Gilbert Boisserie

Successful combination of local CpG-ODN and radiotherapy in malignant glioma

Oligodeoxynucleotides containing CpG motifs (CpG‐ODN) display broad immunostimulating activity and are currently under clinical trial in various malignancies, including recurrent glioblastomas. Combining CpG‐ODN with another therapy that could induce antigen release might enhance tumor‐specific immune response. We investigated whether radiotherapy (RT) could be associated advantageously to intratumoral injections of CpG‐ODN. Fisher rats bearing 9L glioma were treated with various combinations of RT and CpG‐28, an oligonucleotide with good immunostimulating activity. RT and CpG‐28 induced complete tumor remission in one‐third of the animals. When both treatments were combined, complete tumor remission was achieved in two‐thirds of the animals (p < 0.001 when compared to non‐treated rats, p < 0.03 when compared to CpG‐28 alone). Such efficacy was not observed in nude mice, underlying the role of T cells in antitumor effects. The combination of both treatments appeared optimal when the delay between RT and CpG‐28 administration was <3 days (from 100% survival for a 3 days delay, to 57% survival for a 21 days delay, p < 0.05). Tumor infiltration by immune cells and expression within tumors of the CpG receptor, TLR9, were not modified by irradiation. These results support an attractive strategy of sequential radiotherapy and immunotherapy by CpG‐ODN and have potential implications for future clinical trials with CpG‐ODN.

Radiosurgery for re-irradiation of brain metastasis: results in 54 patients

PURPOSE To evaluate in terms of probabilities of local-regional control and survival, as well as of treatment-related toxicity, results of radiosurgery for brain metastasis arising in previously irradiated territory. PATIENTS AND METHODS Between January 1994 and March 2000, 54 consecutive patients presenting with 97 metastases relapsing after whole brain radiotherapy (WBRT) were treated with stereotactic radiotherapy. Median interval between the end of WBRT and radiosurgery was 9 months (range 2-70). Median age was 53 years (24-80), and median Karnofski performance status (KPS) 70 (60-100). Forty-seven patients had one radiosurgery, five had two and two had three. Median metastasis diameter and volume were 21 mm (6-59) and 1.2 cc (0.1-95.2), respectively. A Leksell stereotactic head frame (Leksell Model G, Elektra, Instrument, Tucker, GA) was applied under local anesthesia. Irradiation was delivered by a gantry mounted linear accelerator (linacs) (Saturne, General Electric). Median minimal dose delivered to the gross disease was 16.2 Gy (11.8-23), and median maximal dose 21.2 Gy (14- 42). RESULTS Median follow-up was 9 months (1-57). Five metastases recurred. One- and 2-year metastasis local control rates were 91.3 and 84% and 1- and 2-year brain control rates were 65 and 57%, respectively. Six patients died of brain metastasis evolution, and three of leptomeningeal carcinomatosis. One- and 2-year overall survival rates were 31 and 28%, respectively. According to univariate analysis, KPS, RPA class, SIR score and interval between WBRT and radiosurgery were prognostic factors of overall survival and brain free-disease survival. According to multivariate analysis, RPA was an independent factor of overall survival and brain free-disease survival, and the interval between WBRT and radiosurgery longer than 14 months was associated with longer brain free-disease survival. Side effects were minimal, with only two cases of headaches and two of grade 2 alopecia. CONCLUSION Salvage radiosurgery of metastasis recurring after whole brain irradiation is an effective and accurate treatment which could be proposed to patients with a KPS>70 and a primary tumour controlled or indolent. We recommend that a dose not exceeding 14 Gy should be delivered to an isodose representing 70% of the maximal dose since local control observed rate was similar to that previously published in literature with upper dose and side effects were minimal.

Radiotherapeutic factors in the management of cervical-basal chordomas and chondrosarcomas.

OBJECTIVE:To define prognostic factors for local control and survival in 90 consecutive patients treated by fractionated photon and proton radiation for chordoma or chondrosarcoma of the cranial base and upper cervical spine. METHODS:Between December 1995 and December 2000, 90 patients (median age, 51.3 yr; range, 10–85 yr; male/female ratio, 3:2) were treated by a combination of high-energy photons and protons. Sixty-four patients had a chordoma, and 26 had a chondrosarcoma. The proton component was delivered by the 201-MeV proton beam of the Centre de Protonthérapie d’Orsay. The median total dose delivered to the gross tumor volume (GTV) was 67 cobalt Gray equivalents (range, 22–70 cobalt Gray equivalents). RESULTS:With a median follow-up of 34 months (range, 3–74 mo), treatment of 25 tumors failed locally. The 3-year local control rates were 69.2% (±6.0%) and 91.6% (±8.4%) for chordomas and chondrosarcomas, respectively. According to multivariate analysis, a small tumor volume excluded from the 95% isodose line (P = 0.032; relative risk [RR], 0.098; 95% confidence interval [CI], 0.01–0.81) and a controlled tumor (P = 0.049; RR, 0.19; 95% CI, 0.04–0.99) were independent favorable prognostic factors for overall survival. On multivariate analysis, a high minimum dose (P = 0.02; RR, 2.8; 95% CI, 1.2–6.6), a high tumor control probability (P = 0.02; RR, 3.8; 95% CI, 1.2–12.5), a high dose delivered to 95% of the GTV (P = 0.03; RR, 3.4; 95% CI, 1.15–10.2), a high GTV encompassed by the 90% isodose line (P = 0.01; RR, 3.29; 95% CI, 1.29–8.44), and a small GTV excluded from the 90% isodose line (P = 0.036; RR, 0.4; 95% CI, 0.1–0.9) were independent favorable prognostic factors for local control. CONCLUSION:In chordomas and chondrosarcomas of the cranial base and cervical spine treated by surgical resection and then by high-dose photon and proton irradiation, local control is mainly dependent on the quality of radiation, especially dose uniformity within the GTV. Special attention must be paid to minimize underdosed areas because of the close proximity of critical structures and to redefine and possibly escalate dose constraints to tumor targets in future studies in view of the low toxicity observed to date.

The use of a specific hypofractionated radiation therapy reg imen versus classical fractionation in the treatment of breast cancer: A randomized study of 230 patients

An ongoing randomized study of a specific regimen of hypofractionated radiation therapy (IHF) versus classical or standard radiation therapy (IC) for breast cancer was begun in the Department of Radiation Therapy of the Necker Hospital, Paris France, in January 1982. Breast cancer patients entered into this study received either IC to deliver 45 Gy in 25 fractions over 33 days or a specific IHF regimen to deliver 23 Gy in 4 fractions over 17 days. As of June 1989, 525 patients had been entered into the study. The first 230 patients treated from 1982 through December 1984 had a minimum follow-up of 4 years (range: 4 to 7 years). Preliminary analysis of the results in these first 230 patients are presented. The distribution of patients in this initial group according to clinical staging, associated treatments, and pathological nodes is as follows: T1 = 22%, T2 = 61%, T3 + T4 = 17%, palpable nodes = 28%, inflammatory signs = 7%, surgical treatment = 79% (mastectomy = 35%, tumorectomy + Ir.192 = 44%), radiation alone + neoadjuvant chemotherapy = 21%, N+ = 50% of patients undergoing surgery. Loco-regional recurrences developed in 7% (9/125) of patients in the IHF group and in 5% (5/105) of patients in the IC group. Complications were minor. The addition of the percentage of each complication noted results in a total of 23% for the IHF group and 19% for the IC group (one patient could present several complications). As we had previously observed when comparing these two fractionation regimens in other studies with other tumors, these preliminary results showed no evident difference in the effectiveness and rate of complications whether IHF or IC was used to treat patients with breast cancer.

Radiosurgery for brain metastasis: impact of CTV on local control

PURPOSE The purpose of the present analysis was to assess whether adding a 1 mm margin to the gross tumour volume (GTV) improves the control rate of brain metastasis treated with radiosurgery (RS). PATIENTS AND METHODS All the patients had one or two brain metastases, 30 mm or less in diameter, and only one isocentre was used for RS. There were 23 females and 38 males. The median age was 54 years (34-76). The median Karnofsky performance status was 80 (60-100). At the time of RS, 23 patients had no evidence of extracranial disease and 38 had a progressive systemic disease. Thirty-eight patients were treated up-front with only RS. Twenty-three patients were treated for relapse or progression more than 2 months after whole brain radiotherapy. From January 1994 to July 1995, clinical target volume (CTV) was equal to GTV without any margin (33 metastases). From August 1995 to August 2000, CTV was defined as GTV plus a 1 mm margin (45 metastases). A dose of 20Gy was prescribed to the isocentre and 14Gy at the margin of CTV. RESULTS The median follow-up was 10.5 months (1-45). The mean minimum dose delivered to GTV was 14.6Gy in the group without a margin and 16.8Gy in the group with a 1 mm margin (P<0.0001). The response of 11 metastases was never assessed because patients died before the first follow-up. Ten metastases recurred, eight in the group treated without a margin and two in the group treated with a 1 mm margin (P=0.01). Two-year local control rates were 50.7+/-12.7% and 89.7+/-7.4% (P=0.008), respectively. Univariate analysis showed that the treatment group (P=0.008) and the tumour volume (P=0.009) were prognostic factors for local control. In multivariate analysis, only the treatment group with a 1 mm margin was an independent prognostic factor for local control (P=0.04, RR: 5.8, 95% CI [1.08-31.13]). There were no significant differences, either in overall survival rate or in early and late side effects, between the two groups. CONCLUSION Adding a 1 mm margin to the GTV in patients treated with RS significantly improves the probability of metastasis control without increasing the side effects.

Three irradiation treatment options including radiosurgery for brain metastases from primary lung cancer

PURPOSE To determine local control and survival rates in 92 patients with 145 brain metastases treated with three options of radiotherapy including stereotactic radiosurgery (SR). METHODS Between July 1994 and August 2002, 92 consecutive patients with 145 metastases were treated with a SR, 34 with initially SR alone, 22 initially with an association of whole-brain radiotherapy (WBRT) and 36 with SR alone for recurrent new brain metastasis after WBRT. At time of treatment, extracranial disease was controlled in 46 (50%) and uncontrolled in 46 (50%). Pathologies were adenocarcinoma in 54 cases (59%), squamous cell carcinoma in 14 cases (15%), small cell carcinoma in 10 cases (11%) and miscellaneous in 14 cases (15%). All patients underwent only one treatment fraction for 1 or 2 metastases in 73 cases (83%) and for more than 2 metastases for the others. RESULTS The characteristics of patients and metastases in the group treated initially with SR alone and in the group treated initially with WBRT+SR were comparable. Median follow-up was 29 months (18-36). Overall, the median and the 1- and 2-year rates of overall survival were, respectively, 9 months, 37 and 20%. A controlled extracranial disease, a high Karnofsky index and a low number of metastasis were independent prognostic factor of overall survival, respectively, HR 0.53 (95% CI 0.31-0.90, P=0.01), HR 0.95 (95% CI 0.92-0.97, P=0.0002), and HR 0.48 (95% CI 0.25-0.90, P=0.02). Thirteen metastases were not controlled (9%). Six-month and 1-year local control rate were, respectively, 93 and 86%. High delivered dose was an independent prognostic factor of local control, HR 0.41 (95% CI 0.18-0.95, P=0.03). A controlled extracranial disease was favourable independent prognostic factor of brain free-disease free survival, HR 0.47 (95% CI 0.2-0.98, P=0.04). Although there was a trend of a better local control, overall and brain disease free survivals rates in the WBRT+SR group compared to SR alone one, the difference were not statistically different. CONCLUSION Local control and survival rates are acceptable for a palliative treatment for the three option of treatment. In this series, the number of patients is not enough great to conclude to the necessity of the association of WBRT to SR. Re-irradiation is a safe treatment after new metastases appeared in previously irradiated area.

LINAC radiosurgery for brain metastasis of renal cell carcinoma

The purpose of the study was to evaluate the efficacy and toxicity of stereotactic radiotherapy in the treatment of the brain metastasis of renal cell carcinoma. From 1994 to 2001, 28 patients presenting with 65 metastases of renal cell cancer were treated by radiosurgery. Median age was 55 years (35-75), and median Karnofski performance status ranges between 50 and 100. Seven patients had received whole brain radiotherapy (WBRT) before radiosurgery. Twelve patients were treated by radiosurgery for 1 metastasis, 5 patients for two metastases and 6 for three, and 5 for more than three metastases. One procedure was performed in 22 patients and, 2 or 3 procedures for 6 patients. Median metastasis diameter was 19 mm (5-55 mm). Median metastasis volume was 1.28 cc (0.02-28 cc). Irradiation was delivered by linear accelerator. Median minimal dose (on the 70% isodose) was 14.7 Gy (10.8 Gy, 19.5 Gy), median maximal dose (at the isocenter) 20.5 Gy (14.3 Gy, 39.6 Gy). Median follow-up was 14 months (1-33). Two metastases progressed (3%), 2 and 12 months after radiosurgery. Overall, crude local control rate was 97% and 3-, 6- and 12-month local control rates were 98% +/- 2%, 98% +/- 2%, and 93% +/- 5%, respectively. In univariate analysis, no prognostic factor of local control was retrieved. Median brain disease-free survival was 25 months after RS. the 3-, 6- and 12-month distant brain control rates were 91% +/- 4%, 91% +/- 4%, and 70% +/- 12%, respectively. Median survival duration was 11 months. The 3-, 6-, 12- and 24-month overall survival rates were 82% +/- 7%, 67% +/- 9%, 48% +/- 10%, and 33% +/- 10%, respectively. According to univariate analysis, only site of metastasis was overall survival prognostic factor. Radiosurgery for brain metastasis of renal cell carcinoma is an effective and accurate treatment. The use of radiosurgery alone is an appropriate management strategy for many patients with brain metastasis of renal cell carcinoma. Radiosurgery is efficient even after development of new metastasis appearing after WBRT.

Radiation-induced cognitive dysfunction: An experimental model in the old rat

PURPOSE To develop a model of radiation-induced behavioral dysfunction. METHODS AND MATERIALS A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. RESULTS Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p < or = 0.001) and two-way avoidance (18% vs. 40%, p < or = 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p < or = 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. CONCLUSION Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes.

Brachytherapy of glioblastoma recurring in previously irradiated territory: predictive value of tumor volume

PURPOSE To evaluate the impact of tumor volume on survival of patients reirradiated with (192)Ir for recurrent glioblastoma. METHODS AND MATERIALS Between 1993 and 1997, 42 patients with recurrent glioblastomas (29 males and 13 females, age 18-69 years, median age 49) were treated with (192)Ir implantation. Previous treatments included surgery, external beam radiotherapy, and chemotherapy. Maximum diameter of the recurrent tumor was 1.2-10.1 cm (median: 5.7 cm) and tumor volume was 1.6-122 cm(3) (median: 23 cm(3)). Karnofsky performance status score was 50-100 (median: 80). Brachytherapy dose was 40-60 Gy. RESULTS Probability of overall survival was 80% at 6 months, 48% at 1 year, and 11% at 2 years. Median survival was 50 weeks. Univariate analysis showed that both tumor volume (T < or T > or = 30 cm(3)) and Karnofsky performance status score were significant predictors of survival. Multivariate analysis showed that smaller tumor volumes were associated with a higher probability of survival (p < 0.001). CONCLUSION Tumor volume less than 30 cm(3) was associated with a higher probability of, and quality of, survival than larger lesions for patients reirradiated by brachytherapy for recurrent glioblastoma.

Linac Radiosurgery for Brain Metastasis of Melanoma

Purpose: To evaluate the efficacy and toxicity of stereotactic radiotherapy in the treatment of brain metastases of melanoma. Patients and Methods: From 1994 to 2001, 25 patients presenting with 61 metastases of cutaneous melanoma were treated with radiosurgery. Median age was 47 years (range: 25–73 years) and median Karnofski performance status 80 (range: 50–100). Twenty patients had one radiosurgery, 5 had two or three. Median metastasis diameter was 21 mm (range: 6–54.4 mm), and median metastasis volume was 1.7 cm3 (range: 0.4–25.6 cm3). Irradiation was delivered by a linear accelerator. Median minimal dose was 14.1 Gy (range: 10–19.4 Gy), and median maximal dose was 20.5 Gy (range: 16–48 Gy). Results: Mean follow-up was 12.6 months (range: 1–85 months). Five metastases progressed (9.8%), 2–12 months after radiosurgery. Three-, 6- and 12-month local control rates were 95 ± 3, 90 ± 5 and 84 ± 7%, respectively. By univariate analysis, only absence of extracranial tumor was a prognostic factor of local control. Three-, 6- and 12-month brain-disease-free survival rates were 75 ± 9, 68 ± 11 and 38 ± 13%, respectively. According to univariate analysis, only the Score Index for Radiosurgery in brain metastases (SIR) was a prognostic factor of brain-event-free survival (p = 0.03). Median survival was 8 months. Three-, 6- and 12-month overall survival rates were 75 ± 9, 53 ± 10, and 29 ± 10%, respectively. According to univariate analysis, extracranial controlled disease status (p = 0.03), and SIR (p = 0.04) were prognostic factors for overall survival. According to multivariate analysis, none was an independent prognosticator for overall survival. Complications were minimal. Conclusion: Radiosurgical treatment of brain metastases of melanoma is effective and accurate. The use of radiosurgery alone is an appropriate management strategy for many patients with brain metastases of melanoma.