Observer variation in contouring gross tumor volume in patients with poorly defined non-small-cell lung tumors on CT: the impact of 18FDG-hybrid PET fusion.

PURPOSE: To quantify interobserver variation in gross tumor volume (GTV) localization using CT images for patients with non-small-cell lung carcinoma and poorly defined tumors on CT and to determine whether variability would be reduced if coregistered 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-hybrid positron emission tomography (PET) with CT images were used. METHODS AND MATERIALS: Prospectively, 30 patients with non-small-cell lung carcinoma had CT and FDG-hybrid PET examinations in radiation treatment position on the same day. Images were coregistered using eight fiducial markers. Guidelines were established for contouring GTVs. Three radiation oncologists performed localization independently. The coefficient of variation was used to assess interobserver variability. RESULTS: The size of the GTV defined showed great variation among observers. The mean ratios of largest to smallest GTV were 2.31 and 1.56 for CT only and for CT/FDG coregistered data, respectively. The addition of PET reduced this ratio in 23 of 30 cases and increased it in 7. The mean coefficient of variation for GTV based on the combined modalities was significantly smaller (p < 0.01) than that for CT data only. CONCLUSIONS: High observer variability in CT-based definition of the GTV can occur. A more consistent definition of the GTV can often be obtained if coregistered FDG-hybrid PET images are used.

Computed tomographic simulation of craniospinal fields in pediatric patients: improved treatment accuracy and patient comfort.

PURPOSE: To reduce the time required for planning and simulating craniospinal fields through the use of a computed tomography (CT) simulator and virtual simulation, and to improve the accuracy of field and shielding placement. METHODS AND MATERIALS: A CT simulation planning technique was developed. Localization of critical anatomic features such as the eyes, cribriform plate region, and caudal extent of the thecal sac are enhanced by this technique. Over a 2-month period, nine consecutive pediatric patients were simulated and planned for craniospinal irradiation. Four patients underwent both conventional simulation and CT simulation. Five were planned using CT simulation only. The accuracy of CT simulation was assessed by comparing digitally reconstructed radiographs (DRRs) to portal films for all patients and to conventional simulation films as well in the first four patients. RESULTS: Time spent by patients in the CT simulation suite was 20 min on average and 40 min maximally for those who were noncompliant. Image acquisition time was <10 min in all cases. In the absence of the patient, virtual simulation of all fields took 20 min. The DRRs were in agreement with portal and/or simulation films to within 5 mm in five of the eight cases. Discrepancies of > or =5 mm in the positioning of the inferior border of the cranial fields in the first three patients were due to a systematic error in CT scan acquisition and marker contouring which was corrected by modifying the technique after the fourth patient. In one patient, the facial shield had to be moved 0.75 cm inferiorly owing to an error in shield construction. CONCLUSIONS: Our analysis showed that CT simulation of craniospinal fields was accurate. It resulted in a significant reduction in the time the patient must be immobilized during the planning process. This technique can improve accuracy in field placement and shielding by using three-dimensional CT-aided localization of critical and target structures. Overall, it has improved staff efficiency and resource utilization.

Multiorgan fatal chronic complications following radiation treatment for cancer of the cervix--results of fibroblast assay.

We report a case of severe chronic normal tissue injury following conventional irradiation in a 33-year-old patient with a strong family history of cancer. Her cultured fibroblasts exhibited a response to low-dose-rate irradiation similar to fibroblasts taken from a normal individual. For acute irradiation her fibroblasts showed a slight increased sensitivity to single doses compared to fibroblasts from a normal individual. This difference was much larger when fractionated irradiation was given. It is concluded that the hypersensitive response of this patient was due to the fractionated radiotherapy and not to the low-dose-rate brachytherapy. We believe that this is the first report of this form of cellular radiosensitivity which is mainly expressed in fractionated radiotherapy.

Childhood medulloblastoma in Ontario, 1977-1987: population-based results.

A retrospective review was carried out to study children, not more than 16 years old, with a confirmed diagnosis of medulloblastoma, who were residents of the Province of Ontario at the time of diagnosis between 1977 and 1987 inclusive. The provincial tumour registry provided the population database. One hundred and eight children with medulloblastoma were identified of whom 72 (67%) were initially treated at University of Toronto Centres and 36 (33%) at other Health Science Centres, hospitals, and Regional Cancer Centres (RCC) in Ontario. The hospital/Cancer Centre records were reviewed. The 5-year relapse-free survival (RFS) for all patients treated in Ontario was 58% (SE = 5%). Those treated in Toronto had a 5-year RFS of 65% (SE = 6%) compared to 44% (SE = 8%) for those treated in other RCCs in the province (P = 0.02). Relapse-free survival for the RCCs ranged from 25 to 60%, with a trend for improved survival with increasing centre size. Univariate analysis of determinants of relapse-free survival for all 108 patients showed the following variables to be significant: T-stage (Tx + T1 + T2 vs. T3A + T3B) P = 0.0004, M-stage (M0 + Mx vs. M1-4) P = 0.0006, extent of resection (total vs. less than total) P = 0.002, radiotherapy (craniospinal irradiation and posterior fossa boost vs. other) P = 0.02, and treatment centre (Toronto centres vs. RCC) P = 0.02. Cases treated at centres outside metropolitan Toronto had a nearly two-fold (relative risk = 1.93; 95% confidence interval = 1.07, 3.47) greater risk of recurrence or death than those seen in Toronto. However, in multivariate analysis this difference was not quite significant (P = 0.07) after controlling for stage (T and M), extent of resection, meningitis, and gender. These data suggest that patients with medulloblastoma should be referred for treatment to large centres with major pediatric neurosurgical and oncology resources.

Enhancement of sensitivity to hyperthermia by lonidamine in human cancer cells.

Human glioma (87MG) and squamous cell carcinoma of the head and neck UMSCC-1 were shown to be sensitized to hyperthermia by Lonidamine treatment before and during hyperthermia. The degree of thermal sensitization increased with increasing heating times and temperatures. In addition, the thermal sensitization by Lonidamine as well as cellular thermal sensitivity were dependent on pH and increased with the more acidic pH. Even though plateau phase cells were more thermally resistant than exponentially growing cells, Lonidamine treatment caused thermal sensitization under both conditions. These data show that Lonidamine may hold potential to enhance the effectiveness of hyperthermia in cancer treatment and that especially in tumours with low pH an enhanced therapeutic gain may be achieved.

Hyperthermia enhancement of radiation response and inhibition of recovery from radiation damage in human glioma cells.

Three human glioma cell lines were tested for the effectiveness of hyperthermia and thermal radiosensitization. Thermal sensitization was evaluated from the perspective of increased radiosensitivity as well as inhibition of recovery from radiation damage. The three glioma cell lines tested showed large shoulders on the radiation survival curve and a large capacity for recovery of potentially lethal radiation damage. Hyperthermia caused radiosensitization in all three cell lines, which was primarily characterized by the reduction of the survival curve shoulder with moderate decreases in the survival curve slope. The radiosensitization was dependent on the time and temperature of the hyperthermia treatment. At 45 degree C for 60 min the shoulder of the radiation survival curve could be completely eliminated and the degree of enhanced cell killing at the 2 Gy level ranged from factors of 10 to 20 under the various conditions. When hyperthermia was given to cells which were irradiated and then plated immediately, or delayed for 8 h before plating to allow recovery, hyperthermia was found to cause radiosensitization under both conditions. In addition, when the hyperthermia dose was increased the difference between the immediate plating and the delayed plating survival curve decreased and for 45 degrees C for 60 min this difference was completely eliminated, concomitantly with the elimination of the survival curve shoulder. These data indicate that hyperthermia may play a role in radiosensitization for the treatment of human glioma.

The effect of lonidamine (LND) on radiation and thermal responses of human and rodent cell lines.

Rodent and human cells were tested for response to Lonidamine (LND) (1-(2,4 dichlorobenzyl) 1-indazol-3-carboxylic acid) combined with radiation or hyperthermia. Lonidamine exposure before, during, and after irradiation caused varying degrees of inhibition of potentially lethal damage (PLD) repair which was cell line dependent. In human glioma, melanoma, squamous cell carcinoma, and fibroblasts, LND exposure did not inhibit or only partially inhibited repair of potentially lethal damage. LND up to 100 micrograms/ml produced only a low level of toxicity in these cells and only slightly inhibited glucose consumption at the maximum concentration. In human glioma cells, LND treatment alone did not inhibit PLD repair, but when combined with hyperthermia treatment at moderate levels easily achievable in the clinic, there was complete inhibition of potentially lethal damage repair. These data suggest that LND effectiveness is cell type dependent. Combinations of LND, hyperthermia, and radiation may be effective in cancer therapy especially in tumors such as glioma in which repair of potentially lethal damage may be extensive.

The effect of lonidamine alone and in combination with cisplatin on in vitro growth and viability of lung squamous cell carcinoma cell lines.

Two non small cell lung cancer (NSCLC) cell lines were tested in vitro to evaluate the effect of lonidamine, cisplatin and combinations of these two agents using different doses and schedules. Lonidamine alone at concentrations greater than 50 micrograms/ml caused inhibition of cell growth in both monolayer and spheroid cell cultures. Cisplatin at concentrations of 10-20 microM caused a concentration dependent toxicity and inhibited growth in monolayer and spheroid cell cultures. Combination treatment of lonidamine and cisplatin caused concentration dependent effects. For 25 micrograms/ml lonidamine, there was no additive and in some cases an antagonistic effect when used with cisplatin. For higher lonidamine concentrations (75 and 100 micrograms ml), an additive effect with cisplatin (10-15 microM) was observed. This effect saturated for cisplatin concentrations of 20 microM. These data show some potential for lonidamine and cisplatin combination therapy but treatment doses and schedules will have to be identified so that the additive effect can be achieved at concentrations clinically attainable.

The in vitro effects of lonidamine combined with cisplatin in human small cell lung cancer cell lines.

Two human small cell lung cancer (SCLC) cell lines were used to evaluate the in vitro response to lonidamine and cisplatin exposure. The two cell lines both showed growth inhibition when exposed to lonidamine alone at concentrations greater than 50 micrograms/ml; however, one cell line (H69) was more sensitive. When cisplatin was combined with lonidamine a synergistic interaction was observed when cells were exposed to 10 microM cisplatin for 1 hour combined with lonidamine at concentrations of 50 micrograms/ml or greater. At a concentration of 25 micrograms/ml lonidamine combined exposure with cisplatin had no effect on cell growth or viability.

Lonidamine can enhance the cytotoxic effect of cisplatin in human tumour cells and rodent cells.

Lonidamine combined with cisplatin treatment was tested in human glioma (U87MG) human squamous cell carcinoma (UMSCCl) and Chinese hamster (HA1) cells. The order of sensitivity to cisplatin was HA1 greater than U87MG greater than UMSCCl. Lonidamine caused little sensitization in U87MG cells, moderate sensitization in HA1 cells and large sensitization in UMSCCl cells. The degree of sensitization was correlated to the effect of lonidamine on cell growth. The degree of sensitization to cisplatin by lonidamine treatment was dependent on lonidamine exposure concentration, time and treatment sequence. Lonidamine shows potential for enhancement of cisplatin chemotherapy but this appears to be cell type specific and should be tested for cells derived from sites of clinical interest for such drug therapy.

A comparison of heat and radiation sensitivity of three human glioma cell lines.

Three human glioma cell lines were tested for radiation and hyperthermia sensitivity and compared to the responses of a normal human fibroblast cell line. The radiation response of the glioma cell lines exhibited a large shoulder on the radiation survival curve indicating radioresistance when compared to the more radiosensitive fibroblast cell line. The hyperthermia response for the glioma cell lines was qualitatively similar to responses reported for other cell lines. When compared to normal human fibroblasts the glioma cells were found to be more sensitive to hyperthermia than the normal fibroblasts indicating hyperthermia may be a promising method or adjunct to radiotherapy in the treatment of resistant glioma cells or tumors. The results also show that both the radiation and thermal response is influenced by cell culture conditions and growth status. Two of the cell lines grown to confluency and treated in confluency showed an increased radiation resistance at low doses and the cell lines showed decreased resistance at high doses compared to cells plated to confluency (see Methods and Materials). An increased thermal resistance, especially at the lower heating temperatures, was also observed for cells grown to confluency. Measurements of residual glucose in the culture medium at the time of irradiation was about the same for the two culture methods (55%-65%). Cell cycle analysis showed that the differences were not related to changes in cell cycle distribution.

Impact of local radiation in the management of salivary gland carcinomas.

Seventy patients with salivary gland carcinoma (63% major gland and 37% minor gland) are reviewed. Histologies included adenoid cystic (54%), mucoepidermoid (16%), and adenocarcinoma (14%). Patients were analyzed according to extent of surgery and whether or not adjuvant postoperative radiotherapy was given. There is no difference in survival in patients who had complete excision of gross tumor with or without adjuvant radiotherapy. Patients who did not undergo radiotherapy had a 62% actuarial risk of locoregional failure at 5 years, with a 20% risk in the adjuvantly irradiated group (P less than 0.001). A failure analysis demonstrates that among the 44% of patients with recurrence 71% (22/31) failed locoregionally and 69% (21/31) had distant metastases. Twenty-seven percent (19/70) died of disease, with 31% (6/19) dying of locoregional disease and 26% (5/19) of distant disease. Implications for management are discussed.

Combination chemo-radiotherapy for residual, recurrent or inoperable carcinoma of the rectum: E.C.O.G. study (EST 3276).

Thirty evaluated patients were randomized to either continuous radiation + 5-FU (16 patients), or split-course radiation + 5-FU (14 patients) for the treatment of residual, recurrent, or inoperable carcinoma of the rectum or recto-sigmoid. Twenty-one of these patients received maintenance MeCCNU + 5-FU chemotherapy following radiation. Entry was terminated when late treatment reactions were seen in the precursor pilot study. Twenty-four of the patients have died; the estimated median survival is 17 months in each of the treatment arms. Performance status was the only significant prognostic factor for survival. The rate of severe, acute reactions during the radiation treatment period was higher for the continuous-course than for the split-course regimen (69 vs. 21%, p = .01). The rates of severe late treatment reactions, 23% (7 of 30), and severe chemotherapy toxicity, 48%, were similar for the two treatment programs. Late treatment reactions, primarily bowel complications, were seen from 3 to 23 months after radiation in 3 patients treated with continuous course, and 4 patients treated with split course. Ten of 21 patients (48%) who received maintenance chemotherapy had severe or worse toxicity. Toxicity was seen for 6 of 12 continuous-course, and 4 of 9 split-course patients. Twenty-seven patients have had disease progression, and the median length of disease control is 11 months.

Is cancer treatment toxicity accurately reported?

To assess current documentation of treatment-related toxicity, 46 out-patients attending the Ottawa Civic Hospital Cancer Clinic were randomly selected. Physician's charting of toxicities was compared to patient's perception of toxicity, as recorded on a brief questionnaire. As a group, patients reported significantly more toxicities than had been recorded by their physician. The greatest disparity was observed for the following categories: nausea, vomiting, alopecia, and decreased performance status. The best-documented toxicities were: skin and mucosal reactions, and urinary symptoms. To the question concerning their most bothersome symptoms, patients described nausea, vomiting, mucosal reaction, and decreased performance status as the most common. In 46% of cases, the physician's notes failed to identify the patient's worst symptom. From our study; toxicity is probably under-reported, and unrecognized by oncologists. A self-administered questionnaire appears to be a better way of accurately identifying and reporting treatment toxicities, when compared to the oncologist's evaluation, as recorded in the patient's permanent record.

The acute radiation syndrome. A memorial to William Michael Court-Brown.

The pattern of symptoms in 189 patients irradiated with a large single dose to one half of the body are described. Radiation sickness developed in 83 and 39% of upper half-body irradiation and lower half-body irradiation treatments respectively and the incidence is not reduced by sedatives or anti-emetics. Following treatment there is a latent period up to 90 min before a phase of acute upset and nausea and vomiting starts. This phase persists for about 6h with an average of six bouts of vomiting and is then followed by recovery.