Jean Philippe Maire

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.

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6-7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.

Inter-clinician variability in making dosimetric decisions in pediatric treatment: A balance between efficacy and late effects

PURPOSE To investigate variability of clinical target volume (CTV) delineation and deviations according to doses delivered in normal tissue for abdominal tumor irradiation in children. MATERIAL AND METHODS For a case of nephroblastoma six French pediatric radiation oncologists outlined post-operative CTV, on the same dosimetric CT scan according to the International Society for Pediatric Oncology 2001 protocol. On a reference CTV and organs at risk (OAR), we performed dosimetric planning with the constraints as 25.2 Gy for CTV, V(20 max) to 50% for liver, V(12) <15% for kidney. Data were analyzed with Aquilab software. RESULTS Final CTVs showed inter-clinician variability: 44.85-120.78 cm(3). The recommended liver doses were not respected in four cases: V(20) from 74% to 88% of the volume; for kidney, in two cases: V(12) of 17.6% and 25%, respectively. For vertebral bodies, no deviations were noted. CONCLUSION Variability not only affected CTV delineation but also dose distribution to OAR with different compromises. This practice training demonstrates the hudge lack of data about correlation between dose, volume and risk of late effects in pediatric radiotherapy. We intend to record prospectively the dose/volume histogram of each OAR in a national database in order to characterize late effects occurring in relation to treatment modalities.

Epithelial growth factor receptor (EGFR) pathway and renal cell carcinoma

The epidermal growth factor receptor (EGFR) pathway is a very well-known pathway implicated in proliferation, growth and metastatic development of various tumor types. Consequently, EGFR pathway inhibitors have provided clinical benefits in many tumor types. EGFR expression is reported in up to 95% of renal cell carcinoma (RCC) and is considered high (3+) in up to 60%. In preclinical models, the EGFR pathway appears implicated in tumor development. Its mode of action includes the common EGFR signal transduction cascades, but it also interacts with the angiogenic pathway, especially the vascular endothelial growth factor receptor (VEGFR) pathway. Monotherapy with EGFR pathway inhibitors does not appear to modify the history of metastatic RCC (MRCC) and does not justify further experiments in this setting. The issues now requiring attention are the degree to which the EGFR pathway is involved in RCC tumors expressing high EGFR levels—a phase III study suggests that it influences outcome in these patients—and the clinical benefit of associating antiangiogenic therapy and EGFR pathway inhibitors in the light of successive phases II trials. In conclusion, the EGFR pathway is probably not a major pathway in RCC development compared to the antiangiogenic pathways, but could play a role in association with antiangiogenics or in the event of progression after antiangiogenic therapy. Additional preclinical data is needed to support these hypotheses.

Clinical InvestigationsImpact of targeting deviations on outcome in medulloblastoma: study of the French society of pediatric oncology (SFOP)1

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.

Impact of targeting deviations on outcome in medulloblastoma: study of the French society of pediatric oncology (SFOP)11Participating institutions including more than one patient: Centre Paul Papin—Angers (M. Mege); Bruxelles (C. De Vriendt); Centre Claudius Regaud—Toulouse (F. Soum); Hôpital Charles Nicolle—Rouen (S. Seng); Institut Jean Godinot—Reims (X. Panis); Hôpital Bellevue—Saint-Etienne (T. Schmitt).

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.