C. Norman Coleman

CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment ☆

Multiple systems have been developed for grading the adverse effects (AEs) of cancer treatment. The National Cancer Institute Common Toxicity Criteria (CTC) system has substantially evolved since its inception in 1983. The most recent version, CTCAE v3.0 (Common Terminology Criteria for Adverse Events version 3.0) represents the first comprehensive, multimodality grading system for reporting the acute and late effects of cancer treatment. The new CTC requires changes in the application of AE criteria including new guidelines regarding late effects, surgical and pediatric effects, multimodality issues, and for reporting the duration of an effect. It builds on the strengths of previous systems, represents a considerable effort among hundreds of participants, and signifies an international collaboration and consensus of the oncology research community. This article updates recent progress in the evolution of adverse effects grading systems and reviews the development of CTCAE v3.0.

Pretreatment Nomogram for Prostate-Specific Antigen Recurrence After Radical Prostatectomy or External-Beam Radiation Therapy for Clinically Localized Prostate Cancer

PURPOSEnTo present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease.nnnPATIENTS AND METHODSnA Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT.nnnRESULTSnPretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality.nnnCONCLUSIONnMen at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.

Analysis of prostate and seminal vesicle motion: Implications for treatment planning

PURPOSEnTo quantify prostate and seminal vesicle positional changes (target motion) between treatment planning and delivery, and to identify the factors contributing to target motion.nnnMETHODS AND MATERIALSnThirty patients with adenocarcinoma of the prostate were prospectively evaluated by analyzing two sequential planning computerized tomography (CT) scans (S1, obtained prior to treatment, and S2, obtained during the fourth week of treatment) for each patient. All anatomical volumes of interest (soft tissue and bony) were reconstructed from transverse CT images and projected onto anterior and lateral beams-eye view projections. Positional changes between S1 and S2 were eliminated by applying a rigid body translation and rotation. Target motion was then measured by recording the positional change between S1 and S2 at the edges (right, left, superior, inferior). Potential correlation of target motion with bladder volume, rectal volume, and rectal diameter changes were evaluated by linear regression analysis.nnnRESULTSnNeither the prostate nor seminal vesicles remained fixed with respect to bony anatomy between S1 and S2. The distribution of positional changes were generally small (< 0.5 cm), but maximum displacements of 1.5-2.2 cm did occur, particularly in the lateral view. In this study, bladder volume changes between the scans were small and did not correlate with target motion (P = 0.67). Both rectal volume and rectal diameter changes correlated with target motion for both the prostate (p = 0.004 and 0.005, respectively) and seminal vesicles (p < 0.001 and < 0.001, respectively). However, neither the initial rectal volume nor the initial rectal diameter could be used to predict subsequent target motion when evaluated either singly or as part of a multiple regression model.nnnCONCLUSIONSnTarget motion occurs during the course of treatment planning and delivery and should be considered when designing conformal radiation fields. Although the target position at the time of planning CT may differ substantially from the mean treatment position, target motion cannot be predicted by evaluating simply measured parameters from a single scan, or double scan sequence.

REAL-TIME MAGNETIC RESONANCE IMAGE-GUIDED INTERSTITIAL BRACHYTHERAPY IN THE TREATMENT OF SELECT PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSEnThis study was performed to establish the dose-localization capability and acute toxicity of a real-time intraoperative magnetic resonance (MR) image-guided approach to prostate brachytherapy in select patients with clinically localized prostate cancer.nnnMETHODS AND MATERIALSnNine patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1cNxM0 prostate cancer, prostate-specific antigen (PSA) < 10 ng/ml, biopsy Gleason score not exceeding 3 + 4, and endorectal coil MR stage T2 disease were enrolled into this study. The prescribed minimum peripheral dose was 160 Gy to the clinical target volume (CTV), which was the MR-defined peripheral zone (PZ) of the prostate gland. Using a real-time 0.5 Tesla intraoperative MR imaging unit, 5-mm image planes were obtained throughout the prostate gland. The PZ of the prostate gland, anterior rectal wall, and prostatic urethra were identified on the T2 weighted axial images by an MR radiologist. An optimized treatment plan for catheter insertion was generated intraoperatively. Each catheter containing the 125Iodine sources was placed under real-time MR guidance to ensure that its position in the coronal, sagittal, and axial planes was in agreement with the planned trajectory. Real-time dose- volume histogram analyses were used intraoperatively to optimize the dosimetry.nnnRESULTSnFor the 9 study patients, 89-99% (median 94%) of the CTV received a minimum peripheral dose of 160 Gy and > or = 95% of the volume of the prostatic urethra and 42-89% (median 70%) of the volume of the anterior rectal wall received doses that were below the reported tolerance. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and no patient required more than a limited course (< or = 3 weeks) of oral alpha-1 blockers for postimplant urethritis.nnnCONCLUSIONSnReal-time MR-guided interstitial radiation therapy provided the ability to achieve the planned optimized dose-volume histogram profiles to the CTV and healthy juxtaposed structures intraoperatively, with minimal acute morbidity.

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

PURPOSEnThe 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.nnnMETHODS AND MATERIALSnFrom 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.nnnRESULTSnOne 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.nnnCONCLUSIONnThe 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.

Stereotactic radiosurgery for intracranial arteriovenous malformations using a standard linear accelerator

We have previously described the development of a technique which utilizes a standard linear accelerator to provide stereotactic, limited field radiation. The radiation is delivered using a modified and carefully calibrated 6 MV linear accelerator. Precise target localization and patient immobilization is achieved using a Brown-Roberts-Wells (BRW) stereotactic head frame which is in place during angiography, CT scanning, and treatment. Seventeen arteriovenous malformations (AVMs) have been treated in 16 patients from February 1986 to July 1988. Single doses of 1500-2500 cGy were delivered using multiple non-coplanar arcs with small, sharp edged x-ray beams to lesions less than 2.7 cm in greatest diameter. The dose distribution from this technique has a very rapid dropoff of dose beyond the target volume. Doses were prescribed at the periphery of the AVMs, typically to the 80-90% isodose line. Eleven of 16 patients have been followed by repeat angiography at least 1 year following treatment. Five of 11 have had complete obliteration of their AVM in 1 year and an additional three patients have achieved complete obliteration by 24 months. There have been no incidences of rebleeding or serious complications in any patient. We conclude that stereotactic radiosurgery using a standard linear accelerator is an effective and safe technique in the treatment of intracranial AVMs and the results compare favorably to the more expensive and elaborate systems that are currently available for stereotactic treatments.

Equivalent biochemical failure-free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of 4–20 ng/ml

PURPOSEnBiochemical failure-free survival stratified by the pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (bGl) is determined for prostate cancer patients managed definitively with external beam radiation therapy or radical retropubic prostatectomy.nnnMETHODS AND MATERIALSnA Cox regression multivariable analysis evaluating the variables of PSA, bGl, and clinical stage was used to evaluate the end point of time to PSA failure in 867 and 757 consecutive prostate cancer patients managed definitively with external beam radiation therapy or radical retropubic prostatectomy, respectively. PSA failure-free survival was determined using Kaplan-Meier analysis. Comparisons were made using the log rank test.nnnRESULTSnThe pretreatment PSA, bGl, and clinical stage (T3,4 vs. T1,T2) were found to be independent predictors of time to post-treatment PSA failure for both surgically and radiation managed patients using Cox regression multivariable analysis. Patients with a pretreatment PSA of > 4 ng/ml and < or = 20 ng/ml could be classified into risk groups for time to post-therapy PSA failure: low = PSA > 4-10 ng/ml and bGl < or = 4; intermediate = PSA > 4-10 and bGl 5-7; or PSA > 10-20 ng/ml and bGl < or = 7; high = PSA > 4-20 ng/ml and bGl > or = 8. Two-year PSA failure-free survival for surgically managed and radiation-managed patients, respectively, were 98% vs. 92% (p = 0.45), 77% vs. 81% (p = 0.86), and 51% vs. 53% (p = 0.48) for patients at low, intermediate, and high risk for post-therapy PSA failure.nnnCONCLUSIONSnThere was no statistical difference in the 2-year PSA failure-free survival for potentially curable patients managed definitively with surgery or radiation therapy when a retrospective comparison stratifying for the pretreatment PSA and bGl was performed.

Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas

Background. Despite optimal therapy with surgery and radiotherapy, the prognosis of patients with glioblastomas remains poor. Stereotactic brachytherapy involves the accurate placement of radioactive isotopes within brain tumors, significantly increasing the dose of radiation that can be delivered to the tumor bed without substantial risk to surrounding normal tissue, potentially improving local tumor control and patient survival.

Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis

Background. The etiology of Hodgkin disease remains uncertain. Patterns of presentation of Hodgkin disease are analyzed by histologic subtype with implications for etiology and pathogenesis.

Premenopausal breast cancer patients treated with conservative surgery radiotherapy and adjuvant chemotherapy have a low risk of local failure

The use of adjuvant chemotherapy in premenopausal breast cancer patients with positive nodes is now routine, but the optimal local treatment of these patients is uncertain. To determine the effect of adjuvant chemotherapy on the likelihood of local recurrence as the first site of failure in premenopausal patients treated with conservative surgery (CS) and radiotherapy (RT), we examined the outcome of 74 patients treated with CS, RT, and adjuvant chemotherapy and compared it to the outcome in 192 patients treated with CS and RT alone. Adjuvant chemotherapy consisted of four or more cycles of either a doxorubicin-containing regimen or cyclophosphamide, methotrexate, and 5-fluorouracil. All patients were less than 50 years old, had UICC-AJCC Stage I or II breast cancer treated between 1968 and 1981, had gross excision of the primary tumor, and had a total radiation dose to the primary tumor bed of greater than or equal to 6000 cGy. Factors predicting for local recurrence, such as extensive intraductal carcinoma and age less than 35, were equivalent in the two groups. Women treated with adjuvant chemotherapy had significantly worse T- and N-stages than women treated with conservative surgery and radiotherapy alone: 61% versus 36% had T2 tumors (p = 0.0003), 34% versus 6% had clinically positive nodes (p less than 0.0001), and 97% versus 4% had pathologically positive nodes (p less than 0.0001). Despite the poorer prognosis of patients treated with adjuvant chemotherapy, within 5 years of diagnosis, 4% of patients who received adjuvant chemotherapy had their initial relapse in the breast and 24% had initial failure elsewhere, compared with 15% local failure first and 14% failure elsewhere first for those treated without chemotherapy (p = 0.01). We conclude that premenopausal patients with positive nodes treated with combined modality therapy (conservative surgery, radiation therapy, and adjuvant chemotherapy) have a low risk of local recurrence as a first site of failure. These results suggest a possible interaction between radiation therapy and chemotherapy in their effects on local tumor control.