Clinical outcome of low-risk differentiated thyroid cancer patients after radioiodine remnant ablation and recombinant human thyroid-stimulating hormone preparation.

AIM: Recombinant human thyroid-stimulating hormone (rhTSH) has been approved in Europe as a preparation tool for radioiodine ablation of post-surgical thyroid remnants in patients with low-risk differentiated thyroid cancer (DTC). Published studies report that, both thyroid hormone withdrawal and rhTSH preparation result in similar rates of successful remnant ablation, but few studies have determined the effectiveness of rhTSH preparation on disease recurrence. We sought to determine the clinical outcome, considering both ablation success and disease recurrence, of low-risk DTC patients who underwent (131)I ablation. MATERIALS AND METHODS: This retrospective study describes the clinical outcome of 100 patients treated with (131)I remnant ablation after preparation with rhTSH. After ablation, patients were classified as in complete remission, as having no evidence of persistent disease, or as having clinical recurrence on the basis of a subsequent diagnostic whole body scan with (131)I, stimulated thyroglobulin and cross-sectional imaging studies. RESULTS: Overall assessment of ablation success was verified and obtained in 75% of patients (75/100). Considering only patients who underwent a diagnostic whole body scan and stimulated thyroglobulin without interfering anti-thyroglobulin antibody, complete ablation was obtained in 96% of patients (75/78). After a follow-up of about 4 years, 78 patients are in complete remission: 75 with initial ablation success and three who achieved a complete remission during subsequent follow-up. Among the remaining 22 patients, 21 have no clinical evidence of disease (NCED), indicating the inability to verify the complete remission or to detect residual disease, as in patients with positive thyroglobulin antibody, whereas one has persistent disease demonstrated only by stimulated thyroglobulin. No recurrences were observed. Of four patients initially classified as having persistent disease, one obtained a complete remission and two are now considered NCED. CONCLUSION: Our data confirm the favourable outcome, with low rates of recurrence and persistent disease, of patients with low-risk DTC who underwent (131)I ablation after rhTSH. Moreover, our results compare favourably with those reported in the literature in patients prepared with rhTSH, but also in patients prepared with hormone withdrawal.

A novel boronated-porphyrin as a radio-sensitizing agent for boron neutron capture therapy of tumours: in vitro and in vivo studies.

A water-soluble [meso-tetra(4-nido-carboranylphenyl)porphyrin] (H(2)TCP) bearing 36 boron atoms was studied for its accumulation and its radio/photo-sensitization efficiency towards murine melanotic melanoma cells. The amount of H(2)TCP in the cells increased with the porphyrin dose in the incubation medium up to 100 microM with no significant dark toxicity. Fluorescence microscopy observations showed that the porphyrin was largely localized intracellularly. Based on these "in vitro" results our investigations were pursued using the B16F1 melanotic melanoma subcutaneously transplanted in C57BL6 mice as "in vivo" model. Phormacokinetic studies were performed by injection of H(2)TCP intratumorally (1 mg/kg) and intravenously (10 mg/kg). At 0.5h after i.t. administration or at 24 h after i.v. injection, the amounts of (10)B in the tumour were about 60 ppm and about 6 ppm, respectively. The distribution of H(2)TCP in the tumour after intravenous or intratumoural injection was also assessed by fluorescence microscopy analyses. Under these conditions, preliminary BNCT studies were carried out using a new thermal column called HYTOR (HYbrid Thermal spectrum sHifter TapirO Reactor) inserted in the fast nuclear reactor Tapiro at Enea Casaccia, Italy. The mice were exposed to HYTHOR radiation field for 20 min at a reactor power of 5 kW. In spite of different amounts of (10)B in the tumour at the irradiation time, a similar significant delay in tumour growth (5-6 days) was induced by neutron irradiation in intratoumorally and intravenously injected mice. The response of the melanotic melanoma to H(2)TCP-BNCT was compared with that obtained by irradiation after intraperitoneal injection of boron-phenylalanine.

Imaging before and after multimodal treatment for malignant pleural mesothelioma.

PURPOSE: Computed tomography (CT), magnetic resonance (MR) and positron emission tomography (PET) have a very important role in the diagnosis of malignant pleural mesothelioma (MPM) in the choice of chemoradiotherapy alone or in combination with surgery and in evaluating possible recurrence. It is also essential for assessing the possible benefits of radical surgery (pleuropneumonectomy) in terms of patient survival. MATERIALS AND METHODS: We considered 28 patients suffering from MPM whose mean survival after diagnosis was 15-18 months. Sixteen of these patients had radiotherapy or chemoradiotherapy alone, according to standard protocols, while 12 also underwent surgery. The CT features of MPM were thoroughly examined, as was the role of PET and CT-PET in achieving accurate disease staging and consequent selection of candidates for surgery. RESULTS: Nine of the 12 patients who underwent pleuropneumonectomy had no significant survival advantage over the mean survival in the 16 who were not operated whereas the other three lived 1-3 years longer. Two patients underwent surgery after an optimal response to chemoradiotherapy, but both survived less than a year due to particularly aggressive recurrences. CONCLUSIONS: CT, PET and CT-PET are indicated for diagnosis and, above all, for staging of MPM, in the selection of patients who might benefit from surgery after neoadjuvant therapy and also in identifying small recurrences and/or remote metastases. Being highly specific, PET is essential in the follow-up of patients undergoing chemoradiotherapy alone and/or surgery. Each imaging modality has its advantages and limitations, but their combined use is crucial in determining the most appropriate treatment options for patients with MPM.

Acute and late morbidity after limited resection and focal radiation therapy in craniopharyngiomas.

Aggressive surgery of craniopharyngioma can cause severe, life-long hypothalamic and pituitary dysfunctions and possibly further impair visual function; conventional radiation therapy (RT) can affect intellectual functioning and cause secondary tumours. Because of the severe morbidity associated with aggressive surgery, many authors nowadays recommend a less radical approach followed by RT. This combined approach allows achieving 70-83% 10-year local control rates which are comparable to that achieved with aggressive surgery. The main morbidity of this conservative combined approach is represented by pituitary dysfunction secondary to RT, however, sparing severe hypothalamic disturbances. The interval between treatment and onset of the disorder is much longer than in the case of aggressive surgery and this can have a beneficial impact on quality of life, especially in children. This alternative therapeutic approach has become more appealing now that modern RT techniques allow safer delivery of the RT, particularly in childhood.

Molecular analysis of the androgen receptor gene in testicular cancer.

Testicular cancer (TC) is the most common solid tumour in white males aged 20-34 years, and its incidence has doubled over the past 40 years. Some risk factors for TC have been proposed, such as cryptorchidism, infertility and testicular dysgenesis. However, the causes of TC remain still largely unknown. Recently a genetic basis for TC has been proposed, but specific genetic alterations have not been identified. The risk of TC is markedly increased in subjects with androgen insensitivity and some authors have suggested that mutations in the androgen receptor (AR) gene or disorders of CAG and GGC repeats could be related to TC. However, definitive data have not been produced. In this study, we analysed the AR gene for mutations and CAG and GGC triplets in exon 1 in 123 patients affected by TC. In three patients (2.3%) we found a mutation in the AR gene, two of which represent a novel mutation. Evaluation of CAG and GGC repeat numbers showed no difference with respect to controls when these variables were analysed separately. However, when joint distributions of CAG and GGC were considered, we found that the combination CAG=20/GGC=17 was significantly more frequent in TC patients (8.1%) with respect to controls (1.7%, P<0.05). Furthermore, we observed that in TC subjects, differently from controls, the joint analysis of CAG and GGC showed a statistically significant dependence among these variable repeats. In conclusion, our data show for the first time a high prevalence of AR gene mutations in patients affected by TC and suggest that some CAG/GGC combinations might be more frequently associated with an increased risk of TC.

A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.

BACKGROUND: Oxaliplatin (OXA) significantly enhanced the antitumour activity of 5-fluorouracil (FUra) in patients with advanced colorectal cancer and displayed radiosensitising properties in preclinical studies. This study was thus performed to test the feasibility, identify the recommended doses (RDs) and explore preliminarily the clinical activity of weekly OXA and infused FUra combined with preoperative pelvic radiotherapy. PATIENTS AND METHODS: Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m2, weekly for 6 weeks) and FUra (200-225 mg/m2/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level. RESULTS: In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m2/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0. CONCLUSIONS: Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.

Photofrin as a specific radiosensitizing agent for tumors: studies in comparison to other porphyrins, in an experimental in vivo model.

The use of ionizing radiation for tumor treatment represents a well established therapeutic modality. The efficiency and selectivity of radiotherapeutic protocols can be often enhanced by the addition of specific chemical compounds that optimise the response of the tumor to the incident radiation as compared with peritumoral tissue districts. The results of this study showed that Photofrin, a porphyrin derivative which is presently used as a tumor-photosensitizing agent in photodynamic therapy (PDT), can also act as an efficient tumor radiosensitizer. To test this possibility, we used nude mice subcutaneously implanted with human bladder cancer RT4. The mice were injected with different porphyrin-type photosensitizing agents, including Photofrin, 5-aminolevulinic acid, chlorin e(6), haematoporphyrin, protoporphyrin, Zn-tetrasulphophtalocyanine, and irradiated with 5 and 15 Gy using a Siemens X-ray device. Even though all the porphyrins accumulated in significant amounts in the neoplastic lesion, only Photofrin significantly improved the response of the tumor to irradiation by increasing the doubling time of the tumor volume from 6.2 days in the untreated control group to 10.9 days in the 5 and 15 Gy-irradiated groups. The tumor response was maximal with injected Photofrin doses of 7.5 mg/kg, and was not further enhanced by injection of higher doses. Our hypothesis is, that the radiosensitizing effect of Photofrin seems to be due to some oligomeric constituents which could specifically react with radiogenerated-radicals thereby amplifying the effect of the X-ray radiation.

Photofrin II as an efficient radiosensitizing agent in an experimental tumor.

BACKGROUND AND OBJECTIVE: The use of ionizing irradiation as radiation therapy (RT) for tumor treatment represents a well-established method. The use of photodynamic therapy (PDT), especially with Photofrin II, for tumor treatment is also known. Chemical modifiers enhancing the action of radiation therapy are well known and widely used in medicine. None of these compounds, however, is a selective radiosensitizer. MATERIALS AND METHODS: Several series of animal experiments were performed. The highly differentiated human bladder cancer cell line RT4 was implanted subcutaneously in nude mice. The mice were injected 10 mg/kg Photofrin II and irradiated with 5 Gy. RESULTS: Photofrin II has proved to be a chemical modifier of ionizing irradiation, enhancing the tumor doubling time (tumor growth) from 6.2 to 10.9 days in the control group with the use of irradiation and injection of porphyrin. CONCLUSION: Photofrin II shows a high activity as radiosensitizer and, in the future, can be used as a selective radiosensitizer for tumor treatment with ionizing radiation.

The role of external beam radiotherapy in the management of differentiated thyroid cancer.

Well differentiated thyroid cancers (DTC), usually having an indolent course, are generally treated by surgery, i.e., total or near total thyroidectomy, followed by radioiodine and TSH suppressive therapy with thyroid hormone. The beneficial effect of external beam radiotherapy (EBRT) in the treatment of selected metastatic sites (i.e., brain and bone) or for palliation in cases of locally advanced inoperable disease is widely accepted. In contrast, its efficacy in improving postoperative locoregional disease control is still controversial. A better definition of subgroups of patients at high risk of local failure is mandatory. At present, patients older than 40-45 years affected by papillary cancers with macro- or microscopic postoperative residual disease and with extensive extrathyroid invasion appear to benefit from EBRT performed in addition to surgery and radioiodine. The role of EBRT in patients with radioiodine non-responsive progressive disease will also be discussed.

Desmoplastic small round cell tumour in children and adolescents.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare highly aggressive neoplasm, and clinical studies are scarce. PROCEDURE: We report six cases of children and adolescents (median age 14 years, range 6.9-17.5) with DSRCT (5 abdominal, 1 paratesticular) registered by the Italian Cooperative Group (ICG) for soft tissue sarcoma over a 9-year period. Patients received a multidisciplinary treatment, including aggressive initial or delayed surgery and radiotherapy. Chemotherapy regimen was based on the use of ifosfamide, vincristine, dactinomycin, and a few doses of antharacyclines (doxorubicin or epirubicin). RESULTS: Complete surgical resection was possible only for the paratesticular tumour. Among the patients with abdominal lesions, macroscopically radical excision was possible in only one case. All patients received multidrug chemotherapy, and tumour reduction was obtained in the 4 evaluable patients. No relapses were evident in the irradiated fields in the 4 patients who received radiotherapy. Two patients remained progression-free 22 and 63 months after diagnosis, one is in third complete remission, whereas three died 10-25 months after diagnosis. CONCLUSIONS: DSRCT is a chemosensitive tumour, but survival rates remain disappointing despite aggressive multimodality therapy. Our results support surgical tumour removal and radiotherapy to achieve local control. Our experience and a review of the literature suggest that patients with localised abdominal tumours or a paratesticular primary may have a better prognosis.

Importance of local treatment in pediatric soft tissue sarcomas with microscopic residual after primary surgery: results of the Italian Cooperative Study RMS-88.

BACKGROUND: The goal of primary excision in soft tissue sarcomas is the complete removal of the tumor by a nonmutilating procedure. However, microscopic residuals may be left after a conservative procedure because of inadequate preoperative assessment or difficulties during the operation. The purpose of this report is to describe the treatment and the outcome in patients, enrolled in the Italian Cooperative Study RMS-88, with microscopic residuals after primary excision (IRS Group IIa). PROCEDURE: Microscopic residuals were evident at histology in 52 of 90 patients who had a macroscopic complete primary excision: 25 rhabdomyosarcomas (RMS) and 27 nonrhabdo-soft tissue sarcomas (NRSTS). Eighteen patients were treated with primary reexcision (PRE) and chemotherapy (CT) using VA or IVA regimens; 27 patients received radiation therapy (RT; 40 Gy) and IVA; 7 children in whom PRE was not feasible and RT could not be administered for age <3 years were treated with CT (IVA) alone. RESULTS: Of the 18 patients who underwent a successful PRE + CT, the local relapses were 3 (16.6%); of 27 cases who had RT + CT there were 4 local relapses (14.8%); 3 local relapses occurred in those 7 patients in whom CT alone was administered (43%). CONCLUSIONS: Microscopic residuals after primary surgery were difficult to manage because of the absence of a measurable target. PRE represented the treatment of choice for children <3 years of age who cannot receive RT and for paratesticular sites. PRE and RT showed similar results in achieving local control in extremity and trunk sites, but they could not always avoid local recurrence. In particular PRE was not effective in tumors larger than 5 cm. If microscopic residuals could not be avoided and PRE was not possible, adequate RT was effective both for RMS and for NRSTS.

Bone marrow transplantation for transfused patients with severe aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning therapy: long-term follow-up from a single center.

In transfused patients with aplastic anemia, incidence of graft rejection remains significant. Seventeen transfused patients with severe aplastic anemia received BMT from HLA-identical sibling donors after conditioning with cyclophosphamide (CY, 50 mg/kg/day for 4 days) plus total lymphoid irradiation (TLI, 750 cGy in a single dose). For graft-versus-host disease (GVHD) prophylaxis one patient received methotrexate, five patients received CsA and 11 received CsA in association with methylprednisolone. All patients had sustained engraftment. The actuarial survival of patients was 76% with a median follow-up for surviving patients of 11 years (range 0.3-14.5 years). The incidence of grade II-III acute GVHD was 24%, and chronic GVHD 35%. Median Karnofsky score of surviving patients is 100 (range 90-100). Only one patient developed interstitial pneumonia. None of the patients has developed a malignancy after BMT. The role of limited field irradiation in development of malignant neoplasms after BMT for aplastic anemia is discussed. We conclude that a conditioning regimen using CY + TLI in sensitized aplastic anemia patients results in a high survival rate on long-term follow-up.

Clinical approach in patients with metastatic differentiated thyroid carcinoma and negative 131I whole body scintigraphy: importance of 99mTc MIBI scan combined with high resolution neck ultrasonography.

AIMS AND BACKGROUND: The aim of this study was to define the clinical impact of MIBI scan combined with neck ultrasonography on the detection of metastates in differentiated thyroid carcinoma (DTC) patients with elevated serum Tg levels but negative 131I scan (non-functioning DTC). METHODS AND STUDY DESIGN: Eighty-two patients with non-functioning DTC, 19 patients with 131I-positive metastases (functioning DTC), and 24 DTC patients who were disease free after therapy (no cancer patients) were enrolled. 131I scan was performed after administration of low diagnostic and high therapeutic tracer doses. Early and delayed images were obtained after MIBI injection. Neck-chest CT scan and/or MRI were also performed in patients with non-functioning DTC. RESULTS: In the group of non-functioning DTC patients, metastatic foci were detected in 71/82 cases: in the cervical lymph nodes in 51 cases (sensitivity 94.1% with MIBI, 90.2% with US, 35.3% with CT/MRI), mediastinal lymph nodes in 31 cases (sensitivity 100% with MIBI, 58% with CT/MRI), lungs in 8 cases (sensitivity 100% with both MIBI and CT/MRI), and bone in 2 cases (sensitivity 50% with MIBI, 100% with MDP bone scan). Among the 19 patients with functioning DTC a close relationship between MIBI and 131I findings was observed. As regards the 24 tumor-free patients, MIBI was correctly negative in all cases, while US visualized enlarged cervical lymph nodes that were suspected to be neoplastic but proved to be inflammatory lesions at cytology in three patients. CONCLUSIONS: On the basis of these data, MIBI scan combined with neck US could be proposed as a first-line diagnostic imaging modality in the follow-up of DTC patients with elevated serum Tg levels and negative 131I scan.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy. AIEOP/FONOP-TMO Group. Italian Association of Paediatric Haemato-Oncology.

From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3-21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in >2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1-42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in >2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P < 0.0001) and TBI containing regimen (TBI vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in >2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P < 0.0001). In conclusion, ABMT is an effective treatment after one early IE relapse. Few patients can be rescued after BM relapse.

Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associzione Italiana Emato-Oncologia Pediatrica.

The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.

Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group.

The principal aim of this report is to present the results of multivariate analyses conducted to identify clinical prognostic factors in 92 children aged < 16 years with ependymoma (EPD) retrospectively collected in seven Italian centres. They were treated over a 16-year period (1977-1993). Treatment modalities varied. Surgery and radiotherapy (RT) was the "gold standard" management method for the majority of these children. Only in the late 1980s did some of them receive chemotherapy (CT), mainly with vincristine, lomustine (CCNU) and prednisone. The median follow-up of the entire study population is 36 months (average 43 months; range 12 to 214 months). The 10-year overall (OS) and the progression-free survival (PFS) of the study population were 55.5% (CI 41.4-69.4%) and 34.7% (CI 21.4-47.8%), respectively. Age (< 5 years; > 5 years), sex, site (infratentorial vs. supratentorial), histology (anaplastic/malignant vs. non-anaplastic/non-malignant), type of resection (complete vs. incomplete); use and fields of RT, and of CT employed were entered in a multivariate regression model to test their impact on OS and PFS. On univariate analysis, radical surgery, the use of RT and age more than 5 years at the time of diagnosis achieved statistically significant values for predicting long-term OS and PFS. Histology reached marginal statistical significance but only for PFS. When those variables were entered in a multivariate analysis only radical resection (P = 0.00142 and 0.0001) resulted a significant factor for predicting long-term OS and PFS, while the use of RT reached a marginal statistical significance, but only for PFS (P = 0.05). Children who had the tumour completely resected did significantly better than all the others who had less than a complete resection, with a 10-year OS and PFS for the two groups of patients of 69.8% (CI 53-86.5%) and 57.2% (CI 40.3-75%) and of 32.5% (CI 8.5-57.6%) and 11.1% (0-24.4%), respectively. These findings suggest that, for childhood EPD, radical resection should be pursued as much as reasonably possible. Thus, it seems justified proposing for future trials, patient stratification by entity of surgical resection.

Remission in hairy cell leukemia-variant following splenic radiotherapy alone.

The therapeutic approach to hairy cell leukemia (HCL) is in some instances still debated. A variant form of HCL (HCL-V) characterized by high white cell count, splenomegaly, hypercellular and aspirable bone marrow has been described; differential diagnosis often arises with some other B-cell disorders which also show circulating hairy or villous lymphocytes. Conventional treatment for HCL is often less effective in HCL-V. In this report we describe a case with features consistent with HCL-variant treated with splenic radiotherapy. We not only obtained an hematological response but also the near total disappearance of bone marrow infiltration, compatible with a clinical complete remission. Clinical and biological implications of this phenomenon are discussed on the basis of this unexpected therapeutic result, obtained with splenic radiotherapy alone.

Hybrid MOPP/ABVD and radiotherapy in advanced Hodgkin's disease.

BACKGROUND: In patients with advanced Hodgkin's disease (HD), the alternation of MOPP with ABVD or hybrid MOPP/ABVD are associated with a high CR rate and a high probability of 5-year survival. However, even after effective chemotherapy the risk of nodal relapse is not negligible, and not only in initial bulky site(s) of disease. For this reason, in an attempt to prevent relapses after combination chemotherapy alone, we performed a prospective study to evaluate the efficacy and toxic effects of 6 courses of hybrid MOPP/ABVD followed by radiotherapy (RT) in stages II A bulky, II B, III and also in stage IV with bulky disease of residual after chemotherapy. PATIENTS AND METHODS: From January 1985 to August 1993, 133 patients with HD (128 newly diagnosed, stage II A bulky-IV, 5 in first relapse after RT) were treated according to the following program: 6 courses of the hybrid MOPP/ABVD regimen followed by RT (STNI + spleen in stages II A, II B, III without pelvic lymph node involvement, TNI + spleen in stage III with pelvic lymph node involvement, involved field in stage IV with bulky disease or residual after chemotherapy). The total dose of RT was 4000 cGy to the sites of bulky or residual disease and 2000 cGy to the other sites. RESULTS: After hybrid MOPP/ABVD, 107 of 130 (82.3%) fully evaluable patients were classified as in CR or CR(U). After completion of RT, 108 patients were in CR and 3 were in PR, for an overall response rate of 85%. With a median follow-up duration of 45 months, the actuarial 5-year survival is 76% and the progression-free survival 68.6%. So far, only 14 patients have relapsed (6 within the irradiation field) and the 5-year relapse-free survival is 82.5%. CONCLUSION: Six courses of hybrid MOPP/ABVD followed by RT in stages II A bulky, II B, III and in stage IV with bulky disease or residual after chemotherapy produced a high CR rate with low risk of relapse. However, a longer follow-up is necessary to evaluate the late effects of combined therapy.

Paratesticular rhabdomyosarcoma (RMS) and paraaortic lymphadenectomy.

This study is based on the experience of the Italian Cooperative Studies "AIEOP-RMS 79 and RMS 88". Between October 1979 and December 1989 299 children under 15 years of age with a histologically proven rhabdomyosarcoma (RMS) were examined. We analyzed the problem of the paratesticular localization paying particular attention to the role of surgery in dealing with paraaortic nodes. In the first study (RMS 79) the surgical exploration of retroperitoneal nodes was required: this procedure performed in 11 out of 14 patients affected by paratesticular RMS confirmed the negative data observed with diagnostic investigations. In RMS 88 study the sampling of retroperitoneal nodes was not required in cases with negative radiological findings but suggested in those cases with uncertain signs; two out of 8 patients underwent a laparotomy. In these two cases the results were negative. These 22 children were treated with an adjuvant chemotherapy after surgery and at present they show no evidence of disease.

Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas.

BACKGROUND: Locoregional control of soft tissue sarcomas of the limbs is achieved generally using a multidisciplinary approach consisting of conservative surgery combined with radiation therapy, intraarterial chemotherapy, or hyperthermic antiblastic perfusion (HAP). Before surgery, HAP seems to be the more suitable tool in decreasing tumor mass and allowing limb-sparing surgery. The authors' aim was to ascertain the activity of HAP with doxorubicin against intermediate or high grade limb tumors. METHODS: In 23 patients with limb sarcomas (2 patients International Union Against Cancer Stage IIA, 4 stage IIB, 1 stage IIIA, 11 stage IIIB, and 5 stage IVB) doxorubicin was administered via HAP 4-6 weeks before surgery. The drug (bolus, 0.7-1.4 mg/kg) was perfused for 60 minutes with a tumor temperature of at least 40.5 degrees C (range, 40.5-42.6 degrees). Tumor necrosis was then assessed radiologically and pathologically. RESULTS: Systemic toxicity was hematologic grade (G) 2 in 2 patients, gastrointestinal (hepatic) in 6, G1 in 2, G2 in 3, and G3 in 1; 2 patients had alopecia; locoregional toxicity (graded according to Wieberdink) was G1 or G2 in 18, G3 in 4, and G4 in 1. Tumor necrosis was more than 50% in 17 patients (74%). Limb-sparing surgery was feasible in 20 patients (91%). At present, 14 patients are alive. Six had local recurrences, and eight had distant metastases. CONCLUSIONS: Our findings show that HAP with doxorubicin is an active and well-tolerated procedure within a multidisciplinary approach to treatment of limb sarcomas.