Ding-Jen Lee

Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas

PURPOSE The objectives of this study were to determine the efficacy and toxicity of Etanidazole (ETA), a hypoxic cell sensitizer, when combined with conventional radiotherapy (RT) in the management of advanced head and neck carcinomas. METHODS AND MATERIALS From March 1988 to September 1991, 521 patients who had Stage III or IV head and neck carcinomas were randomized to receive conventional RT alone (66 Gy in 33 fractions to 74 Gy in 37 fractions, 5 fractions per week) or RT+ETA (2.0 g/m2 thrice weekly for 17 doses), of whom 504 were eligible and analyzable. Treatment assignments were stratified before randomization according to the primary site (oral cavity + hypopharynx vs. supraglottic larynx + oropharynx + nasopharynx), T-stage (T1-3 vs. T4), and N-stage (N0-2 vs. N3). Pretreatment characteristics were balanced. In the RT-alone arm, 39% of patients had T3 and 34% had T4 disease, whereas in the RT+ETA arm, 42% of patients had T3 and 33% had T4 disease. Thirty-eight percent of the RT-alone patients and 37% of the RT+ETA patients had N3 disease. The median follow-up of surviving patients was 3.38 years, with a range between 0.96 and 5.63 years. RESULTS One hundred and ninety-four of the 252 (77%) RT+ETA patients received at least 14 doses of the drug. Overall RT protocol compliance rate was 82% in the RT-alone arm and 86% in the RT+ETA arm. No Grade 3 or 4 central nervous system or peripheral neuropathy was observed in the RT+ETA arm. Eighteen percent of the patients developed Grade 1 and 5% developed Grade 2 peripheral neuropathy. Other drug related toxicities included nausea/vomiting (27%), low blood counts (15%), and allergy (9%). Most of these toxicities were Grade 1 and 2. The incidence of severe acute and late radiation effects were similar between the two arms. The 2-year actuarial local-regional control rate (LCR) was 40% for the RT-alone arm and 40% for the RT+ETA arm. Two-year actuarial survival was 41% for the RT-alone arm and 43% for the RT+ETA arm (p = 0.65). Multivariate analyses were performed to investigate the influence of covariates on treatment effects. A strong treatment interaction with N-stage was revealed: LCR (50% vs. 40% at 2 years), RT+ETA improved for patients with N0-2 disease but not for N3 patients (22% for RT+ETA and 40% for RT). Further analyses showed that RT+ETA was more advantageous in N0-1 patients, with a 2-year LCR of 55% for RT+ETA vs. 37% for RT only (p = 0.03). A similar phenomenon was observed when using survival as the end point. CONCLUSION The results showed that adding Etanidazole to conventional RT produced no global benefit for patients who had advanced head and neck carcinomas. There was a suggested benefit for patients who had N0-1 disease, and that needs to be confirmed by another study.

Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a phase II study

PURPOSE To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

On-line measurement of field placement errors in external beam radiotherapy

An on-line electronic portal imaging system was used in a quantitative measurement of field placement errors in external beam radiotherapy. Data from 30 patients, giving a total of 150 portals with 66% in the thoracic region and 34% in the abdominal region, were analysed. Displacements from the prescription delineated by physicians were measured. The displacements included errors to block malposition, field malposition, field malrotation and patient malposition, and these were classified in two categories of displacements, those associated with the portal boundary and those with anatomic structures. Except for one rotational error, only translational errors were found. Displacements greater than 1 cm amounted to 17% with respect to the portal boundary and between 10% and 46% with respect to anatomic landmarks within the portal. From the results of the study, a margin of 1 cm around the tumour is barely sufficient if a 5% accuracy in dose delivery is desired.

A new design of microwave interstitial applicators for hyperthermia with improved treatment volume

New 915 MHz microwave interstitial applicators with improved treatment volume have been developed for clinical hyperthermia. The applicators are made from semi-rigid miniature coaxial cables by removing sections of the outer copper conductor to create multiple nodes while preserving the integrity of the teflon dielectric insulators. The homogeneity of the temperature distribution along the longitudinal axis is optimized by empirically adjusting the spacing of the gaps between sections of the outer conductor along the length of the applicator. In vitro and in vivo testing of the two-node and three-node microwave applicators show that the treatment volume can be improved by 100% over that of a one-node microwave applicator.

SECOND NEOPLASMS IN PATIENTS WITH CARCINOMAS OF THE VOCAL CORD: INCIDENCE AND IMPLICATIONS FOR SURVIVAL

A retrospective analysis was performed for 218 patients who were managed for carcinomas of the glottic larynx from 1975 to 1988. With a median follow-up of 51 months (range: 24 to 120 months), 41 patients developed a second malignant neoplasm. Six patients had synchronous and 35 had metachronous second malignant neoplasms. The median interval between the diagnosis of glottic carcinoma and a second malignant neoplasm was 31 months. This median interval increased to 43 months when only the metachronous tumors were analyzed. The average annual risk of developing a second malignant neoplasm (SMN) in a 10-year period was 3.1%. Seventy-one percent of them occurred in the upper aerodigestive tract or lungs. When analyzed according to the initial stage of the glottic carcinoma, 23 of 145 (16%) patients with T1 or T2 glottic carcinomas developed a second malignant neoplasm, whereas 18 of 73 (25%) patients T3 or T4 lesions did so. For the T1/T2 group, the average annual risk was 2.5%, as compared to 4.8% for the T3/T4 group (p = 0.023). The development of a second malignant neoplasm adversely affected survival. The 10-year actuarial survival for these patients who did not develop a second malignant neoplasm was 45%, as compared to 19% for those who did develop a second malignant neoplasm (p = 0.008). Although second malignant neoplasms occurred in only 19% of the total patient population, their impact on the survival rate of the overall population was equal to that of glottic carcinomas. The median survival after the diagnosis of a SMN was 6 months. The high incidence of second malignant neoplasms in patients with glottic carcinomas warrants careful follow-up and clinical investigation of the use of chemopreventive agents.

Logistics in designing clinical trials for etanidazole (SR 2508): An RTOG experience☆

In a Phase II study of etanidazole (SR 2508), the dose of 17 x 2 g/m2 (total drug dose: 34 g/m2) was tested in 33 patients and the toxicity was deemed acceptable. A Phase III trial is now in progress comparing conventional radiotherapy with conventional radiotherapy plus etandizole (2 g/m2 i.v. 30 to 60 min before radiotherapy each Monday, Wednesday, and Friday to 34 g/m2 in 17 doses) in patients with unresectable head and neck carcinomas. A recent analysis showed only 14.7% grade 1 and 3.9% Grade 2 peripheral neuropathy. In the initial study design, 133 evaluable patients per treatment arm could achieve an 80% level of power of detecting a 15% difference in local-regional control rates between the radiotherapy arm (25% local-regional control at 2 years) and the radiotherapy plus etanidazole arm (assuming a 40% rate). Allowing for 20 ineligible cases in each arm, a total number of 306 was required. An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug. It is assumed that less than 14 drug doses will not produce any therapeutic gain, therefore, a true 40% local-regional control rate in the radiotherapy plus etanidazole arm will be observed as a 36% rate when analyzed by assigned treatment. Using this information, the study was modified to have an 80% level of power in detecting a difference between a 25% local-regional control rate in the radiotherapy group and a 36% rate in the radiotherapy plus etanidazole group. Allowing for a 10% patient ineligibility rate, 518 patients are required. With 12 patients entered per month, it is estimated that patient accrual to this study will continue through October 1991.

Electron arc therapy: Beam data requirements and treatment planning

In electron arc therapy a long narrow beam defined by a secondary collimator is used to sweep across the treatment area of the patient. Central axis percentage depth doses and off-axis ratios measured with such a collimator show variations with the source-to-surface distance (SSD). Errors may be introduced into isodose distributions calculated with the effective SSD method when beam data measured at a fixed SSD are used. A treatment planning algorithm using beam data measured at two SSDs to allow an interpolation and extrapolation procedure to account for SSD variations has been implemented. For calculations in off-axis planes, off-axis ratios normal to the plane of rotation are also required. Results of the calculations were checked with film dosimetry measurements and found to be in good agreement.

Tissue compensator fabrication using a simple photographic technique

A simple method of fabricating photon beam tissue compensators is described. A plaster cast of the patients surface contours is partially immersed in a mixture of India ink and water to obtain a topographic map relative to a reference plane which is perpendicular to the photon beam. The contours are photographed, and successive contours corresponding to different missing tissue thicknesses are used to fabricate a compensator from lead sheets cut to the same shape with the proper magnification.