Predictive factors of human cytomegalovirus reactivation in newly diagnosed glioblastoma patients treated with chemoradiotherapy.

The human cytomegalovirus (HCMV) is a ubiquitous herpes virus which infects 40 to 99% of the population. HCMV reactivation may occur in the context of immunosuppression and can induce significant morbidities. Several cases of HCMV infections or HCMV reactivation have thus been reported in glioblastoma (GBM) patients treated with radio(chemo)therapy. With the aim to identify the main risk factors associated with HCMV reactivation, we reviewed all patients treated for a newly diagnosed GBM in our institution from October 2013 to December 2015. Age, sex, Karnofsky performance status (KPS), absolute lymphocyte count (ALC), serological HCMV status, and steroid doses were recorded at the start and 1 month after the end of radiotherapy (RT). Within the 103 patients analyzed, 34 patients (33%) had an initial negative serology for HCMV, and none of them developed a seroconversion after treatment. Among patients with positive HCMV IgG (n = 69), 16 patients (23%) developed a viremia at one point during treatment. Age (> 60 years), steroid intake, and ALC (< 1500/mm3) before RT were correlated with HCMV reactivation. HCMV viremia was associated with neurological decline 1 month after chemoradiotherapy but progression-free survival was not impacted. A shorter overall survival was seen in these patients when compared with the others, but this could be biased by the older age in this subgroup. HCMV reactivation needs to be sought in case of a neurological decline during RT especially in older patients treated with steroids and low lymphocytes counts.

Angiotensin II receptor blockers, steroids and radiotherapy in glioblastoma-a randomised multicentre trial (ASTER trial). An ANOCEF study.

BACKGROUND: Glioblastomas (GBMs) induce a peritumoural vasogenic oedema impairing functional status and quality of life. Steroids reduce brain tumour-related oedema but are associated with numerous side-effects. It was reported in a retrospective series that angiotensin receptor blockers might be associated with reduced peritumoural oedema. The ASTER study is a randomised, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care (SOC) can reduce steroid requirement during radiotherapy (RT) in patients with newly diagnosed GBM. PATIENTS AND METHODS: Patients with a histologically confirmed GBM after biopsy or partial surgical resection were randomised between Losartan or placebo in addition to SOC with RT and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain oedema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral oedema on magnetic resonance imaging, tolerance and survival. RESULTS: Seventy-five patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain oedema on the last day of RT, or one month after completion of RT, was seen between both arms. The incidence of adverse events was similar in both arms. Median overall survival was similar in both arms. CONCLUSIONS: Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant RT and TMZ. Trial registration number NCT01805453 with ClinicalTrials.gov.

Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma.

BACKGROUND AND PURPOSE: Despite surgery, radiotherapy (RT) and temozolomide (TMZ), the prognosis of glioblastoma (GBM) patients remains dismal. Normally prescribed with the aim to lower blood pressure, angiotensin-II (Ang-II) inhibitors were reported to reduce angiogenesis and tumour growth in several tumour models including one glioma. Thus whether treatment with Ang-II inhibitors could be associated with a better clinical outcome in GBM patients was investigated. METHODS: A series of 81 consecutive patients, homogeneously treated with RT and TMZ for a newly diagnosed, supratentorial GBM, were analysed. The objective of this retrospective study was to assess the impact of angiotensin-converting enzyme inhibitors (ACEIs) and Ang-II receptor 1 blockers (ARBs) on functional independence, progression-free survival (PFS) and overall survival (OS). RESULTS: Amongst the 81 GBM patients analysed, 26 were already treated for high blood pressure (seven with ACEIs and 19 with ARBs). The number of patients who remained functionally independent at 6 months after RT was higher in the group of patients treated with Ang-II inhibitors compared to the other patients (85% vs. 56%, P = 0.01). In patients treated with Ang-II inhibitors, PFS was 8.7 months (vs. 7.2 months in the other patients) and OS was 16.7 months (vs. 12.9 months). The use of Ang-II inhibitors was a significant prognostic factor for both PFS (P = 0.04) and OS (P = 0.04) in multivariate analysis. CONCLUSION: Treatment with Ang-II inhibitors in combination with RT and TMZ might improve clinical outcome in GBMs. Prospective trials are needed to test this hypothesis.

Value and cost evaluation of routine follow-up for patients with clinical stage I/II endometrial cancer.

The aim of the study was to determine the value and the costs of routine follow-up for the detection of recurrences in patients treated for endometrial cancer. Between 1986 and 1995, 390 women with clinical stage I/II endometrial carcinoma were treated with combined surgery-radiation therapy. After treatment, follow-up was based on the clinical examination, a systematic Papanicolaou (Pap) smear and radiography (chest X-ray and abdomino-pelvic ultrasonography). 27 patients relapsed: 22 patients had symptoms and 5 were asymptomatic. None of the patients had recurrence detected on the routine Pap smear nor on the systematic chest X-ray. In conclusion, the follow-up of patients treated for endometrial cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrences. Follow-up should simply include a clinical examination whose frequency should be based on prognostic factors. Approximately two-thirds of this cost was due to systematic examinations (Pap smears and radiography). Our results indicate that such expenditure could be avoided.

[Conformational radiotherapy: economic evaluation]. / Radiothérapie conformationnelle: évaluation économique.

Conformational radiotherapy is more and more used. It seems that this kind of treatment requests more manpower and material than 2D techniques. The purpose was to estimate its cost. We first tried to estimate the development of 3D radiotherapy. Then we calculated its relative cost compared to classical radiation therapy. To estimate relative costs, we first used the official catalogue. Then we reported results of a study performed in 1998 in two different radiotherapy departments. We conclude that 3D treatment are more expensive. The incremental cost is mainly related to that of dosimetry.

Cost-effectiveness of second-line treatment with irinotecan or infusional 5-fluorouracil in metastatic colorectal cancer.

BACKGROUND: It has been shown that irinotecan is superior to infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer after 5-FU failure. In a recent trial, median survival was 10.8 months for patients treated with irinotecan, compared to 8.5 months in patients receiving infusional 5-FU. Considering the statistically significant but clinically relatively small advantage of irinotecan over 5-FU, cost effectiveness should also be part of treatment decision. PURPOSE: To relate the costs of each management approach to overall survival in patients with metastatic colorectal cancer. PATIENTS AND METHODS: The healthcare costs and medical benefits (treatment-added survival) of second-line chemotherapy in patients (infusional 5-FU: 129, irinotecan: 127) were compared. Data on overall survival were drawn from a multicenter randomised trial that compared infusional 5-FU (continuous infusion, AIO, or LV5-FU2 regimens) to irinotecan alone. Costs were derived from the accounting system in two university hospitals in Paris, France. RESULTS: The range in total healthcare costs was 14,135 to 12,192 US$ patient between management approaches, with irinotecan chemotherapy costing most and 5-FU-continuous infusion least. If survival was included as a treatment benefit, the cost-effectiveness ratio of irinotecan over 5-FU ranged from 9,344 to 10,137 US$ per year of added survival. CONCLUSIONS: The least expensive management for metastatic colorectal was 5-FU infusion but the additional cost of irinotecan was balanced by the added months of survival, with a cost-effectiveness ratio close to that of other cancer treatments.

Postoperative radiotherapy in the management of adult soft tissue sarcoma of the extremities: results with two different total dose, fractionation, and overall treatment time schedules.

PURPOSE: This retrospective study was performed to evaluate two postoperative radiotherapy schedules in terms of dose, fractionation, and overall treatment time in soft tissue sarcoma (STS) of the extremities. METHODS AND MATERIALS: Between January 1984 and December 1993, 62 patients with newly diagnosed localized STS of the extremities were treated with maximal conservative surgery and postoperative radiotherapy (RT). Forty-five patients received 50 Gy with conventional fractionation plus a boost dose (5 to 20 Gy). Seventeen patients had hyperfractionated accelerated radiotherapy (HFART) up to a dose of 45 Gy in 3 weeks. RESULTS: With a median follow-up of 72 months, the 5-year local failure rate was 25%, the 5-year disease-free and overall survival rates were respectively 42% and 62%. The 3-year local relapse, disease-free, and overall survival rates were respectively 16%, 44%, and 70% in the conventional radiotherapy group, and 36%, 47%, and 82% in the HFART group (NS). No factor significantly influenced local control with a trend, however, in favor of conventional RT (p = 0.10). CONCLUSION: HFART at the dose of 45 Gy does not seem to be superior to the standard RT schedule, neither in terms of local control, survival, nor in terms of long-term side effects. However this dose could be considered too low as well as the power of comparison between the two groups to draw definitive conclusions.

[Radiotherapy for leukemias and lymphomas in children]. / Radiothérapie des hémopathies malignes de l'enfant.

Children treated for malignant hemopathy have a very good prognosis, yet late effects of the treatments on the length, endocrine function, cognitive function and the risk of secondary malignant tumors must be decreased. These toxicities are described in this article. New protocols and radiation techniques have been developed to reduce these effects. Radiotherapy is prescribed in the treatment of non-Hodgkin lymphoma to prevent high risk of meninges recurrences or to treat meninges disease associated with chemotherapy. Doses of cranial irradiation are limited to 24 Gy. A SFOP trial concluded that doses of 20 Gy are sufficient after good responses to chemotherapy for the treatment of Hodgkin's disease. The target volume is reduced to the initial site of the disease.

The role of radiation therapy in the management of craniopharyngioma: a 25-year experience and review of the literature.

PURPOSE: To review the outcome and quality of life at 5 years and more of 37 children treated with radiation therapy combined or not with surgical resection for a craniopharyngioma in a single institution. METHODS AND MATERIALS: From January 1969 through December 1992, 37 children received external therapy at the Institut Gustave Roussy (Villejuif, France). Age ranged between 1 and 15 years (mean 7.4), M/F sex ratio was 0.76. In approximately one-half of the cases (18/37), radiation therapy was applied in conjunction with a surgical resection, and in almost one-half of the cases (18/37) as part of a salvage program following local failure. Total dose ranged between 45 and 56 Gy (median 50) given with a conventional fractionation in most children. Survival (S), event-free survival (EFS) were computerized according to the Kaplan-Meier method and prognostic factors for local failure and functional status analyzed. Functional outcome was evaluated according to the Wen score in 4 grades (gr 1: normal with/without hormonal replacement, gr 4: totally dependent, gr 2 and 3: intermediate disabilities). RESULTS: At the time of analysis, 24 children (65%) were alive with NED, 4 (11%) alive after failure, and 9 (24%) dead of various causes. Following therapy, S and EFS regularly degraded and didn't seem to reach a plateau before 9 years (5 and 10 year S and EFS, respectively, 91, 65, and 78 and 56.5%). This was due to the occurrence of late failures (5 and 8.5 years) and late lethal complications (1 in-field glioblastoma multiforme at 9 years). A significant gain on EFS followed the introduction of modern imaging (p = 0.03), the association of surgical resection with RT (p = 0.01) and of higher doses of radiation superior or equal to 55 Gy (p = 0.05); a similar gain on S was observed in patients with a good initial performance status (p = 0.05). It is remarkable that surgical salvage of local failures following RT could induce prolonged remission in 4 children. Functional outcome was impaired in all but 5 children out of 35 fully evaluable (86%) and related with the initial symptomatology and/or therapy. Endocrinological, visual, neurological functions were affected in 97, 34, and 40%, respectively. It appeared correlated with the initial performance status (p = 0.02) and possibly with a younger age at treatment (p = 0.07). CONCLUSIONS: Long-term follow-up beyond 5 years is warranted in craniopharyngioma to assess tumor control and functional outcome after radiation therapy. Although this therapeutical modality provides a high cure rate alone or in combination with surgery and even though at the time of failure, further strategies should aim to limit the severe toxicity (i.e., Wen gr 3 + 4) that was observed in more than one-third of our patients.

[Combined chemoradiotherapy of tumors in the child]. / Les associations chimioradiothérapiques dans les tumeurs de l'enfant.

The high chemosensitivity of pediatric tumors along with their natural propensity for an early distant dissemination have stimulated the interest for chemo-radiation combinations in children since the mid 50s. Following the early experiments in nephroblastomas on the interaction of Actinomycin-D and radiotherapy, multiple national and international studies have been conducted since the mid 70s with considerable success: nowadays most pediatric tumors enjoy a long term survival in excess of 70%. Like their adult counterparts, these associations aim to induce an early control of the primary tumor and distant spreading (spatial cooperation) but also, more specifically in children, to limit the toxicity on normal tissues when treatment intensity can be further reduced. The association of an initial chemotherapy followed by local radiation at a dose and in a volume adapted to the response to chemotherapy along with associated prognostic factors has become widely tested in national and international studies conducted in Hodgkin's disease, Ewing's sarcoma, medulloblastomas, and brain tumors in the very young. Conversely, concomitant associations have remained limited to high-risk subgroups (parameningeal rhabdomyosarcomas for example) due to their potential hazards.

[Late effects of radiotherapy in children]. / Effets tardifs de la radiothérapie chez l'enfant.

Although most pediatric tumors can be cured with lower doses of radiation than their adult counterparts, long-term radiation-induced complications and sequelae remain a major concern both in terms of frequency and intensity. Most of them have been extensively documented in the pre-chemotherapeutic era like those affecting bone, cartilage and soft tissue growth or CNS and endocrine glands. More recently the emphasis has been put on the apparent increasing incidence of reported second malignancies. This could have been favored by the chemo-radiation combinations used in most children but also has been made possible mainly by the extensive follow-up of the increasing cohort of cured children.