries during curative radiotherapy for Hodgkin's disease.

An original surgical method for gonadal protection in young women given pelvic radiation for Hodgkin's disease is presented. Lateral high ovarian transposition (LHAO) consists of the transposition of the ovaries into the paracolic gutter during staging laparotomy, after disconnecting the gonads from the fallopian tubes by dividing the tubo-ovarian vessels. The technique's effectiveness was assessed by a study using clinical investigation, radioimmunoassay (RIA) determination of sex hormones, and dosimetry; of 18 patients treated, 10 participated in the study. All but one have normal menses and hormone values, and one pregnancy occurred. We also calculated the doses absorbed by the ovaries and proved that, during inverted Y irradiation following LHAO, the ovaries are exposed to nearly one-half the dose they receive after traditional medial transposition. During subtotal nodal irradiation after LHAO, the irradiation dose is higher than after medialisation, but absolute values are minimal and castration is not induced.

Endometrial stromal sarcoma: analysis of treatment failures and survival.

The objective of this retrospective multicenter study was to assess the rates, times, and sites of recurrences of 26 patients with low-grade endometrial stromal sarcomas (ESS) (<10 mitoses per 10 high-power fields (HPF) and 40 patients with high-grade ESS (>10 mitoses/10 HPF). Surgery was the initial therapy for all patients. Postoperative treatment was given without well-defined protocols. The median follow-up of survivors was 92 months (range, 4-167). Low-grade ESS: Of the 20 patients with disease confined to the uterus, 5 (25.0%) developed pelvic recurrence after a median of 36 months (range, 4-108). Of the 6 patients with disease outside the uterus, only one recurred in the pelvis after 93 months. High-grade ESS: Of the 20 patients with disease confined to the uterus, 11 (55.0%) developed recurrent disease after a median of 5 months (range, 2-76). The relapse occurred in the pelvis in 3 patients, in upper abdomen in 3, in upper abdomen and extraabdominal sites in 1, and in the pelvis and upper abdomen or extraabdominal sites in 4. Of the 12 patients with extrauterine disease confined to the pelvis, 9 (75.0%) developed recurrent disease after a median of 12 months (range, 1-49). The relapse occurred in the pelvis in 3 patients, in extraabdominal sites in 3, and in the pelvis and upper abdomen or extraabdominal sites in 3. Of the 8 patients with extrauterine disease outside the pelvis, 7 died of disease and 1 is currently alive with progressive disease after 24 months. The disease-free survival was significantly better for low-grade than that for high-grade ESS (P = 0.0001). By log-rank test the disease-free survival of high-grade ESS patients was related to stage (P = 0.0466) and mitotic count (P = 0.0014), but not to age. Cox model showed that mitotic count was the only independent prognostic variable for high-grade ESS (P = 0.006). In conclusion, low-grade and high-grade ESS have a completely different biological aggressiveness and clinical behavior.

Role of thoracic computed tomography in the treatment plan of Hodgkin's disease.

Conventional chest X-rays and CT scans, performed at the time of the initial staging in 67 patients affected by Hodgkin's disease, were reviewed and compared. CT scans provided evidence of disease not shown by concomitant conventional chest X-rays in 10 patients (15%). The impact on patient management of the additional CT data was evident in 8 cases (11.9%), either changing the whole treatment plan (4 patients) or enlarging radiation ports (4 patients). Traditional prognostic features did not influence the outcome, and only hilar adenopathy adversely affected event-free survival, without however reaching statistical relevance (p greater than 0.05). Our data suggest that thoracic CT scan is helpful in drawing up the treatment plan, while its role in identifying new prognostic factors is still uncertain.

Predictive value of the early response to chemotherapy in high-risk stages II and III Hodgkin's disease.

A series of 60 patients with "high risk" Stage II and III Hodgkin's disease (B symptoms, or large mediastinal mass, or E lung disease) were staged without laparotomy and treated with combined modality treatment: mechlorethamine, vincristine, procarbazine, and prednisone (6 MOPP) plus radiotherapy. Patients were restaged after the first three courses of MOPP and the status of response to therapy at that time was called early response to chemotherapy (ERC). The rate of nitrogen mustard and procarbazine delivery (MRD) during the first three cycles of chemotherapy also was assessed. At the completion of the therapy patients were restaged and the final response was assessed. Fifty-two (86.7%) patients entered complete remission (CR). Forty-eight percent of the complete responders achieved CR in the first three courses of MOPP. Eight-year survival and disease-free survival (DFS) rates of the patients achieving CR were 71% and 73%, respectively. Survival and DFS were significantly better for the patients who achieved CR in the first three cycles of chemotherapy than for patients who entered CR at a later stage of therapy: 8-year survival 90% versus 55% (P = 0.00); 8-year DFS 87% versus 59% (P = 0.01). The attainment of a complete ERC was adversely affected by lymphocyte depletion (LD) histologic type (P = 0.01) and MRD less than 65% (P = 0.04). However, when a multivariate regression analysis was used, ERC was the only significant prognostic variable for survival and DFS and its predictive value was confirmed even after correction by MRD. These data suggest that the rapidity of response to chemotherapy could be an important prognostic factor in high-risk Stage II and III Hodgkin's disease.

Use of peripheral blood stem cells to accelerate hemopoietic recovery following autologous bone marrow transplantation.

Twenty-one patients with high risk non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) underwent autologous bone marrow transplantation (ABMT). Nine out of 21 patients received in addition to bone marrow (BM) cells also peripheral blood (PB) cells collected by leucapheresis performed in the recovery phase after high-doses of either cyclophosphamide or etoposide (7 patients), or after ara-C (2 patient). All patients receiving BM + PB cells had ABMT as salvage therapy following extensive relapse or progression of their disease. The addition of PB cells to BM cells allowed a significantly faster recovery after ABMT. Median time to reach WBC greater than 1,000/microL was 14 days versus 20.5 days for patients receiving BM only. Furthermore, a reduced requirement of supportive care and a shorter period of isolation was observed. These results confirm that PB cells combined with BM cells allow a prompt hematopoietic reconstitution after myeloablation. In addition, the data demonstrate the efficacy of PB cells collected after various cytotoxic drugs, even in patients previously exposed to cytoreductive regimens.

Probability of cure in elderly Hodgkin's disease patients.

BACKGROUND: Elderly Hodgkin's disease patients have a poor prognosis. The question arises whether these patients need aggressive treatment or a palliative strategy. So far, as a consequence of the scarcity of trials designed for them, useful information can be obtained only by retrospective analyses. METHODS: We retrospectively studied clinical data from 567 patients recorded from 1982 to 1989 in the Piemonte Hodgkin's Disease Register (PHDR). The 65 patients over 65 years of age were compared to younger ones. We analyzed the role of disease independently of confounding variables, mainly inadequacy of staging and/or treatment, comorbidity and toxicity. RESULTS: In the elderly comorbidity was as high as 35%. Forty elderly patients (60%) entered a suboptimal plan with a low degree of aggressivity, which was different from the usual PHDR protocol. Elderly patients also had a high proportion of subsequent protocol interruptions (25%). Chemotherapy dose intensity was negatively affected by advanced age (p < 0.01 after both 3 and 6 courses of chemotherapy). Toxic deaths were significantly higher in elderly patients than in younger ones (14% vs 1%; p < 0.05). CR rates, overall survival (OS), disease-specific survival (DSS) and event free survival (EFS) were all significantly influenced by age (p < 0.01). Relapse-free survival (RFS) in patients achieving CR did not differ according to age class (77% vs 60%; p = ns). RFS was better in elderly patients entering the PHDR protocols than in those following an alternative plan (75% vs 54%; p = 0.04); however, elderly patients treated according to PHDR guidelines showed a higher incidence of toxic deaths than those treated less aggressively (23% vs 8%). The two groups had similar EFS (36% vs 24%; p = ns). CONCLUSIONS: Elderly patients who achieve CR can have good RFS and cure is possible, but the toxic cost of conventional strategies is unacceptable and selected strategies still must be found.