Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Prognostic impact of abdominal adiposity, waist circumference and body mass index in patients with intermediate-risk prostate cancer treated with radiotherapy.

OBJECTIVE: We tested the potential role of abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues, waist circumference (WC) and body mass index (BMI) as prognostic factors in patients with intermediate-risk prostate cancer (clinical stage T1b-2b, and Gleason Score (GS)=7 and prostate-specific antigen PSA level <15 ng ml(-1), or GS ≤ 6 and PSA between 10 and 20 ng ml(-1)) treated with ultrasound-based image-guided radiotherapy. METHODS: VAT, SAT and WC (measured from planning abdominal computed tomography) and BMI were compared with clinical and pathologic factors using univariate analyses. Cox regression analyses were performed to evaluate whether obesity indices significantly predicted biochemical disease free-survival (bDFS). RESULTS: Of the 112 eligible patients, 30 (27%) were obese. Median BMI at baseline was 27.5 kg m(-2) (range, 19.2-51.5 kg m(-2)). Greater abdominal adiposity, WC and BMI were significantly associated with younger age at diagnosis and increased prostate volume (P=0.003 and P=0.002, respectively). No significant correlation between obesity measures and T-stage, GS, PSA or percentage of positive cores at biopsy was found. On Cox regression analyses, none of the obesity measures predicted for bDFS. No association was observed between obesity indices and surrogate markers of biochemical failure as PSA nadir (nPSA) or time to nPSA. CONCLUSIONS: Abdominal adiposity, WC and BMI are associated with younger age at diagnosis and greater prostate volume but not with an increased risk of biochemical failure in patients with intermediate-risk prostate cancer.

Prospective Phase II Trial of Once-weekly Hypofractionated Radiation Therapy for Low-risk Adenocarcinoma of the Prostate: Late Toxicities and Outcomes.

AIMS: To report the long-term toxicities and sexual quality of life of a once-weekly hypofractionated radiation therapy schedule for low-risk prostate cancer. MATERIALS AND METHODS: A multi-institutional phase II trial was conducted, using a three-dimensional conformal radiation therapy (3D-CRT) approach for low-risk prostate cancer (T1a-T2a, Gleason ≤ 6 and prostate-specific antigen ≤ 10 ng/ml). Forty-five Gray (Gy) were delivered in nine fractions of 5 Gy given on a weekly basis. Acute and late genitourinary and gastrointestinal toxicities were graded according to the Radiation Therapy Oncology Group toxicity scale. Sexual function and sexual bother were assessed with the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Between March 2006 and August 2008, 80 patients were treated, with a median age of 69 years (interquartile range 64-72). The median follow-up was 83 months (interquartile range 73-85 months). At 7 years, overall survival was 88%. No patients died of prostate cancer. Cumulative grade ≥2 genitourinary and gastrointestinal late toxicity was reported for 31.3% and 30% of our patients, respectively. Cumulative grade ≥3 genitourinary and gastrointestinal late toxicity was seen in 3.8% and 12.5% of cases, respectively. Late genitourinary grade 2 toxicity was correlated with the occurrence of acute genitourinary grade 2 toxicity (P = 0.006). The occurrence of late gastrointestinal toxicity was not correlated with acute gastrointestinal toxicity. Pre-treatment EPIC sexual function was low (37.5%) and the mean EPIC sexual function score at 7 years after treatment was 14%. On the other hand, pre-treatment EPIC sexual bother reached 80.5%, meaning little bother, and remained stable during follow-up. CONCLUSIONS: Once-weekly 3D-CRT leads to excellent biochemical disease-free survival and acceptable toxicities. Pre-treatment EPIC sexual function dropped by 42% at 5 years of follow-up. This functional deficit did not bother patients, possibly due to the already low sexual function at baseline.

Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme.

PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model. PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered. RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level. CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Para-aortic irradiation only appears to be adequate treatment for patients with Stage I seminoma of the testis.

PURPOSE: Results of treatment of patients with Stage I seminoma with orchiectomy and radiotherapy are excellent. Even without adjuvant radiotherapy, the relapse rate is only 15-20%; most of the patients fail in the retroperitoneum, with rare failures observed in the pelvis (0.5-2%). In 1991, we began a prospective study evaluating para-aortic lymph node radiation as the only adjuvant treatment for such patients. This paper reports our preliminary results. MATERIALS & METHODS: Between March 1991 and January 1996, 35 patients with histologically proven Stage I seminoma were entered in the study. Median age was 37.9 years (range: 27-65 years). A radical inguinal orchiectomy was performed in all patients. Staging workup consisted of a chest X-ray; B-HCG, alpha-fetoprotein, and CT scan of the abdomen and pelvis in all patients. Lymphangiogram was done in 23 (66%) of 35 patients for further evaluation of the retroperitoneal lymph nodes. Radiotherapy consisted of treatment to the para-aortic region only. Parallel opposed fields extending from the top of T11 to the bottom of L5 were used. The median field size was 8.7 x 21.8 cm (range: 7-11 x 18-26 cm). The median total dose, prescribed at midpoint, was 25 Gy given in 15 daily fractions of 1.66 Gy. Follow-up was performed every 3 months for the first year, every 4-5 months for the second and third years, and every 6 months thereafter. Chest X-ray, tumor markers, and CT scan of the pelvis were performed routinely as part of the follow-up investigation. RESULTS: At a median follow-up of 39.7 months (range: 16-74 months), 34 (97.1%) of 35 patients are alive with no evidence of disease for an overall actuarial survival rate of 97.1% at 5 years and a cause-specific actuarial survival rate of 100%. Treatment morbidity was limited to Grade I-II acute side effects in 18 (51.4%) of 35 patients. No late side effects were seen. CONCLUSION: From our preliminary results, adjuvant radiation treatment limited to the para-aortic lymph node region, without ipsilateral pelvic irradiation, appears to be adequate treatment for Stage I seminoma. Such an approach in our patients resulted in minimal toxicity and excellent disease-free survival.

Experience in charged particle irradiation of tumors of the skull base: 1977-1992.

PURPOSE: To review the experience at University of California Lawrence Berkeley Laboratory in using charged particles to irradiate primary neoplasms of the skull base and those extending to the skull base from the nasopharynx and paranasal sinuses. METHODS AND MATERIALS: During the period from 1977 to 1992, 223 patients were irradiated with charged particles at the Lawrence Berkeley Laboratory for tumors either arising in or extending to the skull base, of whom 48 (22%) had recurrent lesions, either post previous surgery or radiotherapy. One hundred twenty-six patients had lesions arising in the cranial base, mostly chordoma (53), chondrosarcoma (27), paraclival meningioma (27) with 19 patients having other histologies such as osteosarcoma or neurofibrosarcoma. There were also 31 patients with primary or recurrent squamous carcinoma of the nasopharynx extending to the skull base, 44 patients with major or minor salivary gland tumors, mostly adenocarcinoma, and 22 patients with squamous carcinoma of the paranasal sinuses, all with cranial base extension. RESULTS: Local control and survival appeared improved in tumors arising in the skull base, following the ability with charged particles to deliver high doses (mean of 65 Gy-equivalent) with relative sparing of the adjacent normal tissues. The Kaplan-Meier 5-year local control was 85% for meningioma, 78% for chondrosarcoma, 63% for chordoma and 58% for other sarcoma. Follow-up ranged from 4-191 months with a median of 51 months. CONCLUSION: Charged particle radiotherapy is highly effective in controlling cranial base lesions which have have been partially resected. Better tumor localization with CT and MRI, improved 3-D treatment planning and beam delivery techniques have continued to reduce the level of serious complications and increase local control and survival.

The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy.

OBJECTIVE: The aim of this work was to develop a parameter for use during fractionated stereotactic radiotherapy treatment planning to aid in the determination of the appropriate treatment volume and fractionation regimen that will minimize risk of late damage to normal tissue. MATERIALS & METHODS: We have used the linear quadratic model to assess the biologically effective dose at the periphery of stereotactic radiotherapy treatment volumes that impinge on the brain stem. This paper reports a retrospective study of 77 patients with malignant and benign intracranial lesions, treated between 1987 and 1995, with the dynamic rotation technique in 6 fractions over a period of 2 weeks, to a total dose of 42 Gy prescribed at the 90% isodose surface. From differential dose-volume histograms, we evaluated biologically effective dose-volume histograms and obtained an integral biologically-effective dose (IBED) in each case. RESULTS: Of the 77 patients in the study, 36 had target volumes positioned so that the brain stem received more than 1% of the prescribed dose, and 4 of these, all treated for meningioma, developed serious late damage involving the brain stem. Other than type of lesion, the only significant variable was the volume of brain stem exposed. An analysis of the IBEDs received by these 36 patients shows evidence of a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiotherapy. CONCLUSION: We have introduced a new parameter, the IBED, that may be used to represent the fractional effective dose to structures such as the brain stem that are partially irradiated with stereotactic dose distributions. The IBED is easily calculated prior to treatment and may be used to determine appropriate treatment volumes and fractionation regimens minimizing possible toxicity to normal tissue.

Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90-05).

PURPOSE: To determine the maximum acutely tolerable dose of single fraction radiosurgery in patients with recurrent previously irradiated primary brain tumors or brain metastases. METHODS AND MATERIALS: Between August 1990 and September 1993, 102 analyzable patients were entered on Radiation Therapy Oncology Group (RTOG) protocol 90-05, 38 of whom had recurrent primary brain tumors (median prior dose 60 Gy), and 64 of whom had recurrent brain metastases (median prior dose 30 Gy) < or = 40 mm in maximum diameter. Unacceptable toxicity was defined as irreversible Grade 3, any Grade 4, or Grade 5 central nervous system (CNS) toxicity according to the RTOG CNS criteria, occurring in > 20% of patients per treatment arm within 3 months of radiosurgery. RESULTS: Patients were initially entered onto one of three treatment arms according to the maximum diameter of the recurrent lesion. Twelve to 22 patients were entered on each arm. The dose levels were: arm 1, < or = 20 mm, 18 Gy; arm 2, 21-30 mm, 15 Gy; and arm 3, 31-40 mm, 12 Gy. Subsequently, doses were escalated as follows: arm 4, < or = 20mm, 21 Gy; arm 5, 21-30 mm 18 Gy; and arm 6, 31-40 mm, 15 Gy. Unacceptable acute toxicity secondary to cerebral edema occurred in 0, 7 and 5% of patients on Arms 1, 2 and 3, respectively, and in no patients on arms 4, 5, or 6. Multivariate analysis revealed that tumor volume > or = 8200 mm(3) and a ratio of maximum dose to prescription dose (MD/PD) > or = 2 were significantly associated unacceptable toxicity. Of 15 patients with both tumor volume > or = 8200 mm(3) and MD/PD > or = 2, unacceptable toxicity occurred in 2 of 4 treated with a single isocenter and 1 of 11 treated with multiple isocenters. Subsequently, operation for symptomatic radionecrosis was required in 6% of patients. CONCLUSION: We found that the incidence of acute toxicity was acceptable at 0-7% in patients with recurrent, previously irradiated primary brain tumors or brain metastases < or = 40 mm in maximum diameter treated according to the protocol described.

Radiosurgery and accelerated radiotherapy for patients with glioblastoma.

OBJECTIVE: To assess the feasibility, toxicity, and local control of stereotactic radiosurgery followed by accelerated external beam radiotherapy (AEBR) for patients with glioblastoma multiforme. MATERIALS AND METHODS: Six males and eight females, with a median age of 67.5 years (range 45-78 years), entered the study. Karnofsky performance status was 90 for five, 80 for six, and 60 for three patients. Following surgery, the patients were left with a residual mass 4 cm. Radiosurgery was delivered with a single dose of 20 Gy to the 90% isodose surface corresponding to the contrast-enhancing edge of the tumour. A total AEBR dose of 60 Gy in 30 fractions was delivered using a concomitant boost technique over four weeks. RESULTS: Median survival time was 40 weeks (range 17-80 weeks). Actuarial survivals at 12 and 18 months were 43% and 14%, respectively. The median time to progression was 25 weeks (range 2-77 weeks). One patient developed a seizure on the day of stereotactic radiosurgery. Two patients experienced somnolence at 47 and 67 days post-radiotherapy. Eight patients remained steroid-dependent. Radiological evidence of leukoencephalopathy was observed in one patient, and brain necrosis in two additional patients at 30 and 63 weeks. One of these two patients with brain necrosis developed complete loss of vision in one eye, and decreased vision in the contralateral eye at 63 weeks. CONCLUSION: Stereotactic radiosurgery followed by AEBR was feasible but was associated with late complications. The use of such radiosurgical boost for patients with glioblastoma multiforme should be reserved for those patients entering controlled clinical trials.

[Brain metastasis. Palliative treatment with radiosurgery]. / Metástase cerebral. Tratamento paliativo com radiocirurgia.

This is a retrospective review of 52 patients with metastatic brain disease who underwent stereotactic radiosurgery at McGill University in Montreal. The radiosurgical treatment was performed with the dynamic rotation technique in which there is continuous and simultaneous movement of treatment couch and machine gantry of a 10 MV linac. All patients were treated with a single isocenter and a median dose of 1800 cGy was delivered. In 88% of the cases radiosurgery was given after failure from whole brain conventional irradiation. All 52 cases were assessed with brain CT post radiosurgery. The median follow up time was 6 months (range 1-37 months) and the response rate (partial or complete) was 64%. Only 4 patients (7%) developed late complications related to the treatment. These findings are similar to the literature. Stereotactic radiosurgery is a well tolerated, effective and minimally invasive treatment technique which has a high response rate in selected patients with small, well delineated metastatic brain lesion. Its definitive value as a single therapy or combined with whole brain conventional radiotherapy is being studied in prospective and randomized trials.

Liquid embolization material reduces the delivered radiation dose: clinical myth or reality?

BACKGROUND AND PURPOSE: To be radiopaque, BAVM embolization products must contain high-atomic-number materials, which may also attenuate photon beams delivered with radiosurgery. This "shielding effect" has been invoked to explain why radiation therapy may be less effective for previously embolized BAVMs. To evaluate the impact of embolization material on radiation dose, we measured and compared the dose delivered to the center of an AVM model, before and following embolization with various materials in a LINAC. MATERIALS AND METHODS: Two in vitro AVM models were constructed by drilling interconnected tubular perforations in plastic water phantoms to simulate nidal vessels. Phantoms were designed to allow the positioning of a radiation detector at their center. One model was embolized with Onyx 18 and a second model, with a combination of Indermil, Lipiodol, tungsten powder, and Onyx 18. The radiation delivered was compared between embolized and nonembolized controls following irradiation with a standard 250-cGy dose. RESULTS: The mean dose of radiation delivered to the model embolized with Onyx alone was 244 ± 5 cGy before and 246 ± 5 cGy following embolization. The mean dose of radiation delivered to the model embolized with various agents was 242 ± 5 cGy before, and 254 ± 5 cGy after embolization. CONCLUSIONS: Embolic material did not reduce the radiation dose delivered by a LINAC to the center of our experimental BAVM models. The shielding effect may be compensated by scattered and reflected radiation.

Embolization as one modality in a combined strategy for the management of cerebral arteriovenous malformations.

SUMMARY: We attempted to assess clinical results of management of cerebral arteriovenous malformation using a combination of endovascular, surgical and radiotherapeutic approaches. We retrospectively reviewed the angiographic and clinical data on prospectively collected consecutive patients treated by embolization from 1994 to 2004. The general philosophy was to attempt treatment by a combination of approaches only when an angiographic cure was likely or at least possible. The clinical outcome was assessed according to the modified Rankin scale. Although 404 patients were collected, complete files and follow-ups are available for 227 or 56% only. Most patients presented with hemorrhages (53%) or seizures (23%). The final management consisted in embolization alone in 34%, embolization followed by surgery in 47%, embolization and radiotherapy in 16%, and embolization, surgery and radiotherapy in 3% of patients. The embolization procedure itself could lead to an angiographic cure in only 16% of patients. When the management strategy could be completed, the cure rate increased to 66%. Complications of embolization occurred in 22.6% of patients. Overall clinical outcome was excellent (Rankin 0) in 43%, good (Rankin 1) in 38%, fair (Rankin 2) in 10%, poor (Rankin 3-5) in 2%, and the death rate was 7%. A combined strategy initially designed to provide angiographic cures cannot be completed in a significant number of patients; the total morbidity of treatment remains significant. There is no scientific evidence that cerebral arteriovenous malformations should be treated, and no clinical trial to prove that one approach is better than the other. Various treatment protocols have been proposed on empirical grounds. Small lesions can often be eradicated, with surgery when lesions are superficial, or with radiation therapy for deeper ones. There has been little controversy regarding therapeutic indications in these patients (1). The management of larger AVMs, sometimes in more eloquent locations, is much more difficult and controversial (2-4). Endovascular approaches have initially been developed to meet this challenge (5,6). It became quickly evident that embolization alone would rarely suffice to completely cure these lesions. The philosophy behind combined approaches is founded on 2 opinions: 1) There is no proven value of partial embolization, not even "partial benefits", and treatment should aim at an angiographic cure (7) and 2) By appropriately tailoring all available tools to each situation, such a cure could be reached with minimum or reasonable risks. We have used such a combined strategy for more than a decade now. Endovascular techniques and materials have evolved, and it is perhaps possible today to reach a cure by embolization alone in a larger proportion of patients than before (8). Aggressive embolizations, aiming for an endovascular cure, even sometimes in large lesions, have recently been promoted for their power or criticized for their risks (9). But before evaluating the advantages and inconveniences of new treatments, it may be wise to review the results we could achieve with a conventional approach combining endovascular, surgical and radiotherapeutic techniques.

Radiotherapy, hyperthermia, and phototherapy for central nervous system tumors.

Many new modalities and increasing data have become available in the treatment of brain tumors. We will review the growing experience with newer treatment modalities such as brachytherapy, radiosurgery, hyperthermia, and photodynamic therapy.

Low-grade pure and mixed cerebral astrocytomas treated in the CT scan era.

From 1974 to 1992, 63 patients diagnosed with low-grade pure or mixed oligo-astrocytoma were seen and treated at our institution. All patients underwent CT scan pre-operatively. There were 20 female and 43 males ranging in age from 12 to 73 years (median age of 33 years). 15 patients had a stereotactic biopsy as the only surgical procedure. 34 had a partial tumor resection and 14 a gross total tumor resection. 43 patients were treated with post-operative radiotherapy whereas 20 patients underwent surgery only as part of the initial management. 50 to 60 Gy (median 59.4 Gy) were given with daily fractions of 1.8 to 2 GY. Tumor volume ranged from 3.4 to 441 cm3. Median tumor volume was larger for radiotherapy treated patients. Median follow-up was 54 months (range of 4 to 240 months). The overall 10 and 15 actuarial survival rates were 37% and 25% respectively. The 5 years survival rate for patients treated at initial diagnosis with surgery alone was 66% and it was 67.3% for patients treated with radiation therapy (P = NS). Prognostic factors having independent significant impact on survival were: extent of surgery, age gender and tumor volume. As well, survival for patients with low-grade astrocytoma in the CT scan era appears to be improved compared to historical controls in the literature.