Biomedical subjects
Publications and source records attributed to C Kalifa.
Osteosarcoma is the most frequent malignant tumor of bones. The peak incidence is in the second decade and the metaphyseal part of long bones is the site of predilection. This tumor is spontaneously rapidly fatal but recent progresses in chemotherapy and surgery have improved its prognosis (for example initial chemotherapy with high dose methotrexate and postoperative chemotherapy adapted to the histological response of the resected tumor to preoperative treatment).
From May 1981 to June 1989, 84 children with non-B-cell lymphoma (82 lymphoblastic, 1 T-cell immunoblastic, 1 unclassified diffuse lymphoma) were treated in the pediatric department of the Institut Gustave Roussy according to a protocol called LMT81, which was derived from the LSA2L2 protocol of Wollner and modified by the adjunction of 10 courses of high dose methotrexate to improve the CNS prophylaxis. No planned irradiation was performed except in cases of initial tests (2 patients) or CNS (5 patients) involvement and residual mass (2 patients). Sixty patients had mediastinal involvement; for the others, primaries were in the head and neck (7), nodes (2), (sub)cutaneous (4), bone (7), and elsewhere (2). According to Murphy's staging system, there were 2 stage I, 6 stage II, 33 stage III, and 43 stage IV. Among the stage IV patients, 41 had bone marrow involvement, 24 of them with more than 25% blast cells in bone marrow and 19 with blast cells in blood; 7 had CNS involvement. Three patients did not achieve complete remission, 4 died in remission (two measles, one post-transfusion AIDS, one unexplained definitive aplasia) and 13 relapsed at 2 to 29 months (median-13 months). Among the 77 patients without initial CNS involvement, there was only one isolated CNS relapse. With a median follow-up of 57 months (10-106 months), the event-free survival is 75% (SE 2.5) for the 84 patients with a plateau at 29 months, 73% (SE 8) for stage I and II patients, 79% (SE 4) for stage III, and 72% (SE 4) for stage IV patients. Survival was similar in each stage group. Reasons for failure of treatment, however, were different, being toxic deaths in stage II; initial therapy resistance, early relapses, and toxic deaths in stage III; and tumor failures in stage IV. In conclusion, this protocol is efficacious on T and non-T, non-B childhood lymphoma with a low incidence of CNS relapse. A future study will seek to diminish toxicity and long-term sequellae while at least maintaining the same cure rate of patients.
From May 1978 to August 1988, 15 children with a primary malignant liver tumor received radiation therapy as part of their management at the Institut Gustave-Roussy. Age ranged from 4 months to 13 years. The male to female ratio was 1.5. Eleven patients had a histologically proven hepatoblastoma, two a hepatocellular carcinoma, and histology was not documented in two. Resection of the primary liver tumor was performed in nine cases, and all patients also received sequential chemotherapy, generally preoperative and alternating vincristine, doxorubicin, cyclophosphamide with vincristine, cyclophosphamide, and cis-platinum. Radiotherapy was performed postoperatively in eight incompletely resected patients. Six of eight are alive and free of disease 4-83 months following treatment (median 39 months) and 11-98 months since diagnosis (median 45 months). All but one were treated to limited fields to a total dose of 25-45 Gy (median 40 Gy). One patient became resectable by a combination of 24 Gy to the whole liver and concomitant 5FU and Cis-Platinum and remains with no evidence of disease 68 months following radiation therapy. Of four unresectable primaries, only one was controlled by radiotherapy. Neither of two children with pulmonary metastases were controlled by whole lung irradiation to a dose of 18 and 20 Gy, respectively, and one still remains stable 41 months after resection of a residual metastatic nodule. Neither of two hepatocellular carcinomas were controlled by doses up to 40 Gy. This small series suggests that in hepatoblastoma, radiotherapy to a total of 25-45 Gy fractionated doses, combined with chemotherapy, can play a role in selected inoperable children and also in those with minimal postoperative residues below 2 cm. It also indicates that in hepatocellular carcinoma, radiotherapy is ineffective in this dose-range.
Explore the source record for details and available documents.
RATIONALE AND OBJECTIVES: The response of osteosarcoma to preoperative chemotherapy was assessed using dynamic magnetic resonance imaging (MRI) processed by factor analysis of medical image sequences (FAMIS). METHODS: Forty-nine dynamic image sequences, acquired after a bolus injection of gadolinium in 10 patients, were processed by FAMIS: FAMIS is a means whereby physiologic contrast enhancement kinetics, called factors, and their spatial distribution, termed factor images, are estimated. Tumor volumes were measured on static MRIs, and factor images were compared with histologic maps of the resected specimens. RESULTS: A substantial increase in tumor volume reflected a poor response to chemotherapy. Viable tumor was precisely depicted by the early vascular factor image, reflecting rapid uptake by tumor vessels. This early uptake disappeared in all five patients who responded to chemotherapy, whereas it persisted in four of five nonresponders. CONCLUSION: FAMIS of dynamic MRI is proposed as a possible means of predicting the response of osteosarcoma to chemotherapy.
BACKGROUND: The kidneys of non Hodgkin lymphoma patients frequently contain lymphoma cells, but these tumors rarely arise in the renal tissue and are rarely located there. PATIENTS: A diagnosis of non Hodgkin lymphoma of renal origin or predominantly located in kidneys was made in 7 patients aged 2-14 years old. These patients formed part of a total of 450 patients with non Hodgkin lymphomas seen from 1974 to 1987. The first manifestation in these 7 children was an abdominal mass associated with hypertension in 3 cases; 2 of whom presented with acute kidney failure. Ultrasonography showed hypoechogenous masses in one (2 cases) or both kidneys (5 cases). The diagnosis of malignant lymphoma was made directly in only one patient who also presented with mediastinal and abdominal lymph node enlargement. In the others, the first diagnosis was Wilms tumor (5 cases) and polycystic disease of the kidney (1 case); the correct diagnosis of malignant lymphoma was later made from biopsies of renal (4 patients) or extrarenal involved tissue (2 patients). Six of the 7 cases were Burkitt lymphomas, and all 7 were in stage III (3 patients) and IV (4 patients). 6 patients (3 stage III and 3 stage IV) were successfully treated by chemotherapy with a median follow-up of 9 years. CONCLUSIONS: Differential diagnosis between non Hodgkin lymphomas of renal origin and a Wilms tumor may be difficult even though kidney failure is more frequent in lymphoma. Sonography is the best method for diagnosis showing typical hypoechogenous masses and diffuse homogeneous infiltration of the kidneys. In the absence of extrarenal (meningeal, testis, bone marrow) dissemination, definite evidence of lymphoma depends on the histological examination of tumoral tissue obtained by surgical biopsy.
In order to evaluate the effect of intensive combined chemotherapy in pediatric brain tumors, we designed a phase II study of high-dose busulfan and thiotepa followed by bone marrow transplantation (BMT) in children with measurable recurrent brain tumors. As alkylating agents, busulfan and thiotepa were expected to exhibit a steep dose effect and no overlapping extramedullary toxicity. Moreover, both drugs have an excellent distribution into the central nervous system in humans. Since May 1988, 20 children (median age 6 years) have been treated. Busulfan (150 mg/m2/day x 4) given orally was followed by thiotepa (350 mg/m2/day x 3), given as a 1 h i.v. infusion. Cryopreserved bone marrow was reinfused 48 h after completion of chemotherapy. Tumor response was assessed by computed tomography and magnetic resonance imaging 4 to 6 weeks after BMT. Five partial responses were observed (three of six medulloblastomas, one of five ependymomas, one of two primitive neuroectodermal tumors); two patients with medulloblastoma and one with brain stem tumor achieved an objective response. Ten patients had stable disease and one progressive disease. One patient is not evaluable because of early toxic death. Toxicity was high in terms of aplasia and cutaneous, hepatic and neurological complications. The overall response rate of 26% is encouraging since all patients had disease refractory to all conventional therapies.
Thirty-five cases of primary intracranial germ cell tumor treated at the Institut Gustave-Roussy between 1975 and 1987 were reviewed. There were 23 males and 12 females; the median age was 12 years (range: 3 months to 17 years). Tumors originated in the pineal region in 15 cases, in the suprasellar region in 15 cases, and in both region in 5 cases. The diagnosis was confirmed histologically in 20 cases (14 germinomas and 6 non germinomatous germ cell tumors), and cytologically in 5 cases. There were 11 secreting tumors (alpha-foetoprotein or chorionic gonadotrophin) without histological diagnosis in 6 cases. Four patients were treated with a presumptive diagnosis. Surgical resection was performed in 6 cases. Thirty-two patients were irradiated on the tumor site; 17 received a craniospinal irradiation and 7 a cranial irradiation. Six patients received chemotherapy. Twenty-five patients are alive with a median follow-up of 4 years. Prognosis is better in germinomas than in non germinomatous germ cell tumors (survival rates = 88 and 50% respectively). Chemotherapy is presently being evaluated in the treatment of germ cell tumors with the aim of using lower doses of radiotherapy and decreasing its late effects in germinomas and of improving the prognosis of other histological types.
From 1975 to 1986, 75 neonates were treated at the Institute Gustave-Roussy for a malignant solid tumor, comprising 1.7% of the overall oncopediatric population treated during the same period of time. Of these 75 patients, 47 (62%) presented with neuroblastomas, 15 (20%) with mesenchymal tumors, 9 (12%) with germ cell tumors and 4 with various other types of tumors. Treatment consisted of surgery in 63 patients, chemotherapy in 43 and radiotherapy in 18. The 5 year crude survival rate was 77%. Neuroblastomas did the best with a crude survival rate of 89%. The young age of the patients resulted in two types of problems: immediate tolerance and long term sequelae. The therapeutic regimen should take into account the good prognosis of the majority of these tumors in order to decrease delayed effects.
From 1974 to 1987, 450 children with non-Hodgkins' lymphoma (NHL) were seen at the Institut Gustave Roussy (IGR); 14 children had malignant lymphoma of bone (MLB). Eleven of the 14 were newly diagnosed, whereas three presented in relapse. Nine patients presented with multifocal bone involvement. The median age of these eight girls and six boys was 9.5 years (range 1.25-15 years). Bone pain was present in all patients as the initial symptom. Evaluation included physical examination, routine serum chemistries, complete blood count, chest roentgenography, skeletal survey, radionuclide bone scan, lumbar puncture, bone marrow aspiration, and intravenous pyelography, and/or abdominal ultrasonography. Hypercalcemia was found in six patients. Biopsy was performed in 12 patients, revealing high-grade lymphoblastic lymphomas in all. In two patients diagnosis was made on cytological examination of bone marrow aspirate. Immunophenotyping in four cases, demonstrated non-B, non-T cell origin in three and pre-B cell origin in one. Three patients were treated prior to 1982 with Cyclophosphamide/Oncovin/Prednisone/ADriamycin (COPAD) and seven patients, seen after 1982, were treated with a modified LSA2L2 protocol (LMT). None of the previously untreated patients received radiotherapy. All patients treated with COPAD have died, whereas four out of seven treated with LMT are alive with a median follow up of 51 months (range 36-82 months). One child treated on a pilot study died. One of the three children seen at relapse is disease-free with a follow-up of 98 months after high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). Five out of six patients presenting with hypercalcemia have died. Results with LMT are encouraging and together with published results suggest that sufficiently intensive chemotherapy can result in complete remission and cure in MLB. Radiotherapy does not seem to be necessary, avoiding possible serious long-term effects. Hypercalcemia is a bad prognostic feature.
Between January 1982 and December 1987, of 283 children with neuroblastoma treated in the Pediatric Department of Institut Gustave Roussy, 34 were stage IV-S. Two groups were distinguished according to the initial clinical presentation: 16/34 patients had life-threatening symptoms and needed immediate treatment, and 18/34 had no life-threatening symptoms. Hepatic irradiation was used in 12/16 patients of the first group with respiratory distress. Chemotherapy was used in three patients. Of these 16 patients, three patients died of progressive disease (one patient died of a reason not related to the tumor). Twelve are alive in first complete remission and one in second complete remission. Of the 18 patients of the second group, eight had spontaneous complete remission, and one of them relapsed thereafter and died despite treatment. Ten patients needed treatment, radiotherapy, and/or chemotherapy depending on the site of disease progression. Two of them died of the disease. The overall disease-free survival for these 34 patients is 75% at 90 months postdiagnosis. Using this therapeutic strategy, it was possible to avoid any treatment of metastases in 25% of the patients.
Undifferentiated nasopharyngeal carcinoma (UCNT) is known to be radiosensitive and chemosensitive, but the latter has never been studied prospectively with phase II methodology. After an intensive work-up, 49 patients with recurrent (REC) and/or metastatic (MTS) UCNT were treated with three monthly cycles of cisplatin (CDDP) 100 mg/m2 day 1; bleomycin 15 mg intravenously (IV) day 1, and 16 mg/m2/d continuous infusion (CI) days 1 to 5; and fluorouracil (5FU) 650 mg/m2/d CI days 1 to 5 (PBF). Of the 49 patients, 33 were North African. The sex ratio was three males:one female, and the median World Health Organization (WHO) performance status was 1.6. In the 48 patients assessable for response, we observed nine (19%) complete responses (CRs) and 29 (60%) partial responses (PRs) (60%), for a 79% overall response rate (95% confidence interval, 68% to 90%) in the assessable group and a 78% global rate. There were eight CRs (24%) observed in the group without previous chemotherapy (33 patients) compared with one CR in the chemotherapy pretreated group (16 patients). Four patients are still alive without evidence of disease after 52+, 54+, 58+, and 58+ months, respectively. All of them had less than three bone MTS sites, and received radiation therapy in these sites. The results confirm the chemosensitivity of UCNT, and the observation of unmaintained long-term responders makes curability a possible consideration.
Among the 282 neuroblastomas treated at the Institut Gustave-Roussy between 1982 and 1987, 38 dumbbell forms were observed. Therapeutic approaches included: 1) An initial laminectomy in forms with neurological deficit; 2) Surgical excision of the primary tumor; 3) Preoperative chemotherapy for metastatic forms and non-metastatic forms in which primary tumors considered unresectable at diagnosis; 4) Radiation therapy on macroscopic residual disease. Twenty three of 38 children presented with a neurological deficit. A laminectomy was performed in 21 cases. Neurological recovery was good in 8 cases, partial in 5 cases and absent in 5 cases. Three patients were aggravated after the procedure. The event free survival was 76%. This high survival rate is linked with: 1) The predominantly non metastatic stages (25/38); 2) A high proportion of children under 1 year of age (25/38); 3) A high proportion of thoracic locations. Out of the 29 survivors, there were 10 cases of major neurological sequelae (34%) and 9 cases of major orthopedic sequelae (31%). The coexistence of a serious functional prognosis and an excellent vital prognosis led us to analyse the therapeutic modalities and reevaluate the necessity of routine initial neurosurgical excision by laminectomy, and using a first line chemotherapy in selected indications.
Twenty-four children with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose chemotherapy (HDC) with bone marrow transplantation (BMT). HDC comprised in all cases busulfan (16 mg/kg or 600 mg/m2), with either cyclophosphamide (200 mg/kg or 4.4 g/m2) and/or melphalan (140 mg/m2). Twenty-three of these children had received second-line therapy before receiving HDC. There were 16 B cell and eight T cell lymphomas. Twenty-three patients were evaluable at day 30 post-BMT; 19 were in complete remission, four did not respond. Eight patients are long-term survivors between 62 and 296 weeks after BMT. Among the seven children with resistant disease before HDC, only one is a long-term survivor. No toxic deaths occurred. The main adverse side effect was hepatic veno-occlusive disease which occurred in four patients, but resolved completely in all cases. Comparisons with other classic HDC regimens in relapsed childhood lymphomas show that HDC containing busulfan with BMT appears reasonably safe and is effective in refractory or relapsed lymphomas, even in these highly previously treated patients.
A total of 251 patients were given 326 courses of high-dose chemotherapy followed by autologous bone marrow transplantation between February 1979 and August 1988. Ninety-one cases of septicaemia developed in 84 patients, 33 of these cases (36%) were due to streptococci. The outcome was fatal for four patients (12.1%). No specific risk factors were identified which might account for this septicaemia and no clinical feature was significantly associated with these cases of bacterial infection. Pulmonary and neurologic septic complications, however, were of very poor prognosis since all patients with these complications died. The high rate of streptococcal septicaemia and the poor outcome for patients with prolonged and profound neutropenia led us to modify our choice of initial broad-spectrum antibiotic therapy.
The management of osteogenic sarcoma in children has made a fantastic step on the survival rate, but there still remains unexpected late metastatic recurrence even in initially good responders to chemotherapy and lower survival rate in the bad responder group. Therefore, the research on etiology and on the understanding and rating of oncologic power of the tumoral cells as well as other kinds of treatment (vaccine, immunotherapy, and other types of chemotherapy) must be increased. The initial function after replacement is good and is often excellent but increasing deterioration is noticed during each follow-up evaluation. A considerable effort is still to be done for bone and joint replacement. Biocompatible material with mechanical strength and resistance to wear will be used for a long time because of the young age of the patients. There must be better use and understanding of the allograft revascularization, as well as a better biologic connection between the bone host and replacement device. This will probably be used in the future with less cement and more of a modular system. The final prognosis will remain for a long time in the perfect cooperation between the various members of the teams (oncologist, surgeon, imager, pathologist, and research team) who treat the patients.
Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of clonazepam; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with clonazepam:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by clonazepam. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies.
Undifferentiated carcinoma of nasopharyngeal type (UCNT) is a geographically endemic, Epstein-Barr virus-related carcinoma of epidermoid origin with reported 5-year survival rates of 15%-40% when treated with radiotherapy alone. Although UCNT can be well controlled locally by radiation therapy, in advanced nodal stage N3 [International Union Against Cancer-American Joint Committee on Cancer (UICC-AJCC, 1987)] the survival rate is below 20%, primarily because of metastatic spread in 80% of the fatalities. We report a pilot study of 41 patients with nonmetastatic, locoregionally advanced disease (85% of the patients had a nodal status greater than or equal to N2C-N3; 43% had T4 primaries), during which we used a combination of 100 mg of cisplatin/m2 on day 1, 15 mg of bleomycin by intravenous push and 12 mg/m2 by continuous infusion on days 1-5, and 70 mg of epirubicin/m2 on day 1 every 21 days for three cycles before definitive radiation therapy with 70 Gy for 7 weeks. Twenty-seven of 41 patients (66%; 95% confidence interval = 52.5%-80.5%) achieved a clinical complete response, and 40 of 41 (98%) had a major objective response after chemotherapy. Two deaths were treatment related, but side effects were moderate, and the overall treatment sequence was feasible. At the end of radiation therapy, all 39 assessable patients were in complete response, with a median follow-up of 21+ months (greater than 10-greater than 31); 33 (80%) patients had no evidence of disease. We believe that such a complete response rate in a high-volume disease with the use of combined modality treatment indicates a therapeutic gain in UCNT. Researchers performing a multicenter international controlled trial will test this hypothesis and compare local control, disease-free, and overall survival of the therapeutic sequence presented here with radiotherapy alone.