Nayana Vora

A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104.

PURPOSE To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.

Arm lymphedema in patients treated conservatively for breast cancer: Relationship to patient age and axillary node dissection technique

Arm lymphedema (ALE) was evaluated in 74 patients treated conservatively for breast cancer. ALE was defined based upon measurements performed upon 35 volunteer subjects who did not have and were never treated for breast cancer. Multiple variable statistical analysis of 74 breast cancer patients revealed that age at diagnosis was the most important factor related to the subsequent development of ALE. ALE appeared in 7 of 28 patients (25%) 60 years of age or older but in only 3 of 46 (7%) younger patients (p less than 0.02). Axillary node dissection (AND) was the only other statistically significant factor. For the younger patients, obesity and post-operative wound complications appeared to be contributing factors. For the older patients, AND technique was the only significant factor. ALE developed in only 1 of 10 (10%) of the older patients who underwent AND without splitting the pectoralis minor muscle (PMM), but in 6 of 11 (55%) who underwent AND with PMM split (p less than 0.03). Splitting the PMM during AND did not yield more lymph nodes for pathological analysis nor did it yield a higher incidence of patients with nodal metastases. Neither the use of lymph node radiation therapy fields, radiation to the full axilla, nor systemic chemotherapy was associated with ALE. We conclude that older patients are at higher risk of ALE and that this complication can possibly be reduced by not splitting the PMM during axillary node dissection.

Breast retraction assessment: an objective evaluation of cosmetic results of patients treated conservatively for breast cancer☆

Breast Retraction Assessment (BRA) is an objective evaluation of the amount of cosmetic retraction of the treated breast in comparison to the untreated breast in patients who receive conservative treatment for breast cancer. A clear acrylic sheet supported vertically and marked as a grid at 1 cm intervals is employed to perform the measurements. Average BRA value (+/- standard deviation) in 29 control patients without breast cancer was 1.2 cm (+/- 0.7 cm). Average BRA value in 27 patients treated conservatively for clinical Stage I or II unilateral breast cancer was 3.7 cm (+/- 2.1 cm). BRA values in breast cancer patients ranged from 0.0 to 8.5 cm. Statistical analysis revealed that tumor size, employment of adjuvant chemotherapy and use of separate radiation lymph node fields were not factors in breast retraction. Patients who received a local radiation boost to the primary tumor bed site had statistically significantly less retraction than those who did not receive a boost. Patients who had an extensive primary tumor resection had statistically significantly more retraction than those who underwent a more limited resection. In comparison to qualitative forms of cosmetic analysis, BRA is an objective test that can quantitatively evaluate factors which may be related to cosmetic retraction in patients treated conservatively for breast cancer.

Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: Long-term follow-up results of RTOG 83-13

PURPOSE The objective of this study was to examine the incidence of late effects of hyperfractionated radiotherapy for head and neck cancer as a function of the dose delivered, as well as the daily interfraction interval. In addition, we wished to examine the influence of other prognostic factors including age, gender, primary site, T- and N-stage, and overall stage on the late effects of hyperfractionated radiotherapy. METHODS AND MATERIALS Between 1983 and 1987, 479 patients with advanced head and neck cancer were entered on a Phase ILE/II dose escalation trial of hyperfractionated radiotherapy. They were randomly assigned to receive a dose of 67.2, 72.0, 76.8, or 81.6 Gy, delivered at 1.2 Gy/fraction, twice a day (BID), 5 days/week. Of the 451 analyzable patients, 399 patients who received > or = 64.8 Gy and had a follow-up > 90 days were eligible for this study. Acute and late effects were scored with the RTOG/EORTC late radiation morbidity scoring scheme. For this analysis, patients were subclassified by the actual doses delivered and by an average daily interfraction interval of < or = 4.5 h or > 4.5 h. The incidence of late effects was estimated using a cumulative incidence approach. RESULTS Fifty-nine patients received 67.2 +/- 2.4 Gy, 119 received 72.0 +/- 2.4 Gy, 98 received 76.8 +/- 2.4 Gy, and 123 received 81.6 +/- 2.4 Gy. The proportion of patients treated with a daily interfraction interval of > 4.5 h was 32, 50, 43, and 71%, respectively. The four treatment groups were well balanced with respect to pretreatment characteristics. The median follow-up was 1.71 years (range: 0.24-9.6) for all evaluable patients and 6.12 years for 85 alive patients. There was no significant difference in the incidence of late effects between the different dose levels. At 5 years, the cumulative incidence of late effects was 17, 14, 20, and 13% for grade 3, and 7, 3, 7, and 5% for grade 4. However, the incidence of late effects differed significantly with respect to daily interfraction interval. The cumulative incidence of grade 4 late effects increased from 6.3% at 2 years to 7.5% at 3 years to 8.0% at 4 years and 8.6% at 5 years with an interval of < or = 4.5 h, while it remained at a constant of 2.0% with an interval of > 4.5 h during the same period (p = 0.0036). Multivariate analysis showed that among the prognostic factors examined, daily interfraction interval of < or = 4.5 h was the only significant independent prognostic factor for the development of grade 3+ or grade 4 late effects (p = 0.0167 and p = 0.0013, respectively). CONCLUSION Results of this randomized Phase ILE/II trial of hyperfractionated radiotherapy in head and neck cancer showed no apparent dose-response relationship for late effects within the range of 67.2-81.6 Gy. Daily interfraction interval was a significant independent factor for the development of late effects in a multivariate analysis.

Interstitial implant with interstitial hyperthermia

A Phase I Pilot Study combining interstitial or intracavitary irradiation using 192Ir or 137Cs and interstitial hyperthermia in advanced or recurrent tumors is underway at the City of Hope National Medical Center. Hyperthermia is performed using 0.5 megahertz RF (500 kilohertz) radiofrequency localized current fields. In the implanted volume, a temperature of 41° to 45°C is maintained for 30 to 40 minutes. Hyperthermia is performed prior to irradiation in all patients. All patients had either failed previous conventional treatments, including surgery, chemotherapy and/or radiation therapy, or had advanced malignant tumors which were not felt to be controllable by conventional means. Sixteen lesions were implanted in 15 patients. Of the 16 lesions, 11/16 (68%) achieved complete response, and three had no response or recurred locally. The six patients (100%) receiving interstitial implant and hyperthermia as the primary therapy achieved complete response. Normal tissue complications were minimal. Range of response was three to 13 months. Interstitial thermoradiotherapy appears to be a safe and promising mode of therapy in advanced or recurrent accessible malignant tumors.

Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the radiation therapy oncology group protocol 91-04

PURPOSE Little information is available on the importance of pretreatment Mini-Mental Status Exam (MMSE) on long-term survival and neurologic function following treatment for unresectable brain metastases. This study examines the importance of the MMSE in predicting outcome in a group of patients treated with an accelerated fractionation regimen of 30 Gy in 10 daily fractions in 2 weeks. MATERIALS AND METHODS The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastases were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. Two hundred twenty-four patients were entered on the accelerated fractionated arm, and 182 were eligible for analysis (7 patients were judged ineligible, no MMSE information in 29, no survival data in 1, no forms submitted in 1). RESULTS Average age was 60 years; 58% were male and 25% had a single intracranial lesion on their pretherapy evaluation. KPS was 70 in 32%, 80 in 31%, 90 in 29%, and 100 in 14%. The average MMSE was 26.5, which is the lower quartile for normal in the U.S. population. The range of the MMSE scores was 11-30 with 30 being the maximum. A score of less than 23 indicates possible dementia, which occurred in 16% of the patients prior to treatment. The median time from diagnosis to treatment was 5 days (range, 0-158 days). The median survival was 4.2 months with a 95% confidence interval of 3.7-5.1 months. Thirty-seven percent of the patients were alive at 6 months, and 17% were alive at 1 year. The following variables were examined in a Cox proportional-hazards model to determine their prognostic value for overall survival: age, gender, KPS, baseline MMSE, time until MMSE below 23, time since diagnosis, number of brain metastases, and radiosurgery eligibility. In all Cox model analyses, age, KPS, baseline MMSE, time until MMSE below 23, and time since diagnosis were treated as continuous variables. Statistically significant factors for survival were pretreatment MMSE (p = 0.0002), and KPS (p = 0.02). Age was of borderline significance (p = 0.065) as well as gender (p = 0.074). A poorer outcome is associated with an increasing age, male gender, lower MMSE, and shorter time until MMSE below 23. Improvement in MMSE over time was assessed; 62 patients died prior to obtaining follow-up MMSE, and 30 patients had a baseline MMSE of 30 (the maximum), and, therefore, no improvement could be expected. Of the remaining 88, 48 (54.5%) demonstrated an improvement in their MMSE at any follow-up visit. Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23. Analysis of time until death from brain metastases demonstrated that decreasing baseline MMSE (p = 0.003) and primary site (breast vs. lung vs. other p = 0.032) were highly associated with a terminal event. CONCLUSION While gender and perhaps age remain significant predictors for survival, MMSE is also an important way of assessing a patients outcome. Accelerated fractionation used in the treatment of brain metastases (30 Gy in 10 fractions) appears to also be associated with an improvement in MMSE and a lack of decline of MMSE below 23 in long-term survivors.

Electrochemical treatment of mouse and rat fibrosarcomas with direct current

Electrochemical treatment (ECT) of cancer utilizes direct current to produce chemical changes in tumors. ECT has been suggested as an effective alternative local cancer therapy. However, a methodology is not established, and mechanisms are not well studied. In vivo studies were conducted to evaluate the effectiveness of ECT on animal tumor models. Radiation-induced fibrosarcomas were implanted subcutaneously in 157 female C3H/HeJ mice. Larger rat fibrosarcomas were implanted on 34 female Fisher 344 rats. When the spheroidal tumors reached 10 mm in the mice, two to five platinum electrodes were inserted into the tumors at various spacings and orientations. Ten rats in a pilot group were treated when their ellipsoidal tumors were about 25 mm long; electrode insertion was similar to the later part of the mouse study, i.e., two at the base and two at the center. A second group of 24 rats was treated with six or seven electrodes when their tumors were about 20 mm long; all electrodes were inserted at the tumor base. Of the 24 rats, 12 of these were treated once, 10 were treated twice. and 2 were treated thrice. All treated tumors showed necrosis and regression for both mice and rats; however, later tumor recurrence reduced long-term survival. When multiple treatments were implemented, the best 3 month mouse tumor cure rate was 59.3%, and the best 6 month rat tumor cure rate was 75.0%. These preliminary results indicate that ECT is effective on the radiation-induced fibrosarcoma (RIF-1) mouse tumor and rat fibrosarcoma. The effectiveness is dependent on electrode placement and dosage.

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission.

PURPOSE To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

Factors affecting cosmetic outcome in breast-conserving cancer treatment : objective quantitative assessment

SummaryA battery of objective measurements of cosmetic outcome was performed on 114 patients who had been treated by breast-preservation techniques for breast cancer. Cosmetic breast retraction, as determined by Breast Retraction Assessment (BRA) measurements, was significantly greater in patients who underwent extensive primary tumor resection, were more than 60 years old, weighed more than 150 lbs, or had a primary tumor in an upper breast quadrant. While use of a local RT boost, per se, was not a significant factor, those patients with high dose and/or large volume local boosts more frequently had marked retraction. Breast telangiectasia and depigmentation (T/D) was related to use of a local RT boost, patient age greater than 60 years, and use of separate nodal RT fields. Breast T/D was significantly more frequent with use of electron beam local RT boost which delivered a boost skin dose exceeding 1600 cGy.Objective quantitative assessments, such as BRA and T/D area measurements, provide data to determine factors related to each type of cosmetic change and thus provide guidelines for optimizing cosmetic outcome. Limiting the extent of primary tumor resection may minimize the amount of breast retraction. Omitting the local RT boost, particularly large volume, high dose boosts, may reduce the frequency of marked cosmetic retraction and skin T/D.

Patient self-evaluation of cosmetic outcome of breast-preserving cancer treatment

Thirty-two patients with Stage I or II breast cancer who had completed conservative breast-preserving treatment were asked to rate their cosmetic outcomes. Within this group, extent of the surgical excision of the breast tumor varied, with biopsy scars ranging from 2 to 19.5 cm. All patients had received external beam radiotherapy, with local boost doses in 17 cases. The average interval between self-evaluation and the completion of radiotherapy was 19 months. Patients completed a questionnaire rating the appearance of the treated breast, the degree of difference between breasts and overall satisfaction with cosmesis. They were asked to describe differences between breasts and to make any additional comments. Appearance of the treated breast was rated good to excellent by 94%, although 88% noted a difference of slight to moderate degree between treated and untreated breasts. Overall, 78% of patients were very to extremely satisfied, while moderate satisfaction was reported by 19%. Reports of breast differences included reduced size of the treated breast (44%), increased firmness (31%), elevation (25%), and skin color changes (22%). Reasons for dissatisfaction included chronic breast pain in 3 patients, breast edema in one and arm edema in one. Two patients wanted the untreated breast reduced in size. Statistically significant inverse relationships were found between the length of the biopsy scar and patient ratings of both appearance of the treated breast and overall satisfaction. These results indicated that although most patients were satisfied with cosmetic results of breast-preserving treatments, they are quite discriminating in their evaluations of differences between breasts. Functional factors such as pain and edema had a negative impact on satisfaction with cosmesis.