Phase II study of all-trans-retinoic acid and alpha-interferon in patients with advanced non-small cell lung cancer.

Between April 1993 and June 1994, 29 patients (pts) with unresectable, locally advanced, or metastatic non-small cell lung cancer were treated with a combination of p.o. trans-retinoic acid (TRA), 150 mg/m2/day, in three divided doses and s.c. IFN-alpha, 3 x 10(6) units/day. The age range was 41-80 years (median, 63 years). The Eastern Cooperative Oncology Group performance status was 0-1 (24 pts) and 2 (5 pts). Pts had advanced disease, refractory to conventional therapy (5 stage IIIB and 24 stage IV). Twenty-one pts had adenocarcinoma, six had squamous cell carcinoma, and two had large cell carcinoma. Only 3 pts completed 8 weeks of treatment, requiring neither interruption nor dose modification. Fatigue occurred in 88% of pts. A syndrome complex consisting of dry oral and nasal mucosa, recurrent sinus infections, and epistaxis occurred in 64% of pts. Grade II/III dermatitis was seen in 52%. Severe scrotal dermatitis was seen in 7 pts (47% of 15 males). Hypertriglyceridemia was moderate/severe in 11 pts, and 3 pts required gemfibrozil for levels up to 1660 mg/dl. Hematological toxicity was not encountered, and none of the pts had leukocytosis. One pt died with complications of myocardial infarction while on TRA/IFN-alpha. Twenty-five pts had more than 2 weeks of treatment and are evaluable for response; two pts died early with complications of cancer, and two pts declined to continue after only 3 and 5 days of treatment. Final assessment of response was by accepted clinical and radiological criteria at 8 weeks. There have been four objective responses: complete response, 2 (18+ and 17 months) and partial response, 2 (7 and 14 months). Responses were observed in all histologies. Combined differentiation treatment with TRA/IFN-alpha has modest but objective activity in non-small cell lung cancer. Toxicity is considerable. Additional studies to elucidate the biological basis of TRA/IFN-alpha and to define prognostic parameters predicting response are needed.

Adverse impact of multileaf collimator field shaping on lens dose in children with acute leukemia receiving cranial irradiation.

PURPOSE: This study was designed to investigate the impact of multileaf collimator (MLC) on lens dose in children with leukemia undergoing cranial irradiation. METHODS AND MATERIALS: This is a prospective study utilizing three common cranial irradiation techniques. Technique A uses a half-beam, nondivergent radiation field. Technique B has the anterior divergent field edge at the lateral bony canthus. Technique C is similar to B, but with a field collimator angle. Thermoluminescent dosimeter (TLD) lens dose measurements were obtained in children and phantom with all three techniques. RESULTS: Seventeen children were studied. Lens dose measurements were obtained in 14 children with technique A using MLC and blocks. In 7 of 14 children, dose measurements were obtained with MLC only. One child was treated with technique B and 2 children were treated with C, with MLC +/- blocks. In all 3 techniques, with MLC alone, the lens dose increased by 64%, 119%, and 72%, respectively. Similar results were obtained in phantom. CONCLUSION: This study demonstrates that independent of irradiation technique, additional custom blocking is required to maximally protect the lens with MLC shaped fields. This is due to the lack of conformity between MLC and the desired field edge at the lateral bony canthus.

A phase I/II trial of induction chemotherapy with carboplatin and gemcitabine followed by concurrent vinorelbine and paclitaxel with chest radiation in patients with stage III non-small cell lung cancer.

PURPOSE: We designed a phase I/II trial in order to evaluate the efficacy and tolerability of induction carboplatin and gemcitabine and the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of subsequent chemoradiotherapy with weekly vinorelbine and paclitaxel in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients had pathologically confirmed N2-N3 stage NSCLC, adequate end-organ function, and ECOG performance status 0-2. Carboplatin was administered at an AUC of 5 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days, for two cycles, followed by weekly vinorelbine 10-15 mg/m2 and paclitaxel 50 mg/m2 and conventional chest radiotherapy up to 66 Gy. Patients with resectable disease underwent thoracotomy after 40-45 Gy. RESULTS: Thirty-nine eligible patients were enrolled; 17 had stage IIIB NSCLC. Grade 3 esophagitis developed in 4/5 patients on the second dose level of chemoradiotherapy (i.e. vinorelbine 15 mg/m2) and was considered dose-limiting. Of 34 patients treated at the maximum tolerated dose (i.e. vinorelbine 10 mg/m2), 2 patients (6%) had pneumonitis >grade 2 and 3 (9%), esophagitis >grade 2. Induction chemotherapy was well tolerated with only one patient developing >grade 2 non-hematologic toxicity (nausea). Forty-one percent of patients had an objective response after induction chemotherapy and 51% after chemoradiotherapy. Nineteen patients, 16 of whom had stage IIIA, underwent surgical resection. The pathologic complete response rate was 16% (42% in the mediastinal lymph nodes). With a median follow-up of 31 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 23 and 34%, respectively, and the median OS was 25 months. CONCLUSIONS: We identified a well-tolerated and active chemoradiotherapy regimen. Survival results are promising and the addition of a biologic agent to this regimen is of interest.

Outpatient total body irradiation prior to bone marrow transplantation in pediatric patients: a feasibility analysis.

Outpatient total body irradiation (TBI) prior to bone marrow transplantation has been accomplished in a total of 68 pediatric patients. The TBI regimen was fractionated with a total dose of 12 Gy in eight fractions twice daily. Antiemetic therapy consisted of oral ondansetron three times daily throughout the TBI course. Eight patients experienced mild nausea without vomiting, and four patients experienced mild nausea and vomiting. One patient required intravenous hydration after severe nausea and vomiting. Another patient experienced intractable diarrhea and dehydration which required inpatient management. Outpatient TBI prior to bone marrow transplantation is feasible in pediatric patients.

Late postirradiation occlusive vasculopathy in childhood medulloblastoma. Report of two cases.

The authors report two cases of ischemic stroke secondary to occlusive vasculopathy two decades after radiation therapy (RT) for medulloblastoma. Both patients underwent posterior fossa medulloblastoma partial resection, followed by craniospinal RT in which a cobalt 60 source was used; 40 Gy were given to the whole brain plus a 15-Gy boost to the posterior fossa. Both patients received multiagent chemotherapy, immediately following radiation therapy in the first case and after repeated craniotomy for recurrence 13 years after radiation in the second case. They experienced multiple sequelae from radiation and chemotherapy, including growth retardation and psychomotor delay. However, 20 years after treatment, they remained tumor free and able to work, until they presented with focal neurological deficits and seizures. Computerized tomography and magnetic resonance imaging of the brain in both cases showed no tumor recurrence, but did demonstrate ischemia in a posterior cerebral artery distribution. Cerebral angiography revealed multiple mid-sized arterial wall irregularities as well as focal stenoses consistent with a postirradiation vasculopathy. The pathophysiological mechanisms, radiological appearance, and incidence of this syndrome are reviewed from the literature.

Intracranial ependymomas: a review.

Ependymomas are rare neuroectodermal tumors arising from ependymal cells of the ventricular system, choroid plexus, filum terminale, and central canal of the spinal cord (1,2). This review focuses on intracranial ependymomas with special emphasis on pathology, etiology, cytogenetic characteristics, and adjuvant radiation therapy. Recent advances in neurosurgical technique, radiation therapy, and molecular biology have affected management of these tumors and have the potential to increase long-term cure rates. The role of highly advanced radiation therapy techniques such as stereotactic radiosurgery will need to be better defined.

Clinical outcome in children with recurrent craniopharyngioma after primary surgery.

PURPOSE: The purpose of this article is to report the clinical outcome in children with recurrent craniopharyngioma after primary surgery. PATIENT AND MATERIALS: Fourteen children with craniopharyngioma treated with primary surgery developed local recurrence. The median time to recurrence from primary surgery was 19 months (range, 2-156 months). At first recurrence (n = 14), seven children (50%) underwent reoperation. Five children (36%) received radiotherapy, and two children did not undergo any treatment. At second recurrence (n = 7), six children underwent radiotherapy (86%), and one had surgery. External-beam radiation was delivered with 6-MV or 10-MV x-rays by use of three-dimensional conformal technique (n = 4) or fractionated stereotactic radiotherapy (n = 7) using the Laitinen stereoadapter. Total dose ranged from 54 to 55.8 Gy at 1.8 Gy/fraction. RESULTS: The median follow-up from primary surgery is 8.5 years (range, 3-15.8 years). The 5-, 10-, and 15-year overall survival was 100%, 86%, and 86%, respectively, and the disease-free survival was 92%, 60%, and 60%, respectively. The median follow-up from date of first relapse was 6 years (range, 2.5-10 years). After treatment for first recurrence, the 2- and 5-year second-recurrence-free survival was 71% and 29%, respectively. After radiotherapy, the 2- and 5-year second-recurrence-free survival was 100% and 100%, respectively, compared with 43% and 0%, respectively, for surgery alone. Univariate analysis revealed significantly superior local control with radiotherapy compared with surgery. The local control rate at last follow-up, after stratifying for treatment at first and second recurrence, were analyzed at first and second relapse was 90% and 0% after radiotherapy and surgery, respectively. If radiotherapy was used for first or second recurrence, the 5-, 10-, and 15-year relapse-free survival was 100%, 83%, and 83%, respectively, compared with 67%, 0%, and 0%, respectively, for surgery alone. The median time to second relapse after surgery for first relapse was 12 months (range, 2-36 months). After primary surgery, all 14 children developed panhypopituitarism, requiring lifelong hormone supplementation. After surgery at recurrence, three children (3/7, 43%) experienced intraoperative bleeding, resulting in permanent neurologic deficits in two. No child has shown any signs of radiation-induced optic neuropathy. DISCUSSION: In children with recurrent craniopharyngioma after radical resection, the use of three-dimensional conformal radiotherapy or fractioned stereotactic radiotherapy results in very good local control with a low incidence of complications. In young children with stable tiny recurrences, a policy of close surveillance could be adopted for the brain to mature before beginning radiotherapy. The use of secondary surgery for recurrent tumors is associated with a low cure rate and a high risk of complications.

Fractionated stereotactic radiotherapy for pediatric brain tumors: the Chicago children's experience.

Thirty-three children with a total of 35 benign/malignant brain and eye neoplasms were treated with fractionated stereotactic radiotherapy. In the first 11 children immobilization for treatment was achieved with plaster of Paris casts or aquaplast masks. In the remaining 22 children the Laitinen stereoadapter was used. Radiation was delivered with noncoplanar static or rotational beams. The dose fractionation used was 50.4-60 Gy in 28-30 fractions in patients receiving treatment with curative intent, and 10-32 Gy at 2-4 Gy/fraction for reirradiation. The accuracy of daily treatment was < 2 mm. After a median follow-up of 27 months, 22 of the 25 children treated with curative intent achieved local control. One child had progressive brain necrosis following 54 Gy in 30 fractions for a pontine astrocytoma. The exact etiology of this complication is unknown. This series demonstrates that in children fractionated stereotactic radiotherapy using the Laitinen stereoadapter is well tolerated and accurate and results in good local control.

Optic pathway hypothalamic gliomas in children under three years of age: the role of chemotherapy.

OBJECTIVES: Optic pathway/hypothalamic gliomas (OPHGs) tend to occur in young children. Treatment options consist of surgical resection, radiation therapy (RT) and chemotherapy. Due to complications induced by surgery and RT, chemotherapy has gained significant recognition for the treatment of OPHG in young children. Chemosensitivity of OPHG in very young children under 3 years of age has not been well documented. We analyzed 14 patients who were treated with chemotherapy with or without surgery. MATERIALS AND METHODS: Fourteen children younger than 3 years (median age of 10 months) with OPHG were treated between 1988 and 1998. Magnetic resonance imaging was obtained in all cases. Hydrocephalus was present in 8 patients and diencephalic syndrome was noted in 6. Only 3 of these had evidence of neurofibromatosis-1. Five patients had partial tumor resection and 4 had endoscopic biopsy at the time of ventriculoperitoneal shunt placement. Pathological examination revealed low-grade astrocytoma in 5 and juvenile pilocytic astrocytoma in 4. All patients received chemotherapy: carboplatin in 8, a combination of carboplatin and vincristine in 4 and a combination of other agents in 2. RESULTS: Eight (57%) of 14 patients had a sustained reduction of tumor during the follow-up time between 15 months and 8 years. The 5-year progression-free survival was 63%. These tumor reductions were often accompanied by clinical improvements. Diencephalic syndrome responded to chemotherapy alone in 4 of 6 patients. However, 5 others had progressive disease; 3 during the treatment and 2 following the treatment (9 months and 2 years, respectively). All these 5 patients had a partial tumor resection prior to chemotherapy. CONCLUSION: A majority of OPHGs responds to chemotherapy. Due to slow progression of these tumors and adverse effects of other therapeutic modalities, we recommend chemotherapy as a primary treatment for OPHGs. Our present data indicates that partial surgical resection does not enhance chemotherapy effectiveness for OPHGs in infants or children younger than 3 years.

High-dose chemotherapy followed by peripheral blood stem cell rescue for metastatic rhabdomyosarcoma: the experience at Chicago Children's Memorial Hospital.

BACKGROUND: Because outcome for metastatic rhabdomyosarcoma remains poor with standard therapy, and because some patients with extensive unresectable metastatic rhabdomyosarcoma are unable to tolerate standard therapy with the associated large radiation fields, peripheral blood stem cell rescue (PBSCR) following high-dose chemotherapy was offered as consolidative therapy for patients with Stage 4/Group IV rhabdomyosarcoma. PATIENTS AND METHODS: Eight patients with Stage 4/Group IV rhabdomyosarcoma were diagnosed from May, 1992, through November, 1994. Consolidative PBSCR following thiotepa 300 mg/M2 on days -7, -6, and -5; cyclophosphamide 1,500 mg/M2 on days -5, -4, -3, and -2; and carboplatin 600 mg/M2 on days -3 and -2 was offered to those patients who achieved a complete remission with multimodality therapy. Patients with extensive metastatic disease who did not receive full doses of radiation to all sites of disease remained eligible for high-dose chemotherapy and PBSCR. RESULTS: Five of eight patients achieved a complete response. Four patients underwent PBSCR. One of the four patients is alive without evidence of disease 53 months post-PBSCR. All other patients died of progressive disease. CONCLUSIONS: These results, along with the existing literature, show no advantage of high-dose chemotherapy followed by PBSCR as consolidative therapy for patients with Stage 4/Group IV rhabdomyosarcoma over standard dose chemotherapy, radiation, and surgery. For patients with extensive, unresectable disease at diagnosis who cannot receive radiation to all areas of disease based on concerns of marrow reserve, high-dose chemotherapy followed by PBSCR does not appear to provide adequate local control and cannot be offered as curative therapy.

Hyperfractionated craniospinal radiation in medulloblastoma.

From 1986 to 1991, 13 patients at Northwestern Memorial Hospital were entered onto a pilot study designed to test the feasibility of treating children with medulloblastoma (11 patients) or primitive neuroectodermal tumors of the cerebral hemispheres (2 patients) with hyperfractionated craniospinal radiotherapy (HFxRT). Follow-up times ranged from 10 to 96 months with a median of 53 months. The patients were prospectively divided among three treatment arms depending on prior treatment history, if any, and degree of surgical resection. The 3 patients in group I had undergone gross total resection of the primary site, receiving 64.8 Gy to the primary site and 31.2 Gy directed to the craniospinal axis (CSA). Of these 3 patients, patient 1 had residual disease in the thoracic spine at T-10. The 8 patients in group II, who had gross residual disease remaining at the primary site, received 72 Gy to the primary site and 34 Gy to the CSA. Five of these eight patients in group II also received 8-in-1 chemotherapy. The 2 patients in group III had already failed chemotherapy and were then treated with 60 Gy to the primary site and 26 Gy to the CSA. Of the 11 patients in groups I and II, 7 of the 11 (64%) have never recurred. Two of the three group-I patients have not recurred, and 5 of the 7 group-II patients have not recurred. In addition, patient 7 (group II) remains alive after salvage with bone marrow transplant, following a local failure bordering the tentorium. Unfortunately, neither of the group-III patients could be salvaged with HFxRT. Acute/subacute toxicities included 7 cases of external auditory canal or skin desquamation, 2 cases of postradiation somnolence, and 1 case each of poor wound healing and neutropenia. Chronic toxicities included hypothyroidism in 2 patients and growth problems in 2 patients. Neuropsychologic complications affected only the 3 youngest patients in the study. Three patients developed neurologic sequelae attributed to radiation, including 1 with progressive urinary incontinence, 1 who developed a transient ischemic attack, and 1 who became progressively ataxic. Our research, although based on a small number of patients, suggests that hyperfractionated radiation therapy to craniospinal access is feasible and that the survival results are favorable. This treatment strategy should be further explored in a phase-III randomized trial.

Repositioning accuracy with the Laitinen frame for fractionated stereotactic radiation therapy in adult and pediatric brain tumors: preliminary report.

PURPOSE: To determine the repositioning accuracy, patient tolerance, and clinical efficacy of stereotactic radiation therapy for brain tumors in children and adults performed with the Laitinen stereotactic localizer and head holder. MATERIALS AND METHODS: In this retrospective analysis, stereotactic frame tolerance was assessed by recording patient discomfort or pain in the ear and nose during each treatment in 34 patients, including 21 children and 13 adults with 37 lesions treated with fractionated stereotactic radiation therapy. Radiation doses ranged from 10-60 Gy at 1.0-4.0 Gy per fraction. Repositioning accuracy was assessed by comparing portal radiographs with setup fields on computed tomographic (CT) scout images. Clinical efficacy was assessed by analyzing posttreatment CT and magnetic resonance images. RESULTS: The stereotactic localizer was well tolerated. The mean isocenter shifts observed after studying 305 portal radiographs were x-coordinate shift of 1.0 mm +/- 0.7 (SD), y-coordinate shift of 0.8 mm +/- 0.8, and z-coordinate shift of 1.7 mm +/- 1.0. At a median follow-up of 16 months, local control was achieved in 18 of 22 primary and in one of eight of recurrent tumors. CONCLUSION: The Laitinen stereotactic localizer is well tolerated with accurate reproducibility during stereotactic radiation therapy. Preliminary local control rates are consistent with those in other reports.