Long-term results of a prospective trial of mantle irradiation alone for early-stage Hodgkin's disease.

BACKGROUND: To determine the long-term treatment outcome and late effects of mantle irradiation alone in selected patients with early-stage Hodgkin's disease. METHODS: Between 1988 and 2000, 87 patients with pathologic stage (Ann Arbor) I-IIA or clinical stage IA Hodgkin's disease were entered on to a prospective trial of mantle irradiation alone. Patients with B symptoms, large mediastinal adenopathy, or subcarinal or hilar involvement were excluded. The median doses to the mantle field and mediastinum were 36 Gy (range 30.3-40) and 38.6 Gy (range 30.6-44), respectively. The actuarial freedom from treatment failure (FFTF) and overall survival (OS) rates were calculated using the Kaplan-Meier technique. RESULTS: The median follow-up was 107 months (range 23-192). Thirteen of 87 patients (15%) relapsed at a median of 30 months (range 5-62). The 5- and 10-year actuarial FFTF rates were 86% and 84.7%, respectively. All 13 patients who relapsed are alive without evidence of disease at a median of 84 months (range 30-156) post-salvage therapy. Five patients developed a second malignancy at a median of 93 months (range 27-131). The 10-year actuarial risk of a second malignancy was 4.5%. There have been two deaths to date, both due to second malignancies. The 10-year OS rate was 98.2%. CONCLUSION: In selected patients with early-stage Hodgkin's disease, mantle irradiation alone has an excellent long-term survival rate, comparing favorably with the previous standard treatment of extended-field radiation therapy and the current standard of combined modality therapy.

Aggressive multimodal treatment of pleuropulmonary blastoma.

Pleuropulmonary blastoma is a rare intrathoracic neoplasm almost solely confined to childhood. Survival is poor. The authors report 2 children with extensive intrathoracic disease who are long term survivors after multimodal therapy. Both children received multiagent neoadjuvant chemotherapy, followed by surgical resection to remove all gross tumor. Postoperative chemotherapy was given to both children; radiotherapy was also given in the second case because of a question of positive tumor margins. Experience supports the use of multimodal therapy, including an aggressive surgical approach in the potentially curative treatment of this tumor.

Percutaneous coronary intervention and subsequent endovascular beta-radiation brachytherapy in a 14-year-old with repaired anomalous left coronary artery from pulmonary artery.

Anomalous origin of the left coronary artery from pulmonary artery (ALCAPA) is a rare congenital anomaly. Re-establishment of the dual coronary system is the standard treatment, although the long-term outcome after surgical repair is not well defined. We report a case in which coronary stenting was performed to treat left anterior descending artery lesions eight months after surgical repair of ALCAPA. The patient then developed rapid in-stent restenosis within three months, which was successfully treated by rotational atherectomy, balloon angioplasty, and catheter-based beta-radiation brachytherapy. Follow-up angiograms after three and six months showed no recurrent in-stent restenosis. This represents the first report of coronary stenting in the setting of ALCAPA, and the first report of catheter-based intracoronary radiation therapy in a pediatric patient.

Adults with Ewing's sarcoma/primitive neuroectodermal tumor: adverse effect of older age and primary extraosseous disease on outcome.

OBJECTIVE: To assess outcome and prognostic factors for survival of adults with Ewing's sarcoma/primitive neuroectodermal tumor (PNET). BACKGROUND: Ewing's sarcoma/PNET is a disease of childhood rarely seen in adults. Accordingly, there is a relative paucity of published literature pertaining to outcome for adults with this disease. METHODS: Between 1979 and 1996, 37 patients with newly diagnosed Ewing's sarcoma/PNET were evaluated and treated at the Adult Sarcoma Program at Dana-Farber Cancer Institute and Brigham & Women's Hospital. Twenty-six patients had localized disease at presentation and 11 had metastatic disease. All but two patients received multiagent chemotherapy. Local treatment consisted of surgery (7 patients), surgery and radiation therapy (19), radiation therapy (6), or no local treatment (5). Median follow-up for living patients was 100 months (range 8 to 199). RESULTS: The 5-year survival rate for the group overall was 37%+/-9%. The 5-year local control rate was 85%+/-7%. Significant favorable predictors for survival on univariate analysis included localized disease at presentation, primary origin in bone, primary size <8 cm, and a favorable objective response to chemotherapy. Patients with localized disease had a 5-year survival rate of 49%+/-11% compared with 0% for those with metastatic disease at presentation. Multivariate analysis showed three significant independent predictors for death: metastatic disease at presentation, primary origin in extraosseous tissue versus bone, and age 26 years or older. CONCLUSION: Adult patients with Ewing's sarcoma/PNET at highest risk for death are those who are older than 26 years and have metastatic disease or an extraosseous primary tumor. The development of novel therapies should target these high-risk groups.

Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial.

The purpose of this study was to determine the safety, efficacy and impact on quality of life of recombinant human erythropoietin (r-HuEPO) for cancer patients undergoing radiotherapy (RT). An open-labelled randomized design was used, with patients randomized to either treatment or control arms. Patients in the treatment arm received r-HuEPO given by subcutaneous injection at a dose of 200 units kg(-1) day(-1) plus oral iron supplements (ferrous sulphate 325 mg p.o. t.i.d.). Entry was restricted to patients with carcinoma of the lung, uterine cervix, prostate or breast who presented for RT with anaemia parameters reflective of 'the anaemia of chronic disease'. Radiotherapy policies (portals, doses, fraction size, etc.) were determined by the site and stage of disease. Complete blood counts (CBCs) were obtained weekly. The target level of haemoglobin was 15 g dl(-1) for men and 14 g dl(-1) for women. Quality of life (QOL) was assessed weekly by using an analogue scale to judge energy, activities of daily living and overall quality of life. Forty-eight patients were entered in the study, 24 in the treatment arm and 24 in the control arm. The prerandomization demographic characteristics and mean laboratory values were comparable in both arms. The mean haemoglobin at completion was 13.6 g dl(-1) for r-HuEPO-treated patients compared with 11.0 g dl(-1) for control subjects (P = 0.0012). Patients who received r-HuEPO demonstrated a mean weekly haemoglobin increase of 0.41 g dl(-1) compared with a decrease in mean haemoglobin level in controls for 6 of the 7 weeks of the study (mean weekly decrease of 0.073 g dl(-1)). Target levels of haemoglobin were achieved by 41.6% of r-HuEPO-treated patients compared with none of the control subjects. The mean platelet count declined in both arms of the study with RT but the decline from pretreatment was less rapid in r-HuEPO-treated patients (11.2% decrease) compared with controls (26.3% decrease) and was statistically significant during weeks 4-6. Toxicity was minor with only mild irritation at the injection site. Mean quality of life end points were superior in the treatment arm but not statistically significant. r-HuEPO had a beneficial effect on weekly haemoglobin levels in patients undergoing RT with response rates similar to other studies. There was also a less rapid decline in weekly platelet counts in r-HuEPO-treated patients compared with control subjects. Further studies are needed to address the optimum dose and scheduling as well as the impact of r-HuEPO on clinical outcomes.

Childhood soft tissue sarcoma: a 20-year experience.

PURPOSE: To evaluate the disease-free and overall survival of pediatric patients with nonrhabdomyosarcoma soft-tissue sarcomas. METHODS: We retrospectively analyzed the records of 67 pediatric patients with a diagnosis of nonrhabdomyosarcoma soft tissue sarcoma treated with curative intent between 1970 and 1992. Median follow-up time for the 52 survivors was 120 months (range, 7 to 277 months). Fifty-nine patients received external beam radiotherapy, in a median dose of 5400 cGy (range, 1800 to 6660 cGy.) All patients underwent an initial surgical procedure. Eighteen patients had gross residual disease, and 15 had gross total excision with microscopic residual disease or positive margins. Adjuvant chemotherapy was administered to 44 patients (65%). RESULTS: The actuarial 10-year freedom from progression or recurrence and overall survival rates were 76% and 75%, and the 20-year rates were the same. Of 18 patients with gross residual disease, 9 (50%) had local progression and 6 died of local-only disease. By contrast, only one patient with microscopic residual disease who received postoperative radiotherapy had a local recurrence. The disease-free survival rate also correlated with histologic grade. CONCLUSIONS: As with adult soft tissue sarcomas, gross residual disease predicts local failure. Our results suggest that pediatric patients with soft tissue sarcomas treated with surgery and postoperative radiotherapy generally have a favorable overall survival rate.

Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome.

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.

Long-term survival in Hodgkin's disease relative impact of mortality, second tumors, infection, and cardiovascular disease.

PURPOSE: Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals. MATERIALS AND METHODS: Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. RESULTS: Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease. CONCLUSIONS: Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

Improved survival in patients with limited stage IIIA Hodgkin's disease treated with combined radiation therapy and chemotherapy.

PURPOSE: Patients with laparotomy-staged (PS) III 1A Hodgkin's disease confined to the upper abdomen are believed to have a favorable prognosis and require less aggressive treatment than patients with more-extensive stage III disease. We evaluated prognostic factors and outcome in 93 patients with PS III 1A Hodgkin's disease treated either with radiation therapy (RT) alone or combined RT and chemotherapy (combined modality treatment [CMT]) to determine the extent of treatment needed in this subgroup of stage IIIA patients. MATERIALS AND METHODS: We retrospectively reviewed the freedom from relapse (FFR) rate, sites of recurrence, and survival rate of PS III 1A patients selected to receive extended-field irradiation (MPA, n = 27), total-nodal irradiation (TNI, n = 34), and CMT (n = 32) between 1969 and 1987. CMT consisted of six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy and MPA. Patients treated with MPA were part of a prospective trial designed to reduce treatment to patients with minimal stage III disease with very favorable characteristics. RESULTS: Histologic subclass and treatment were the only prognostic factors for FFR and survival rates. Patients with nodular sclerosis or lymphocyte predominance histology had significantly higher FFR and survival rates compared to patients with mixed-cellularity (MC) histology. The 10-year actuarial FFR of PSIII 1A patients treated with MPA was only 39%, versus 55% for TNI (P = .02) and 94% for CMT (v MPA, P < .0001; v TNI, P = .006). The patterns of recurrence in patients who received MPA and TNI were significantly different, with MPA patients relapsing more often in untreated pelvic or inguinal nodes, and TNI patients relapsing more often in extranodal sites with or without nodal sites. The 10-year actuarial overall survival rate for patients treated with CMT was 89% versus 78% for MPA (v CMT, P = .09) and 70% for TNI (v CMT, P = .05). CONCLUSION: Patients with PSIII 1A Hodgkin's disease treated with RT have a significantly higher risk of relapse and potentially a poorer survival compared with patients treated with CMT. These findings suggest that CMT should play a greater role in the treatment of this favorable substage of patients. Management with modified chemotherapy and RT in an attempt to reduce long-term treatment-induced complications may be a preferred approach for future trials.

Mantle irradiation in the upright position: a technique to reduce the volume of lung irradiated in patients with bulky mediastinal Hodgkin's disease.

Many patients with mediastinal Hodgkin's disease radiographically show a wider horizontal width of disease in the supine or prone as compared to the upright position. Yet for most patients mantle treatment in the supine/prone position is still preferable. This position allows good patient immobilization and precise matching between the mantle and paraaortic-splenic pedicle fields that would not be possible in the sitting or upright position. Adequate blocking of the lungs and heart remains possible in the supine position since most patients do not have extensive subcarinal Hodgkin's disease. Even when more extensive disease is present, contoured blocks to protect the heart and lungs can be adjusted to protect a greater portion of normal tissues if the mediastinal nodes respond to treatment. But if sizeable mediastinal disease persists, it may be impossible to protect sufficient heart and lung. Under these circumstances, repositioning the patient upright can shift the configuration of the mass, allowing larger lung blocks to be added. We report the use of a chair to facilitate treatment with mantle irradiation in the upright position for patients whose mediastinal disease when supine is too large to allow adequate blocking of heart and lung. Blocks are made from the initial port films and daily treatment films are taken to confirm an accurate set-up. To avoid excessive dose to the spinal cord, patients who are to receive para-aortic irradiation receive a maximum of 15-20 Gy in the upright position and the remainder of the mantle is given in the supine-prone position. The use of the upright technique allows for the use of radiation in patients who would otherwise be unable to receive adequate doses due to potential lung and cardiac toxicity.