Mark G. Malkin

Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma

Recurrence patterns of glioblastoma multiforme (25) and anaplastic astrocytoma (9) were studied using CT scans of 34 patients who received all or a portion of their surgical treatment at Memorial Sloan-Kettering Cancer Center from January 1983 through February 1987. Thirty-two patients presented with unifocal tumors and two with multifocal tumors. All patients received radiation therapy following initial surgery. Eighteen patients who underwent re-operation following CT evidence of recurrence had histologic verification of recurrent tumor; sixteen patients had radiographic evidence of recurrence only. Seventy-eight percent (25/32) of unifocal tumors recurred within 2.0 cm of the pre-surgical, initial tumor margin, defined as the enhancing edge of the tumor on CT scan. Fifty-six percent (18/32) of tumors recurred within 1.0 cm of the initial tumor margin. Tumors for which a gross total resection was accomplished tended to recur closer to the initial tumor margin than did subtotally resected tumors (p greater than 0.1). Extensive pre-operative edema was associated with a decreased distance between initial and recurrent tumor margins. Large tumors were generally not more likely to recur further from the initial tumor margin than were smaller tumors. No unifocal tumor recurred as a multifocal tumor. Only one tumor (initially near the midline) recurred in the contralateral hemisphere. The findings support the use of partial brain irradiation for post-operative treatment of glioblastoma multiforme and anaplastic astrocytomas, and may help to determine the most appropriate treatment volume for interstitial irradiation.

A Phase II Trial of Temozolomide for Patients with Recurrent or Progressive Brain Metastases

AbstractBackground: Treatment options for patients with recurrent brain metastases are extremely limited. This study was designed to determine the safety and efficacy of temozolomide in the treatment of recurrent or progressive brain metastases. Patients and methods: Forty-one patients (11 men, 30 women) with a median KPS of 80 were treated with temozolomide 150 mg/m2/day (200 mg/m2/day if no prior chemotherapy) for 5 days; treatment cycles were repeated every 28 days. Primary tumor types included 22 non-small cell lung, 10 breast, three melanoma, two small cell lung, two rectal, one ovarian and one endometrial cancer. Results: There were five episodes of grade 3 thrombocytopenia and one grade 4 leukopenia. Significant non-hematologic toxicity possibly related to temozolomide included pneumonitis [2], constipation [1], and elevated liver enzymes [2]. Thirty-four patients were assessed for radiographic response; two had a partial response, 15 stable disease and 17 progressed. Both objective responses were seen in patients with non-small cell lung cancer. Overall median survival was 6.6 months. Conclusions: Single agent temozolomide achieved disease control (PR or SD) in 41% of patients with recurrent brain metastases from a variety of primary malignancies with minimal toxicity. Therefore, temozolomide may be a reasonable treatment option for some patients with recurrent brain metastases.

A phase II study of extended low-dose temozolomide in recurrent malignant gliomas

Temozolomide is an effective agent in the treatment of recurrent malignant gliomas. The standard dosage is 150-200 mg/m2 per day for 5 days in a 28-day cycle. A prior phase I study established a chronic daily temozolomide dose that significantly increased the total dose administered and suggested a superior response rate. In a prospective phase II trial, we treated 35 patients with recurrent malignant gliomas with temozolomide 75 mg/m2 per day for 42 consecutive days in a 70-day cycle. Median age was 55 years (range, 27-73 years) and median Karnofsky performance score was 70 (range, 60-90). Twenty-eight (79%) patients had glioblastoma multiforme, 3 (9%) anaplastic astrocytoma, 2 (6%) anaplastic oligodendroglioma, and 2 (6%) anaplastic oligoastrocytoma. All but one had prior radiotherapy, and 27 had prior chemotherapy. There were 2 partial (anaplastic astrocytoma) and 3 minor (glioblastoma multiforme) radiographic responses; 17 patients had progressive disease at the end of the first cycle. In 55 cycles of temozolomide, there were 8 episodes of asymptomatic drug-related grade 3 toxicity: 6 lymphopenia, 1 neutropenia, and 1 thrombocytopenia. Median progression-free survival and overall survival were 2.5 and 8.7 months (2.3 and 7.7 months in glioblastoma multiforme patients). At 6 months, progression-free survival and overall survival rates were 27% and 67% (19% and 60% in glioblastoma multiforme). Quality of life scores did not change significantly during treatment. We conclude that the extended low-dose schedule of temozolomide is well tolerated in heavily pre-treated patients; however, our results do not support an improved rate of response or survival.

Good performance status of long-term disease-free survivors of intracranial gliomas

PURPOSE To determine the long-term impact on function of treatment for primary cerebral gliomas, Karnofsky Performance Status, employment history, and memory function were used to evaluate the status of adults who are alive and disease-free more than 1 year after cranial irradiation. METHODS AND MATERIALS Of 30 eligible adult patients, seventeen patients had anaplastic astrocytoma, seven had a glioblastoma, four had low grade astrocytoma, one had a mixed glioma, and one had an anaplastic oligodendroglioma. Sixteen patients received partial brain irradiation only, 12 had whole brain irradiation with a partial brain boost, and two had whole brain irradiation only. The total dose ranged from 54-66 Gy, with a fraction size of 1.7-2.0 Gy. Median follow-up was 3.5 years. Eighty-three percent of patients also received adjuvant chemotherapy. RESULTS Karnofsky Performance Status generally remained stable after the completion of irradiation. Mean Performance status was 84 at the end of irradiation and was unchanged at the time of last follow-up. The actuarial freedom from performance status decline after irradiation was 93% at 5 years. The performance status increased in two patients, both within several months of completing irradiation. Most patients (68%) returned to work after irradiation. Sixty-two percent remained at work 1 year later, and 58% were working at the time of last follow-up. No patient who did not return to work within 4 months of completing irradiation was able to work at a later date. All working patients were employed in a capacity similar to their pre-morbid position. Only one patient, with an intercurrent lung cancer, eventually developed deficits that limited self care. CONCLUSIONS Contrary to previously published reports, long-term glioma survivors maintained a relatively good performance status in the absence of recurrence and did not experience a progressive decline in neuropsychologic function after completion of cranial irradiation. A patients function state at the completion of irradiation is a reliable predictor of long-term functional outcome in the absence of recurrence. Although the number of patients in each subgroup is small and no significant differences could be detected, patients treated with partial brain irradiation had a higher and more stable performance status, better memory function, and superior employment history.

A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma.

PURPOSE To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. PATIENTS AND METHODS After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. RESULTS Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. CONCLUSION Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

Glucosephosphate isomerase as a CSF marker for leptomeningeal metastasis

Glucosephosphate isomerase (GPI), also known as phosphohexoisomerase, is a glycolytic enzyme whose activity is elevated in serum and CSF of patients with primary and metastatic CNS tumors. To improve the diagnostic accuracy of leptomeningeal metastasis (LM), we measured GPI levels in CSF of 66 patients with CNS or systemic malignancies with suspected LM. We determined GPI kinetically using a coupled enzyme reaction assay. There were 31 males and 35 females, aged 1 to seventy-six. Thirty-one had primary brain tumors, and 35 had systemic cancer with suspected CNS metastasis. We analyzed 95 samples; GPI values ranged from 0.85 to 329.0 U/l (normal, <20 U/l). Compared with positive CSF cytology and myelography, GPI sensitivity was 53.5% and specificity 92.1% for the group as a whole. There was a highly significant association between elevated CSF GPI (>20 U/1) and LM. The results were similar for both primary CNS and systemic malignancies. Although not very sensitive, an elevated CSF GPI strongly suggests LM and may aid in early diagnosis of this serious complication of cancer.

Psychiatric and psychosocial aspects of neurooncology

Neurologic cancers, including metastases to the central nervous system (CNS), are devastating forms of cancer and their incidence is increasing in the United States. The psychiatric and psychosocial impacts of CNS cancer and its treatment are unique, primarily because of their direct effect on the brain and thus on the mind, personality, memory, and concept of self. Patients can undergo dramatic changes in mood, cognitive integrity, and ability to function independently. The impact of these changes affects not only the patient but also the spouse, family, hospital staff, and other caregivers who are called on to provide an exhausting level of care. All caregivers are called on to provide basic nursing care, control the patients emotional outbursts, and grieve the loss of the patients independence and personality. This article describes the psychiatric, and psychosocial impacts of neurooncologic illness and its treatment on patients, families, and staff. It also describes psychotherapeutic interventions ...

A versatile method for planning stereotactic brain implants

Our approach to planning stereotactic 125I brachytherapy of brain tumors has involved least-squares optimization of individual seed positions within the target contour, followed by repeated combining of seeds from nearest-neighbor catheters in order to achieve an acceptably low number of catheters and an acceptable-separation of entry points. In one option, the catheters diverge from an extra-cranial point that can be close to the skull if all catheters are to be placed through a small craniectomy to treat a larger-diameter target. In another option, catheters converge toward a point beyond the target, to facilitate perpendicularity at the skull surface if a separate opening is to be drilled for each catheter. In either case, the fact that seed orientations are known, permits including anisotropy in dose calculations. Trial seed locations are constrained to a target region defined on a 1-mm mesh, both in the initial optimization of single-seed catheters and in subsequent combinations followed by tune-up optimizations. In the optimization process, sum-of-squares contributions are weighted more heavily when the dose rate is lower than the target dose rate; the weighting imbalance falls short of keeping all target points above the target dose rate and requires targeting on a dose rate about 25% higher than the desired minimum dose rate.

Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the Brain Tumor Study Group.

SummaryPurposeA two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment ofde novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies.MethodsDuring 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75–100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6–8 weeks. All patients who had not received ‘full dose’ radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review.ResultsMedian survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p=0.01) and the VSG (p=0.02). Lifetable analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p=0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.

The Significance of Morphologically Viable Glioma Cells Found at the Time of Operation after Interstitial Brachytherapy

The significance of finding morphologically intact viable glioma cells in tumors treated with high-dose irradiation delivered by interstitial brachytherapy was examined. Freshly resected tissue was taken from 12 patients after (n = 8) or both before and after (n = 4) interstitial brachytherapy. All posttreatment tissue was taken from regions within a radius of 2.0 to 4.0 cm of the radioactive source. From each sample, monolayer cell culture was established. All untreated samples from primary tumors grew well and became established as cell lines within 1 to 3 weeks. In contrast, cells from treated tumors only formed small colonies of 50 to 100 cells each. These cells grew slowly and, within 14 to 21 days, degenerated. Neither the use of conditioned medium or cell extract from established glioma cell lines nor the application of growth factors (platelet-derived growth factor and/or epidermal growth factor) stimulated growth or lengthened survival. The only exception was tumor resected from approximately 4 cm from the nearest radioactive source and from which a viable cell line could be established (IRR). Cytogenetic analysis of tissue from one sample (IR) before source implantation and from another (IRR) after source implantation, both from the same patient, showed that cells IR and IRR were derived from the same stem cell. To establish the reason why cell IRR remained clonogenic despite high-dose irradiation, IRR cells were irradiated with gamma irradiation with a dose rate of approximately 1 Gy/min for 24 hours. This colony-forming assay showed that IRR cells were radiosensitive.(ABSTRACT TRUNCATED AT 250 WORDS)