A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.

PURPOSE: Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. METHODS: Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. RESULTS: Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. CONCLUSION: Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. IMPLICATIONS FOR CANCER SURVIVORS: Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.

Three-dimensional conformal radiation treatment planning and delivery for low- and intermediate-grade gliomas.

Three-Dimensional conformal radiation treatment (3D-CRT) planning and delivery is an external beam radiation therapy modality that has the general goal of conforming the shape of a prescribed dose volume to the shape of a 3-dimensional target volume, simultaneously limiting dose to critical normal structures. 3-Dimensional conformal therapy should include at least one volumetric imaging study of the patient. This image should be obtained in the treatment position for visualizing the target and normal anatomic structures that are potentially within the irradiated volume. Most often, computed tomography (CT) and/or magnetic resonance imaging (MRI) are used; however, recently, other imaging modalities such as functional MRI, MR spectroscopy, and positron emission tomography (PET) scans have been used to visualize the clinically relevant volumes. This article will address the clinically relevant issues with regard to low- and intermediate-grade gliomas and the role of 3D-CRT planning. Specific issues that will be addressed will include normal tissue tolerance, target definition, treatment field design in regard to isodose curves and dose-volume histograms, and immobilization.

Randomized trials of radiation therapy in adult low-grade gliomas.

There are two central questions in the radiotherapeutic management of the adult patient with a supratentorial low-grade (WHO grade II) astrocytoma, oligo-astrocytoma, or oligodendroglioma. The first question is one of timing. Following tissue diagnosis with or without maximum surgical resection, should immediate postoperative radiation therapy (RT) be given, or should RT be deferred to the time of local recurrence? The second question is one of dose. Assuming RT is given, should lower doses (ie, approximately 45-50 Gray (Gy)) or higher doses (ie, approximately 60-65 Gy) be administered? One Phase III prospective randomized clinical trial addressing the first question and two addressing the second question have been performed. Their results suggest that delayed (versus immediate) RT and low-dose (versus high-dose) RT are both acceptable treatment strategies despite the bias amongst radiation oncologists (primarily based on retrospective data) that immediate and high-dose RT would result in better outcome. The schema of the ongoing Radiation Therapy Oncology Group study is presented.

A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.

PURPOSE: Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT). METHODS AND MATERIALS: Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central vein over 60 min immediately before RT. Patients received supplemental O(2) via nasal cannula at 4 L/min during RSR13 infusion and RT. Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed. The pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint tonometry and expressed as an increase in p50, defined as the partial pressure of O(2) that results in 50% SaO(2). The RSR13 dose in the first cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT. RESULTS: Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiologic effect, and then diminished with a half-life of approximately 5 h. CONCLUSIONS: RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.

Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

The results of radiotherapy for ependymomas: the Mayo Clinic experience.

PURPOSE: This analysis was performed to examine the outcome of patients with histologically confirmed ependymomas of the brain or spinal cord who received postoperative radiotherapy. METHODS AND MATERIALS: Eighty patients with histologically confirmed ependymomas were evaluated retrospectively. All were treated with various combinations of surgery, radiotherapy (RT), and chemotherapy. Follow-up ranged from 5 to 30 years (median 10.4 years). RESULTS: The 5- and 10-year survival rates for the entire study group were 79% and 73%, respectively. Patients with low-grade (1 and 2 of 4) tumors had a 5-year survival rate of 87% as compared to 27% for those with high-grade (3 and 4 of 4) tumors (p < 0.0001). Patients with tumors of the spine had a 5-year survival rate of 97% as compared to 68% for those with infratentorial tumors, and 62% for those with supratentorial tumors (p = 0.03). Patients with myxopapillary ependymomas of the spine had a 5-year survival rate of 100% as compared with 76% for patients with other histological subtypes of ependymoma (p = 0.02). Multivariate analysis revealed that the survival rate was independently associated with tumor grade (p = 0.0007) and histological subtype (p = 0.02). Twenty-eight patients (35%) experienced local failure and 10 patients (13%) developed leptomeningeal seeding. The 5-year leptomeningeal failure rate was 10% in patients with low-grade tumors as compared to 41% for patients with high grade tumors (p = 0.01). CONCLUSION: Patients with low-grade tumors, especially those with myxopapillary subtypes, have high 5-year survival rates when treated with post-operative radiotherapy. High grade ependymomas are associated with a much poorer outcome. New forms of therapy are required to improve the outcome of patients with high-grade ependymomas.

Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988.

OBJECTIVE: To establish prognostic factors for recurrence and outcome of surgical treatment, with or without postoperative radiation therapy, in patients with meningiomas. MATERIAL AND METHODS: From 1978 through 1988, 581 patients underwent initial resection of a previously untreated primary meningioma at Mayo Clinic Rochester. In this study cohort, the outcome and prognostic factors associated with radiographic progression-free survival were analyzed. RESULTS: Gross total resection (GTR) of the meningioma was accomplished in 80% of patients; the other 20% underwent less than GTR. Perioperative mortality within 10 days was 1.6%. Overall survival was significantly decreased from that for an age- and sex-matched cohort from the US white population. Progression-free survival at 5 and 10 years was 88% and 75%, respectively, in patients who underwent GTR and 61% and 39%, respectively, in those who underwent less than GTR. Multivariate analysis showed that age younger than 40 years, male sex, less than GTR, optic nerve involvement, and 4 or more mitotic figures per 10 high-power fields were associated with decreased progression-free survival. The 581 patients had 106 first recurrences. A trend toward improved progression-free survival was noted after first recurrence when irradiation with or without operation was used in comparison with only surgical treatment (P = 0.058). CONCLUSION: With only operative treatment of meningioma, the 10-year recurrence rate was 25% in patients who had GTR and 61% in those who had less than GTR. These results emphasize the need for long-term follow-up and for consideration of adjuvant radiation therapy. Patients treated at the time of recurrence seem to benefit from radiation therapy with or without surgical resection. Factors associated with recurrence were (1) less than GTR, (2) involvement of the anterior visual pathway, (3) age younger than 40 years, and (4) increased mitotic index.

The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study.

BACKGROUND: A three-arm Phase III randomized trial was performed to compare response rates, time to local or distant progression, and survival for patients with unresectable (Stage IIIA or IIIB) nonsmall cell lung carcinoma treated with standard fractionated thoracic radiotherapy (SFTRT) versus accelerated hyperfractionated thoracic radiotherapy (AHTRT) with or without combination etoposide and cisplatin chemotherapy. METHODS: This trial was initiated in 1992 by the North Central Cancer Treatment Group. Patients with Stage IIIA or IIIB nonsmall cell lung carcinoma were eligible. They were randomly assigned to either SFTRT (6000 centigray [cGy] in 30 fractions) or AHTRT (150 cGy twice daily to a total dose of 6000 cGy, with a 2-week break after the initial 3000 cGy); the AHTRT was given alone or with concomitant cisplatin (30 mg/m2, Days 1-3 and 28-30) and etoposide (100 mg/m2, Days 1-3 and 28-30). RESULTS: A total of 110 patients were entered on study. Eleven patients were declared ineligible or off study on the day of study entry. This analysis was confined to the 99 eligible patients. This article reports mature follow-up, because more than 80% of the patients have died. The median follow-up of living patients was 2.5 years. There were suggestions of improvement in the rates of freedom from local recurrence and survival for patients treated with AHTRT (with or without chemotherapy) as opposed to SFTRT (P = 0.06 and P = 0.10, respectively). The improvement in survival associated with AHTRT (with or without chemotherapy) was statistically significant for the subgroup of patients with nonsquamous cell carcinoma after adjustment for other potentially confounding factors (P = 0.02). No differences in freedom from systemic progression or survival were found in a comparison of AHTRT with chemotherapy and AHTRT without chemotherapy. CONCLUSIONS: These results suggest that treatment of Stage IIIA or IIIB nonsmall cell lung carcinoma with AHTRT with or without chemotherapy may improve freedom from local progression and survival as compared with SFTRT, especially for patients with nonsquamous cell carcinoma. The statistical powers to detect the observed differences in median time to local progression and survival were approximately 55% and 35%, respectively. Therefore, further investigation comparing SFTRT with AHTRT is warranted.

Spinal cord localization in the treatment of lung cancer: use of radiographic landmarks.

PURPOSE: In the treatment of thoracic malignancies with radiotherapy, the critical dose-limiting structure is the spinal cord. Oblique fields typically are designed to exclude the spinal cord, and by convention, the field edge that shields the spinal cord is placed at the anterior border of the vertebral pedicles. Thus, the purpose of our study was to estimate the distance between the field edge and spinal cord in oblique fields that were designed by using the vertebral pedicle as a radiographic landmark. METHODS AND MATERIALS: The spinal cord of a cadaver was wrapped in wire, and oblique fields were simulated at 15 degree intervals. The distance from the spinal cord to a field edge placed at the anterior border of the pedicle was measured. In the second investigation, a three-dimensional treatment planning system was used to simulate hypothetical fields using actual patient data from computed tomography (n = 10), and measurements identical to those in the anatomical model were made (n = 1,100). RESULTS: The results of the anatomical and computed tomographic models were in close agreement (mean difference, 0.6 mm). The computed tomographic model predicted a mean field edge to spinal cord distance of 8.7 mm (95% confidence interval, 5.6-11.8 mm) for 30 degree/150 degree oblique fields and 8.0 mm (95% confidence interval, 4.7-11.7 mm) for 45 degree/135 degree oblique fields. This distance was greatest at levels T-1, T-2, and T-11 (8 to 20% greater). CONCLUSIONS: The mean distance from a field edge placed at the anterior border of a vertebral pedicle to the spinal cord for commonly used oblique angles constitutes a sufficient margin to account for expected differences in daily positional variations and mechanical uncertainties.

The results of radiotherapy for brainstem tumors.

OBJECTIVE: This analysis was performed to examine the outcome of adult and pediatric patients with brainstem tumors. METHODS AND MATERIALS: Forty patients with brainstem glioma were evaluated retrospectively. Included were 24 females and 16 males ranging in age from 3 to 81 years (median, 29.5 years). These patients were treated with various combinations of surgery, chemotherapy, and radiotherapy (RT). The length of follow-up in survivors ranged from 0.6 to 20 years (median: 3.2 years, mean: 6 years). Survival rates were calculated with the Kaplan Meier method and differences between survival curves were calculated using the log-rank test. RESULTS: The overall 2 and 5-year survival rates were 44% and 34%, respectively. The median survival time was 19 months. The 5-year survival rate was 54% for patients with tumors outside the pons compared to 21% for those with tumors involving the pons (p = 0.04). The 5-year survival rate was 59% for patients with exophytic tumors as compared to 23% for those with intrinsic tumors (p = 0.05). Patients undergoing subtotal resection had a 5-year survival rate of 53% compared to 28% for those having only a biopsy or no surgical intervention (p = 0.04). None of the other potential prognostic or treatment related factors evaluated [patient age, tumor grade, tumor histology, radiotherapy parameters (including BID fractionation, 3-D treatment planning, or the use of doses > 55 Gy), or the administration of adjuvant chemotherapy] evaluated were associated with patient survival. CONCLUSIONS: Brainstem gliomas generally occur in younger individuals. The survival rates were better for patients with exophytic tumors, those involving sites other than the pons, and tumors amenable to subtotal resection. Improvements in the outcome of patients with brainstem gliomas will require new therapeutic approaches.

Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre.

BACKGROUND: An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma. METHODS: Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method. RESULTS: Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking. IMPLICATIONS: Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

The impact of surgical adjuvant thoracic radiation therapy for patients with nonsmall cell lung carcinoma with ipsilateral mediastinal lymph node involvement.

BACKGROUND: Previous nonsmall cell lung carcinoma studies have shown that patients with ipsilateral mediastinal (N2) lymph node involvement who underwent surgical resection have a greater local recurrence rate than those with less lymph node involvement (N0, N1). Therefore, it was hypothesized that complete surgical clearance of subclinical lymph node disease is difficult in N2 patients and that adjuvant postoperative thoracic radiotherapy (TRT) may be beneficial. METHODS: A retrospective review was performed to determine the local recurrence and survival rates for patients with N2 disease undergoing complete surgical resection with or without adjuvant TRT. Between 1987 and 1993 at the Mayo Clinic, 224 patients underwent complete resection of N2 nonsmall cell lung carcinoma. More than one mediastinal lymph node station was sampled in 98% of patients; 39% then received adjuvant TRT (median dose, 50.4 grays). RESULTS: The median follow-up time was 3.5 years for the patients who were alive at the time of the analysis. The surgery alone versus surgery plus TRT groups were well balanced with respect to gender, age, histology, tumor grade, number of mediastinal lymph node stations dissected or involved, and involved N1 lymph node number. There were slightly more patients with right lower lobe lesions (compared with other lobes), patients with multiple lobe involvement, and patients with only one N2 lymph node involved in the surgery alone group. After treatment with surgery alone, the actuarial 4-year local recurrence rate was 60%, compared with 17% for treatment with adjuvant TRT (P < 0.0001). The actuarial 4-year survival rate was 22% for treatment with surgery alone, compared with 43% for treatment with adjuvant TRT (P = 0.005). On multivariate analysis, the addition of TRT (P = 0.0001), absence of superior mediastinal lymph node involvement (P = 0.005), and fewer N1 lymph nodes involved (P = 0.02) were independently associated with improved survival rate. CONCLUSIONS: This study, which to the authors' knowledge is the largest evaluating adjuvant TRT in N2 nonsmall cell lung carcinoma, suggests that adjuvant TRT may improve local control and survival.