Claire Alapetite

IMPACT OF TARGETING DEVIATIONS ON OUTCOME IN MEDULLOBLASTOMA: STUDY OF THE FRENCH SOCIETY OF PEDIATRIC ONCOLOGY (SFOP)

PURPOSE To correlate targeting deviation in external beam radiation therapy with site of relapse in a prospective study of 174 patients treated for medulloblastoma. METHODS AND MATERIALS Between February 1992 and February 1998 the radiotherapy treatment records were reviewed by a panel of radiation oncologists for 174 children treated with radiation therapy for medulloblastoma. The review was done without knowledge of patient outcome. Patterns of relapse were correlated with the results of the quality control review. RESULTS Among the 174 patients five relapsed before the start of radiotherapy. One hundred sixty-nine patients were evaluable for correlation between targeting deviation and site of relapse. Number of major deviations in radiation therapy treatment is strongly correlated with the risk of tumor relapse (67% [95% CI: 28-91] of 3-year relapse rate in patient group with 2 major deviations and 78% [95% CI: 35-96] with 3 major deviations). This is particularly correlated with relapse in the frontal region of the brain: 5 relapses occurred in the frontal region in patients with major deviation in this area. An erroneous choice of electron beam energy is also linked with craniospinal fluid (CSF) relapse (3-year relapse rate of 68% [95% CI: 42-86]). Minor deviations in therapy technique are slightly associated with an increased risk of relapse in the same range as the group with only one major deviation. CONCLUSION The quality of medulloblastoma radiation therapy technique is strongly correlated with outcome. Pretreatment central quality assurance review or standardized computer-designed blocks would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy.

Analysis by alkaline comet assay of cancer patients with severe reactions to radiotherapy: defective rejoining of radioinduced DNA strand breaks in lymphocytes of breast cancer patients.

Therapeutic exposure to ionising radiation reveals inter‐individual variations in normal tissue responses. To examine whether a defect in DNA repair capacity might be involved in such hypersensitive phenotypes, we analysed, using the alkaline comet assay, the response as a function of time to in vitro irradiation at 5 Gy of lymphocytes from 17 breast cancer and 9 Hodgkins disease patients who developed severe reactions to radiotherapy in comparison with 22 patients with “average” reactions and 24 healthy donors. A difference between breast cancer over‐reactors and both patients with normal reactions and healthy donors was observed 30 and 60 min after exposure. A subgroup of breast cancer over‐reactors (7/17) reproducibly demonstrated increased levels of residual damage. When the kinetic analyses were prolonged to 120 min, results were in favour of delayed kinetics of rejoining in these patients. Among Hodgkins disease over‐reactors, only one patient showed defective repair. Interestingly, all patients with the most severe complications (grade 4 RTOG/EORTC), i.e., 5 breast cancer and 1 Hodgkins disease, showed impaired rejoining. Our results suggest that impairment in DNA strand break processing may be associated, in specific subgroups of breast cancer patients, with an individual risk of major toxicity of radiation therapy. Thus, the alkaline comet assay appears to be useful for documenting the DNA repair phenotype in cancer patients. Int. J. Cancer 83:83–90, 1999.

Quality control of radiotherapeutic treatment of medulloblastoma in a multicentric study: The contribution of radiotherapy technique to tumour relapse

Between 06.86 and 11.89, 88 medulloblastoma or primitive neuroectodermic tumour (PNET) localised in the posterior fossa have been included in the M7 multicentric protocol, 82 received the totality of the radiotherapy treatment and were evaluable for this study. Twenty-two of these 82 patients relapsed: their radiotherapy treatment is analysed in the present study. In 10 cases out of the 22 relapses treatment failure was probably due to a radiotherapeutic imperfection. This study confirms the necessity of a strict radiotherapy control, particularly in multicentric study.

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

BACKGROUND We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. CONCLUSIONS Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience

Over the last two decades, chemotherapy has been introduced in protocols for patients with intracranial germinoma with the objective of reducing the volume and the dose of irradiation without compromising survival rates. The aim of this work is to critically analyze the pattern of relapse in a cohort of patients with nonmetastatic germinoma prospectively treated with chemotherapy followed by focal field radiation. Data of all germinoma patients registered in the French protocol for intracranial germ cell tumors between 1990 and 1999 were reviewed. The pattern of relapse, management, and outcome were analyzed in 10 of 60 patients who developed a recurrence after initial treatment. In 9 patients, the site of recurrence was local or loco-regional, notably in the periventricular area for 8. One patient only had isolated distant leptomeningeal relapse. The review of the sites of relapse suggests that most recurrences could have been avoided with a larger ventricular field of radiation. Treatment at first relapse included chemotherapy (10 patients), high-dose chemotherapy and stem cell transplant (8 patients), and/or radiation therapy (4 patients). Five patients experienced a second relapse. At a median follow-up of 72 months since the first relapse, 8 patients are alive in second or third remission. This review identified an excess of periventricular relapses when the focal field of radiation is used in the combined management of germinoma. These relapses are predominantly marginal or outside radiation fields. Ventricular field radiation appears a logical alternative to decrease the incidence of such relapses. Future trials should aim at better identifying patients who may benefit from local and ventricular radiation, respectively.

Childhood Craniopharyngioma: Hypothalamus-Sparing Surgery Decreases the Risk of Obesity

CONTEXT Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

Proton Therapy in Pediatric Skull Base and Cervical Canal Low-Grade Bone Malignancies

PURPOSE To evaluate outcomes and tolerance of high-dose photon and proton therapy in the management of skull base and cervical canal primary bony malignancies in children. PATIENTS AND METHODS Thirty children were treated postoperatively with high-dose photon-proton (29 patients) or protons-only (1 patient) radiotherapy. Twenty-six patients had chordomas (CH), 3 had low-grade chondrosarcomas (CS), and 1 had an aggressive chondroma (AC). The mean age was 12.8 years. At the time of radiation, all but 1 patient had a gross residue. The anatomic sites affected were skull base (n = 16), cervical canal (n = 1), or both (n = 13). Mean total dose was 68.4 cobalt Gray equivalents, conventionally fractionated. RESULTS With a mean follow-up of 26.5 months, 5 of 30 children failed locally: 5 of 5 lesions were CH, 5 of 5 patients had experienced pain at presentation (p = 0.03), and 4 of 5 had cervical extension (p = 0.07). The 5-year overall survival/progression-free survival rates for CS and CH were 100%/100% and 81%/77%, respectively. Side effects were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Acute toxicity ranged between 0 and 2. Late toxicity of radiotherapy was severe in 1 patient (Grade 3 auditory) and minor or mild in the rest of the population (7 patients with Grade 2 pituitary dysfunction). CONCLUSIONS High-dose combined fractionated photon-proton therapy is well tolerated in children and allows excellent local control with minimal long-term toxicity.

Quality-of-life, mood and executive functioning after childhood craniopharyngioma treated with surgery and proton beam therapy.

Primary objective: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality‐of‐life (QoL). Method: This retrospective study analysed QoL, mood disorders, everyday executive functioning and diseases impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SD = 4.1); mean follow‐up period 6 years 2 months (SD = 4.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi‐structured interview and standardized scales evaluating self‐report of QoL (Kidscreen 52) and depression (MDI‐C) and proxy‐reports of QoL (Kidscreen 52), executive functioning (BRIEF) and diseases impact (Hoare and Russel Questionnaire). Results: Twenty‐three families answered the questionnaires completely. Overall QoL self‐report was within the normal range. QoL proxy‐report was lower than self‐report. Eleven patients reported depression; 24–38% had dysexecutive symptoms. A majority of families felt ‘very concerned’ by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction. Conclusion: Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented.

Nonmetastatic pelvic Ewing sarcoma: report of the French society of pediatric oncology.

BACKGROUND Since January, 1984, 59 children with histologically confirmed Ewing sarcoma of the pelvic bone have been treated with three successive chemotherapy protocols recommended by the French Society of Pediatric Oncology. The purpose of the current study was to evaluate the role of surgery and/or radiotherapy in local progression-free, disease-free, and overall survivals (LPFS, DFS, and OS, respectively). PROCEDURE We retrospectively examined 59 children treated for nonmetastatic, pelvic Ewing sarcoma over the last 12 years. All were first treated with chemotherapy according to the current French protocol. Six patients developed progressive disease before local treatment and were excluded for local control and survival analysis. Local treatment was surgery alone in 17 cases, radiation therapy in 27 cases, and surgery plus radiation therapy in 9 cases. RESULTS With a median of follow-up of 6.5 years, no significant differences in local control or survival were observed with the three chemotherapeutic protocols. Of the 53 patients evaluable for local control, 6 relapsed locally only, 8 had local and distant relapses, and 9 had distant metastases only. The 5-year OS rate was worst for patients with radiotherapy alone compared to those with surgery or combined modality treatment (44 % vs. 72 %, P = 0.043). The 5-year LPFS and DFS rates were worst in the radiotherapy-alone group but not significantly (63% vs. 79%, P = 0. 22 and 42% vs 71%, P =0.07, respectively). The importance of surgery to OS and DFS was confirmed by multivariate analysis (P = 0.026 and P = 0.048, respectively). One surviving patient was diagnosed with in-field fibrosarcoma, which was presumably radiation induced. CONCLUSIONS Despite intensive, multiagent chemotherapy, survival from pelvic Ewing sarcoma has not improved over the past decade; however, the survival rate does not seem to be worse than that from Ewing sarcoma at other locations, insofar as at least 50% of the patients were cured. Surgery or a combination of surgery and radiation therapy are the best local treatment; exclusive radiation therapy should be reserved for patients with inoperable lesions or partially or nonchemosensitive tumors or when surgery would be an amputation.

Inhibin B and Antimüllerian Hormone as Markers of Gonadal Function after Treatment for Medulloblastoma or Posterior Fossa Ependymoma during Childhood

OBJECTIVE To evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH). STUDY DESIGN A total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH; <9 IU/L), or abnormal levels of FSH (>9 IU/L) and luteinizing hormone (LH; <5 or >5 IUL). RESULTS Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation. CONCLUSION The plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.