Richard S. Cox

Thyroid dysfunction after radiotherapy in children with Hodgkin's disease

Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkins disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 red or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG‐XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low‐dose group and 31 months in the high‐dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose‐related occult hypothyroidism in children following external irradiation of the neck.

Histologic conversion in the non-Hodgkin's lymphomas.

Between July 1, 1971 and December 31, 1978, 150 patients with favorable subtypes of non-Hodgkins lymphoma [nodular poorly differentiated lymphocytic (NLPD), nodular mixed, or diffuse well differentiated lymphocytic] were entered into prospective randomized clinical trials at Stanford University. Treatments included involved field, total lymphoid, or whole body irradiation, single alkylating agent chemotherapy, combination chemotherapy with cyclophosphamide, vincristine and prednisone (CVP) or with cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP), or various combinations of chemotherapy and irradiation. The initial complete response rate (CR) was 79%. Among patients who achieved a CR, 31% later relapsed. There were 78 patients who either failed to achieve a CR or achieved a CR and later relapsed. Histologic conversion (change from initially favorable to an unfavorable subtype of non-Hodgkins lymphoma) was documented in 22/78 patients (28%). However, the actuarial risk for conversion was actually much greater (60% at 8 yr). The median time to documentation of conversion was 51 mo. The most common type of histologic conversion was from NLPD to diffuse histiocytic lymphoma. Documented histologic conversion was often associated with a more aggressive clinical behavior of the lymphoma, and the median survival after conversion was less than 1 yr. However, those patients who achieved a CR after conversion had a more favorable outcome (actuarial survival 75% at 5 yr). No specific risk factors predictive of histologic conversion could be identified.

Analysis of cosmetic results and complications in patients with Stage I and II breast cancer treated by biopsy and irradiation

Between May, 1973 and December, 1980, 78 Stage I and II breast carcinomas in 76 patients were treated by biopsy and radiotherapy with curative intent. With a maximum follow-up of 10 years, a minimum of 2 1/2 years and a median follow-up of 3 1/2 years, a loco-regional control rate of 97% was obtained. Cosmetic results and treatment complications were studied. Patient characteristics, tumor size, excisional biopsy technique, axillary staging procedure and radiotherapy techniques were analyzed and all found to be important factors affecting cosmesis and complications. The most common complications included transient breast edema observed in 51% of patients, breast fibrosis (usually mild) seen in 23% of the population, axillary hematoma or seroma formation in 15%, mild arm edema in 14% and basilic vein thrombosis in 10% of patients. The causes of these and other less frequent complications are discussed. The overall cosmetic result was excellent in 78%, satisfactory in 18% and unsatisfactory in 4% of patients. Recommendations for improving cosmetic results minimizing complications are made. In our prospective trial, the high loco-regional control and good cosmesis supports the use of excisional biopsy and radiation therapy in patients with Stages I and II breast carcinoma.

Stereotaxic Radiosurgery for Brain Metastases; The Importance of Adjuvant Whole Brain Irradiation

Stereotaxic radiosurgery delivered from a modified 4 MV linear accelerator was used to treat 47 brain metastases in 27 patients at Stanford. Response was assessed in 41 lesions. Histopathologies included adenocarcinoma (24 lesions), renal cell carcinoma (9 lesions), melanoma (6 lesions), and squamous cell carcinoma (2 lesions). Follow-up ranged from 1.0-16.5 months, with a median of 5.0 months. Radiographic local control was achieved in 88% of the lesions. Three patients developed enlarging contrast-enhancing lesions in the radiosurgical field; one of these was biopsied and revealed necrosis with no viable tumor. Adjuvant whole brain irradiation (10 patients) was associated with regional intracranial control in 80% of patients. This was statistically superior (p = 0.0007) to the regional intracranial control rate achieved when radiosurgery alone was employed (6 patients). Most patients reported resolution of their neurologic symptoms, and were able to discontinue dexamethasone without impairment of neurologic function.

Prostate Specific Antigen after External Beam Radiotherapy for Prostatic Cancer: Followup

Between 1986 and 1989, 117 patients with pretreatment and serial posttreatment prostate specific antigen values received external beam radiotherapy at our hospital. Followup ranged from 0.6 to 5.9 years (mean 2.7). No patient had hormonal manipulation before distant recurrence. Biochemical relapse, defined as an increasing prostate specific antigen level after treatment, was observed in 44 patients. To date 30 of these 44 patients (68%) have had clinical relapse. The prognostic factors of advanced local stage, high Gleason score and high elevations of pretreatment prostate specific antigen values predicted for biochemical relapse and subsequent clinical failure. The interval between biochemical and clinical relapse was 156 +/- 46 days. Biochemical relapse is an important end point that can be used to determine the effect of treatment in prostatic cancer research.

Linear accelerator-based stereotaxic radiosurgery for brain metastases:the influence of number of lesions on survival.

PURPOSE To evaluate the influence of the number of brain metastases on survival after stereotaxic radiosurgery and factors that affect the risk of delayed radiation necrosis after treatment. MATERIALS AND METHODS Between March 1989 and December 1993, 120 consecutive patients underwent linear accelerator-based stereotaxic radiosurgery for brain metastases identified by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The influence of various clinical factors on outcome was assessed using Kaplan-Meier plots of survival from the date of radiosurgery, and univariate and multivariate analyses. RESULTS The median survival time was 32 weeks. Progressive brain metastases, both local and regional, caused 25 of 104 deaths. Patients with two metastases (n = 30) or a solitary metastasis (n = 70) had equivalent actuarial survival times (P = .07; median, 37 weeks; maximum, 211+ weeks). Patients treated to three or more metastases (n = 20) had significantly shorter survival times (P < .002; median, 14 weeks; maximum, 63 weeks). Prognostic factors associated with prolonged survival included a pretreatment Karnofsky performance status > or = 70% and fewer than three metastases. Delayed radiation necrosis at the treated site developed in 20 patients and correlated with prior or concurrent delivery of whole-brain irradiation and the logarithm of the tumor volume. CONCLUSION Survival duration is equivalent for patients with one or two brain metastases and is similar to that reported for patients with a solitary metastasis managed by surgical resection and whole-brain irradiation. Survival after radiosurgery for three or more metastases was similar to that reported for whole-brain irradiation.

Analysis of non-Hodgkin's lymphomas with nodular and favorable histologies, stages I and II

Between 1961 and 1980, 124 patients with Stages I and II nodular lymphocytic poorly differentiated (NLPD), nodular mixed histiocytic‐lymphocytic (NM), nodular histiocytic (NH), or diffuse well‐differentiated lymphocytic (DLWD) lymphoma according to the Rappaport classification were treated at Stanford University. Initial staging studies included lymphangiography in 91%, bone marrow biopsy in 93%, and diagnostic or staging laparotomy in 41% of patients. All patients were treated with megavoltage irradiation to either involved field (IF), extended field (EF), or total lymphoid fields (TLI) to a total dose of 3500–5000 rad. Median follow‐up was 5.5 years. Kaplan‐Meier actuarial survival at 5, 10, and 15 years was 84%, 68%, and 42%, respectively. Freedom from relapse at 5 and 10 years was 62% and 54%, respectively. In addition, there was a flattening of the relapse curve suggesting cure of approximately 50% of patients. Patients with NH had a significantly poorer survival (P = 0.03) while there were no differences among the other histologic groups. Freedom from relapse was higher in patients treated with TLI compared with those treated with IF or EF. However, a prospective study of 20 patients who all underwent staging laparotomy and were randomized to treatment with either IF or TLI revealed no significant difference in either survival or freedom from relapse. Utilizing multivariate analysis for the entire group, important prognostic factors included age, stage, histologic subtype, and treatment field. Cancer 52:2300‐2307, 1983.

Stanford University institutional report. Phase I evaluation of equipment for hyperthermia treatment of cancer

From September 16, 1981, through April 4, 1986, a total of 21 radiative electromagnetic (microwave and radiofrequency), ultrasound and interstitial radio-frequency hyperthermia applicators and three types of thermometry systems underwent extensive phantom and clinical testing at Stanford University. A total of 996 treatment sessions involving 268 separate treatment fields in 131 patients was performed. Thermal profiles were obtained in 847 of these treatment sessions by multipoint and/or mapping techniques involving mechanical translation. The ability of these devices to heat superficial, eccentrically located and deep-seated tumours at the major anatomical locations is evaluated and the temperature distributions, acute and subacute toxicities, and chronic complications compared. Average measured tumour temperatures between 42 degrees C and 43 degrees C were obtained with many of the devices used for superficial heating; average tumour temperatures of 39.6 degrees C to 42.1 degrees C were achieved with the three deep-heating devices. When compared to the goal of obtaining minimum tumour temperatures of 43.0 degrees C, all devices performed poorly. Only 14 per cent (118/847) of treatments with measured thermal profiles achieved minimum intratumoural temperatures of 41 degrees C. Fifty-six per cent of all treatments had associated acute toxicity; 14 per cent of all treatments necessitated power reduction resulting in maximum steady-state temperatures of less than 42.5 degrees C. Direct comparisons between two or more devices utilized to treat the same field were made in 67 instances, including 19 treatment fields in which two or more devices were compared at the same treatment session. The analyses from direct comparisons consistently showed that the static spiral and larger area scanning spiral applicators resulted in more favourable temperature distributions. Three fibreoptic thermometry systems (Luxtron single channel, four channel and eight channel multiple [four] probe array), the BSD Bowman thermistor system and a thermocouple system were evaluated with respect to accuracy, stability and artifacts. The clinical reliability, durability, and patient tolerance of the thermometry systems were investigated. The BSD Bowman and third generation Luxtron systems were found clinically useful, with the former meeting all of our established criteria.

Treatment of lymphoblastic lymphoma in adults.

Forty-four adult patients with lymphoblastic lymphoma (LBL) were treated according to one of two protocols. Both included (1) induction with cyclophosphamide, doxorubicin, vincristine, prednisone, and L-asparaginase; (2) CNS prophylaxis; and (3) maintenance therapy with methotrexate (MTX) and 6-mercaptopurine. In the second protocol, CNS prophylaxis began earlier than in the first protocol and included cranial irradiation and intrathecal (IT) MTX rather than simultaneous high-dose systemic and IT MTX. The overall response rate was 100% (95% complete). With a 26-month median follow-up, the 1-and 3-year actuarial freedom from relapse (FFR) for the composite patient group was 70% and 56%, respectively. The incidence of CNS relapse was reduced from 31% in the first protocol to 3% in the second protocol (P = .04, Gehan). Patients can be assigned retrospectively to low (n = 19) and high (n = 25) risk prognostic groups, as indicated by a multivariate analysis of pretreatment prognostic factors. High-risk is defined by Ann Arbor stage IV disease with bone marrow or CNS involvement or initial serum lactate dehydrogenase (LDH) concentration of greater than 300 IU/L (normal, less than 200). FFR of low- and high-risk groups at 5 years are 94% and 19%, respectively (P = .0006). Low-risk patients are highly curable using this approach to adult LBL. More intensive treatment for high-risk patients is warranted.

The accuracy of dose localization for an image‐guided frameless radiosurgery system

A compact X-band accelerator mounted on a robotic arm is under development for frameless stereotaxic radiosurgery. The therapy beam is aimed at the lesion by an imaging system comprised of two diagnostic x-ray cameras that view the patient during treatment. Patient position and motion are measured by the cameras and communicated in real time to the robotic arm for beam targeting and patient motion tracking. The tests reported here measured the pointing accuracy of the therapy beam and the present targeting and tracking capability of the imaging system. The results show that the system achieves the same level of targeting precision as conventional frame-based radiosurgery.