Impact of Neuroradiology-Based Peer Review on Head and Neck Radiotherapy Target Delineation.

BACKGROUND AND PURPOSE: While standard guidelines assist in target delineation for head and neck radiation therapy planning, the complex anatomy, varying patterns of spread, unusual or advanced presentations, and high risk of treatment-related toxicities produce continuous interpretive challenges. In 2007, we instituted weekly treatment planning quality assurance rounds as a joint enterprise of head and neck radiation oncology and neuroradiology. Here we describe its impact on head and neck radiation therapy target delineation. MATERIALS AND METHODS: For 7 months, treatment planning quality assurance included 80 cases of definitive (48%) or postoperative (52%) head and neck radiation therapy. The planning CT and associated target volumes were reviewed in comparison with diagnostic imaging studies. Alterations were catalogued. RESULTS: Of the 80 cases, 44 (55%) were altered, and of these, 61% had clinically significant changes resulting in exclusion or inclusion of a distinct area or structure. Reasons for alteration included the following: gross or extant tumor, 26/44 (59%); elective or postoperative coverage, 25/44 (57%); lymph nodes, 13/44 (30%); bone, 7/44 (16%); skull base, 7/44 (16%); normal organs, 5/44 (11%); perineural, 3/44 (7%); distant metastasis, 2/44 (5%); and eye, 1/44 (2%). Gross tumor changes ranged from 0.5% to 133.64%, with a median change in volume of 5.95 mm3 (7.86%). Volumes were more likely to be increased (73%) than decreased (27%). CONCLUSIONS: A collaborative approach to head and neck treatment planning quality assurance has an impact. Cases likely to have challenging patterns of infiltrative, intracranial, nodal, orbital, or perineural spread warrant intensive imaging-based review in collaboration with a diagnostic neuroradiologist.

SU-E-J-84: Investigating the Use of Deformable Algorithms to Register and Accumulate Dose to the Spinal Cord for Head-And-Neck Radiotherapy Patients.

PURPOSE: Mega-voltage cone-beam CT (MVCBCT) imaging can be used to monitor changes in neck flexion and calculate the true spinal cord dose during radiotherapy. To sum the dose over multiple fractions and compare with the planned dose requires deformable image registration. This study investigates the accuracy of deformable registration of the spine in kilovoltage CT (kVCT) to MVCBCT images for head-and-neck patients. METHODS: Head-and-neck kVCT and MVCBCT images were selected from five patients who exhibited large changes in neck flexion. The spinal canal was contoured in each image. MVCBCT images were rigidly registered to the kVCT image by aligning the C1-C2 vertebrae. Variations of a commercial deformable registration algorithm using the B-spline method were applied to a volume of interest surrounding the spine to deform the spinal cord structure from the kVCT to the MVCBCT. The Dice similarity index (DSI) was calculated between rigidly registered structures (DSI1), and compared against the DSI calculated between the MVCBCT structure and the structure deformed from kVCT to MVCBCT (DSI2). The difference between DSI2 and DSI1 was calculated to investigate the ability of the deformation algorithm to match the change in neck flexion. RESULTS: In this data set, a single-pass B-spline deformation algorithm was the most effective in deforming the kVCT spinal canal to the MVCBCT spinal canal, with a mean improvement in DSI (DSI2 - DSI1) of 0.134. The mean change in DSI for a single-pass algorithm with a contrast correction was 0.111; for a multiple-pass algorithm was 0.105; and for a multiple-pass algorithm with contrast correction was 0.075. CONCLUSIONS: Several versions of a commercially implemented B-spline deformation algorithm were found to improve the registration of the spinal canal in kVCT and MVCBCT head-and-neck images. The resulting accuracy in the calculation of the cumulative dose to the spinal cord is under investigation. We acknowledge Velocity for providing the registration software.

Treatment results and prognostic factors of advanced T3--4 laryngeal carcinoma: the University of California, San Francisco (UCSF) and Stanford University Hospital (SUH) experience.

PURPOSE: To review the UCSF-SUH experience in the treatment of advanced T3--4 laryngeal carcinoma and to evaluate the different factors affecting locoregional control and survival. METHODS AND MATERIALS: We reviewed the records of 223 patients treated for T3--4 squamous cell carcinoma of the larynx between October 1, 1957, and December 1, 1999. There were 187 men and 36 women, with a median age of 60 years (range, 28--85 years). The primary site was glottic in 122 and supraglottic in 101 patients. We retrospectively staged the patients according to the 1997 AJCC staging system. One hundred and twenty-seven patients had T3 lesions, and 96 had T4 lesions; 132 had N0, 29 had N1, 45 had N2, and 17 had N3 disease. The overall stage was III in 93 and IV in 130 patients. Seventy-nine patients had cartilage involvement, and 144 did not. Surgery was the primary treatment modality in 161 patients, of which 134 had postoperative radiotherapy (RT), 11 had preoperative RT, 7 had surgery followed by RT and chemotherapy (CT), and 9 had surgery alone. Forty-one patients had RT alone, and 21 had CT with RT. Locoregional control (LRC) and overall survival (OS) were estimated using the Kaplan--Meier method. Log-rank statistics were employed to identify significant prognostic factors for OS and LRC. RESULTS: The median follow-up was 41 months (range, 2--367 months) for all patients and 78 months (range, 6--332 months) for alive patients. The LRC rate was 69% at 5 years and 68% at 10 years. Eighty-four patients relapsed, of which 53 were locoregional failures. Significant prognostic factors for LRC on univariate analysis were primary site, N stage, overall stage, the lowest hemoglobin (Hgb) level during RT, and treatment modality. Favorable prognostic factors for LRC on multivariate analysis were lower N stage and primary surgery. The overall survival rate was 48% at 5 years and 34% at 10 years. Significant prognostic factors for OS on univariate analysis were: primary site, age, overall stage, T stage, N stage, lowest Hgb level during RT, and treatment modality. Favorable prognostic factors for OS on multivariate analysis were lower N stage and higher Hgb level during RT. CONCLUSION: Lower N-stage was a favorable prognostic factor for LRC and OS. Hgb levels > or = 12.5 g/dL during RT was a favorable prognostic factor for OS. Surgery was a favorable prognostic factor for LRC but did not impact on OS. Correcting the Hbg level before and during treatment should be investigated in future clinical trials as a way of improving therapeutic outcome in patients with advanced laryngeal carcinomas.

Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival.

BACKGROUND: The prognosis of anaplastic thyroid carcinoma (ATC) has been dismal. The objective of this study was to identify prognostic factors in patients who had prolonged survival. METHODS: Patients with ATC were identified from a computer database at a tertiary referral center. Univariate and multivariate analyses for survival differences were performed using the Kaplan-Meier log-rank statistic and the Cox proportional hazards model, respectively. RESULTS: Of the 33 evaluable patients, median survival was 3.8 months. Median age was 69 years. Prior goiter was present in 6 patients (18%), and 6 (18%) had prior thyroid carcinoma. Median tumor size was 6 cm, and 12 (36%) had adjacent well-differentiated carcinoma. Of the 26 patients who underwent neck exploration, 8 patients were potentially cured and received postoperative chemotherapy and irradiation; 4 (50%) were surgically macroscopically free of disease, and 4 (50%) patients had minimal residual disease after total thyroidectomy and resection of tumor adherent to adjacent structures. Four of these 8 patients survived longer than 2 years; their 5-year survival estimate was 50%. Eighteen patients underwent palliative resection of neck disease, leaving macroscopic residual disease or distant metastases; postoperative adjuvant chemotherapy and irradiation were administered in 16 of these 18 patients. Seven patients were treated with only chemotherapy and irradiation. In patients treated with potentially curative resection, median survival was 43 months compared with 3 months with palliative resection (P =0.002); the median survival of 3.3 months with only chemotherapy and irradiation was no different than palliative resection (P =0.63). No association was found between survival and age, prior goiter, prior thyroid carcinoma, adjacent differentiated carcinoma, or tumor size. CONCLUSIONS: Although the prognosis of most patients with ATC continues to be poor, complete resection of ATC combined with postoperative adjuvant chemotherapy and irradiation resulted in long-term survival, even with persistent minimal disease that remained on vital structures. An aggressive attempt at maximal tumor debulking followed by adjuvant therapy was found to be warranted in patients with localized ATC.

Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California-San Francisco experience.

PURPOSE: To review our experience with three-dimensional intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma. METHODS AND MATERIALS: We reviewed the records of 35 patients who underwent 3D IMRT for nasopharyngeal carcinoma at the University of California-San Francisco between April 1995 and March 1998. According to the 1997 American Joint Committee on Cancer staging classification, 4 (12%) patients had Stage I disease, 6 (17%) had Stage II, 11 (32%) had Stage III, and 14 (40%) had Stage IV disease. IMRT of the primary tumor was delivered using one of the following three techniques: (1) manually cut partial transmission blocks, (2) computer-controlled autosequencing static multileaf collimator (MLC), and (3) Peacock system using a dynamic multivane intensity-modulating collimator (MIMiC). A forward 3D treatment-planning system was used for the first two methods, and an inverse treatment planning system was used for the third method. The neck was irradiated with a conventional technique using lateral opposed fields to the upper neck and an anterior field to the lower neck and supraclavicular fossae. The prescribed dose was 65-70 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the clinical target volume (CTV), and 50-60 Gy to the clinically negative neck. Eleven (32%) patients had fractionated high-dose-rate intracavitary brachytherapy boost to the primary tumor 1-2 weeks following external beam radiotherapy. Thirty-two (91%) patients also received cisplatin during, and cisplatin and 5-fluorouracil after, radiotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local-regional progression-free, distant metastasis-free survival and overall survival were estimated using the Kaplan-Meier method. RESULTS: With a median follow-up of 21.8 months (range, 5-49 months), the local-regional progression-free rate was 100%. The 4-year overall survival was 94%, and the distant metastasis-free rate was 57%. The worst acute toxicity was Grade 2 in 16 (46%) patients, Grade 3 in 18 (51%) patients and Grade 4 in 1 (3%) patient. The worst late toxicity was Grade 1 in 15 (43%), Grade 2 in 13 (37%), and Grade 3 in 5 (14%) patients. Only 1 patient had a transient Grade 4 soft-tissue necrosis. At 24 months after treatment, 50% of the evaluated patients had Grade 0, 50% had Grade 1, and none had Grade 2 xerostomia. Analysis of the dose-volume histograms (DVHs) showed that the average maximum, mean, and minimum dose delivered were 79.5 Gy, 75.8 Gy, and 56.5 Gy to the GTV, and 78.9 Gy, 71.2 Gy, and 45.4 Gy to the CTV, respectively. An average of only 3% of the GTV and 2% of the CTV received less than 95% of the prescribed dose. The average dose to 5% of the brain stem, optic chiasm, and right and left optic nerves was 48.3 Gy, 23.9 Gy, 15.0 Gy, and 14.9 Gy, respectively. The average dose to 1 cc of the cervical spinal cord was 41.7 Gy. The doses delivered were within the tolerance of these critical normal structures. The average dose to 50% of the right and left parotids, pituitary, right and left T-M joints, and ears was 43. 2 Gy, 41.0 Gy, 46.3 Gy, 60.5 Gy, 58.3 Gy, 52.0 Gy, and 52.2 Gy, respectively. CONCLUSION: 3D intensity-modulated radiotherapy provided improved target volume coverage and increased dose to the gross tumor with significant sparing of the salivary glands and other critical normal structures. Local-regional control rate with combined IMRT and chemotherapy was excellent, although distant metastasis remained unabated.

Dose optimization for the treatment of anaplastic thyroid carcinoma: a comparison of treatment planning techniques.

PURPOSE: To evaluate and compare dose optimization for the treatment of anaplastic thyroid carcinoma using a 3D conformal plan, and two 3D intensity-modulated inverse plans. METHODS AND MATERIALS: After patient immobilization using an alpha cradle and head-mask system, a postoperative CT scan was obtained to delineate the gross tumor volume (GTV), the clinical tumor volume (CTV), and adjacent critical structures. Treatment plans were generated using UM-Plan (University of Michigan), PeacockPlan and Corvus (NOMOS Corporation, Sewickley, PA). Isodoses were displayed in the sagittal, coronal, and multiple axial planes, and dose-volume histograms (DVH) were generated for the GTV, CTV, and critical normal tissues. Treatment times were estimated to compare the practicality of delivering each plan in a busy radiotherapy department. RESULTS: All three treatment planning systems were able to deliver a minimum dose of 60 Gy to the GTV while keeping the maximum spinal cord dose at or below 45 Gy. However, there were differences in the doses delivered to 50% and 5% of the cord, the minimum CTV dose, and the overall treatment time. The PeacockPlan best spared the uninvolved tissues of the posterior neck, and provided the lowest dose to the cord without compromising the CTV. CONCLUSIONS: Inverse treatment planning provides superior dose optimization for the treatment of anaplastic thyroid carcinoma. The radiobiologic impact of intensity modulation for this tumor should be further tested clinically.

Randomized trial of radiation for age-related macular degeneration.

PURPOSE: To assess external beam radiation efficacy for subfoveal neovascularization associated with age-related macular degeneration. METHODS: All patients were evaluated in the same institution. In this prospective trial, 27 eyes (27 patients) with subfoveal neovascularization associated with age-related macular degeneration were randomized to either single fraction radiation (750 centigray) or observation. Endpoints were assessed by fluorescein angiography and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. Examiners were masked to patient treatment status. Parametric and nonparametric statistical analyses were performed. RESULTS: Twenty-seven patients were entered into the trial with a mean age of 76 years (range, 64 to 89) and a mean follow-up of 17 months (range, 7 to 32). The visual acuity loss was slightly less in the irradiated group, a finding of borderline significance (P < .046). There was no significant difference in fluorescein angiographic evidence of subretinal neovascular membrane change in the control group vs the irradiated group. CONCLUSIONS: External beam radiation, at this dose and fractionation, did not appear harmful. There was slightly less visual loss in irradiated eyes. No difference in fluorescein angiographic characteristics of subfoveal neovascularization size or progression in eyes with age-related macular degeneration was noted.

A comparison of cause-specific melanoma mortality and all-cause mortality in survival analyses after radiation treatment for uveal melanoma.

OBJECTIVE: To determine the causes and patterns of mortality after uveal melanoma radiation. DESIGN: A cohort study from a single institution was performed. Mortality was modeled using semiparametric survival techniques. All cause and cause-specific mortality analyses were performed. Mortality was compared with expected mortality from the U.S. census data. PARTICIPANTS: A total of 731 patients were studied, and 710 (97%) of these had medium or large melanomas. The mean tumor diameter was 11.3 mm, and the mean tumor thickness was 5.8 mm. Ciliary body was involved in 122 (17%) of patients. Complete follow-up was available on 99.6% (728 of 731) of patients. MAIN OUTCOME MEASURES: The authors analyzed the distribution and causes of post-treatment mortality. RESULTS: The 5- and 10-year all-cause Kaplan-Meier survival rates were 75.6% and 62.3%, respectively. Both melanoma risk factors (older age, ciliary body involvement, and larger tumor diameter) and nonmelanoma risk factors (older age and medical condition) were significant prognostic factors of all-cause mortality. Deaths from nonmelanoma causes accounted for 91 (42.3%) of 215 deaths. The 5-year and 10-year estimates of nonmelanoma deaths were 8.3% and 15.9%, respectively. Nonmelanoma mortality was similar to that observed in the general U.S. population (91 observed, 98.1 expected). Melanoma metastases accounted for 124 (57.7%) of 215 deaths. The 5- and 10-year estimates for probability of metastatic death were 16.1% and 21.8%, respectively. The largest tumor diameter was the best predictor for melanoma mortality; ciliary body involvement, older age, and distance from the fovea also were significant in multivariate analyses. CONCLUSION: A significant proportion of patients with uveal melanoma die of nonmelanoma causes after radiation. In analyzing prognostic factors, considerable information may be lost if analyses are based on all-cause mortality rather than cause-specific mortality.

15 years experience with helium ion radiotherapy for uveal melanoma.

PURPOSE: To review the long-term experience of helium ion therapy as a therapeutic alternative to enucleation for uveal melanoma, particularly with respect to survival, local control, and morbidity. METHODS AND MATERIALS: 347 patients with uveal melanoma were treated with helium ion RT from 1978-1992. A nonrandomized dose-searching study was undertaken, with doses progressively reduced from 80 GyE in five fractions to 48 GyE in four fractions, given in 3-15 days, mean of 7 days. RESULTS: Local control was achieved in 96% of patients, with no difference in the rate of local control being seen at 80, 70, 60, or 50 GyE in five fractions. At the lowest dose level of 48 GyE in four fractions, the local control rate fell to 87%. Fifteen of 347 patients (4%) had local regrowth in the eye requiring enucleation (12 patients), laser (1 patient) or reirradiation (2 patients). The time of appearance of local regrowth ranged from 4 months to 5 years posttreatment, with 85% occurring within 3 years. Of the 347 patients, 208 are alive as of May 1, 1997. The median follow up of all patients is 8.5 years, range 1-17 years. Kaplan-Maier (K-M) survival is 80% at 5 years, 76% at 10 years, and 72% at 15 years posttreatment. Patients with tumors not involving the ciliary body have a 15-year K-M survival of 80%. The results for patients whose tumors involved the ciliary body are poor, with a 15-year K-M survival of 43%. Seventy-five percent of patients with tumors at least 3.0 mm from the fovea and optic nerve, and initial ultrasound height less than 6.0 mm, retained vision of 20/200 or better posttreatment. Patients with tumors larger than 6 mm in thickness, or with tumors lying close to the optic nerve or fovea, have a reduced chance of retaining useful vision. The enucleation rate is 19%, 3% for local failure and 16% because of complications of the helium RT, particularly neovascular glaucoma, which occurred in 35% of patients. CONCLUSIONS: Local control and retention of the eye are excellent. Complications of therapy reduce vision and eye preservation. Twenty-four percent of patients manifested distant metastases 6 to 146 months posttreatment, mean of 43 months, median of 36 months. Late-appearing distant metastases do not appear to be caused by persistent tumor in the eye. The risk of metastases is high for patients with tumors greater than 7 mm in initial ultrasound height (37%), anterior tumors involving the ciliary body (47%), and in those with local failure (53%). Patients with tumors not involving the ciliary body and initial dimensions less than 10 mm had only an 8% chance of death from melanoma. A search for effective adjuvant therapy is needed for patients at high risk of metastases (large tumors, ciliary body involved, local regrowth in eye).

Metastatic risk for distinct patterns of postirradiation local recurrence of posterior uveal melanoma.

OBJECTIVE: The purpose of the study is to compare the prognostic significance of horizontal/marginal versus vertical/diffuse patterns of postirradiation local recurrence of posterior uveal melanoma. DESIGN: The study design was a nonrandomized, retrospective clinical study. Semiparametric and nonparametric statistical techniques were used. PARTICIPANTS: Seven hundred sixty-six posterior uveal melanoma patients were studied. INTERVENTION: Either iodine-125 plaque or helium ion radiation therapy was performed. MAIN OUTCOME MEASURES: Local tumor recurrence and systemic metastasis were measured. RESULTS: Local tumor recurrence was detected in 66 (8.6%) of 766 irradiated tumors. The 5-year actuarial rate of local recurrence was 10%. The recurrence pattem was horizontal/marginal in 27 patients (41%) and vertical/diffuse in 39 patients (59%). Systemic metastasis was detected in 5 patients (19%) with horizontal/marginal recurrence and in 19 patients (49%) with vertical/diffuse recurrence. After known metastatic risk factors were controlled, the relative risk for metastasis was 2.2 for horizontal/marginal recurrence and 5.1 for vertical/diffuse recurrence (P = 0.05). The actuarial rate of systemic metastasis was 2.9% per year for all patients, 6.3% per year for patients with horizontal/marginal recurrence, and 15.5% per year for patients with vertical/diffuse recurrence. CONCLUSIONS: Postirradiation local recurrence of posterior uveal melanoma is a risk factor for systemic metastasis. Vertical/diffuse recurrences may be associated more strongly with metastatic disease than horizontal/marginal recurrences.

Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma.

PURPOSE: To evaluate the influence of fraction size, overall time, total dose, and other prognostic factors on local control of T1 and T2 glottic carcinomas. METHODS AND MATERIALS: Between 1956 and 1995, 398 consecutive patients with early glottic carcinoma (315 T1 and 83 T2) were treated with once-a-day definitive radiotherapy at the University of California, San Francisco, and associated institutions. Treatment was delivered 5 days per week. Minimum tumor dose ranged from 46.6 to 77.6 Gy (median: 63 Gy). The fraction size was < 1.8 Gy in 146; 1.8-1.99 Gy in 128; 2.0-2.24 Gy in 62, and > or = 2.25 Gy in 62 patients. Overall time ranged from 34 to 75 days (median: 50 days). The majority of patients treated with a fraction size of 2.25 Gy completed therapy within 43 days. Median follow-up of all alive patients was 116 months (range 3-436 months). RESULTS: Five-year local control was 85% for T1 and 70% for T2 glottic carcinomas (p = 0.0004). For T1 lesions, within the dose and time range evaluated, there was no apparent relationship between fraction size, overall time, total dose, and local control on multivariate analysis. Treatment era was the only significant prognostic factor (p = 0.02), and anterior commissure (AC) involvement was of borderline significance (p = 0.056). Five-year local control was 77% for patients treated between 1956-1970, 89% for between 1971-1980, and 91% for between 1981-1995; 80% for patients with AC involvement and 88% for those without. For T2 lesions, prognostic factors for local control on multivariate analysis were: overall time (p = 0.003), fraction size (p = 0.003), total dose (p = 0.01), impaired vocal cord mobility (p = 0.02), and subglottic extension (p = 0.04). Five-year local control was 100% for T2 lesions treated with overall time < or = 43 days vs. 84% for overall time > 43 days; 100% for fraction size > or = 2.25 Gy vs. 44% for fraction size < 1.8 Gy; 78% for total dose > 65 Gy vs. 60% for total dose < or = 65 Gy; 79% for normal cord mobility vs. 45% for impaired cord mobility, and 58% for lesions with subglottic extension vs. 77% for those without. The severe complication rate for the entire group was low: 1.8%. CONCLUSIONS: Total dose, fraction size, and overall time were significant factors for local control of T2 but not T1 glottic carcinomas. Anterior commissure involvement was associated with decreased local control for T1 but not T2 lesions. For T1 lesions, local control improved over the treatment era. For T2 lesions, local control decreased with impaired cord mobility and subglottic extension.

Candidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy.

OBJECTIVES: Radiotherapy-induced hyposalivation encourages oral candidal colonization that often leads to oral/pharyngeal candidiasis. The purpose of this study was to quantitate oral candidal colonization, assess signs, symptoms, and response to antifungal management, speciate Candida, and evaluate the influence of smoking and dentures. STUDY DESIGN: Forty-six patients undergoing radiation therapy for oral/pharyngeal squamous cell carcinoma were evaluated clinically and by Candidal cultures before, during, and after irradiation. RESULTS: All patients complained of progressive xerostomia. There was a significant increase in the prevalence of positive candidal cultures (P = < 0.0001): baseline 43%, completion of radiotherapy 62%, and follow-up timepoint 75%. Smoking and denture wearing were not statistically significant risk factors for increased candidal colonization (p = 0.085 and p = 0.420, respectively). Eight patients developed clinical candidiasis. Although five responded clinically to systemic antifungal medication, all follow-up cultures remained positive. Candida albicans was the predominant species at baseline and completion of radiation (85% and 68%, respectively). CONCLUSIONS: When salivary glands are included in the field of radiation, xerostomia occurs, causing progressive increases in oral Candida colonization. Because 17.4% developed clinical candidiasis during radiotherapy and the question of fungal resistance remains speculative, a recommendation for the prophylactic use of antifungal medication is unresolved.

Irradiated uveal melanomas: cytopathologic correlation with prognosis.

PURPOSE: We analyzed the additional prognostic information from cytopathologic data obtained at the time of uveal melanoma irradiation. METHODS: Fine-needle aspiration biopsies (FNABs) were performed and reviewed in a masked manner. These data and standard prognostic variables were correlated with survival and local tumor recurrence using Kaplan-Meier and Cox model statistical techniques. RESULTS: Cytopathologic assessment of cell type added to prognostic accuracy. In 116 patients, the percentage of epithelioid cells on FNAB and ciliary body involvement were most strongly correlated with melanoma-related mortality. CONCLUSIONS: FNAB data improved our prognostic accuracy in irradiated uveal melanoma patients.

Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.

PURPOSE: Definitive chemoradiation (CR) has replaced radical surgery as the preferred treatment of epidermoid carcinoma of the anal canal. To determine the importance of mitomycin (MMC) in the standard CR regimen and to assess the role of salvage CR in patients who have residual tumor following CR, a phase III randomized trial was undertaken by the Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS: Between August 1988 and December 1991, 310 patients were randomized to receive either radiotherapy (RT) and fluorouracil (5-FU) or radiotherapy, 5-FU, and MMC. Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT plus 5-FU at 1,000 mg/m2/d for 4 days, and 146 received RT, 5-FU, and MMC (10 mg/m2 per dose for two doses). Patients with residual tumor on posttreatment biopsy were treated with a salvage regimen that consisted of additional pelvic RT (9 Gy), 5-FU, and cisplatin (100 mg/m2). RESULTS: Posttreatment biopsies were positive in 15% of patients in the 5-FU arm versus 7.7% in the MMC arm (P = .135). At 4 years, colostomy rates were lower (9% v 22%; P = .002), colostomy-free survival higher (71% v 59%; P = .014), and disease-free survival higher (73% v 51%; P = .0003) in the MMC arm. A significant difference in overall survival has not been observed at 4 years. Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5 toxicity; P < or = .001). Of 24 assessable patients who underwent salvage CR, 12 (50%) were rendered disease-free. CONCLUSION: Despite greater toxicity, the use of MMC in a definitive CR regimen for anal cancer is justified, particularly in patients with large primary tumors. Salvage CR should be attempted in patients with residual disease following definitive CR before resorting to radical surgery.

125I plaque therapy for uveal melanoma. Analysis of the impact of time and dose factors on local control.

BACKGROUND: 125I episcleral plaque therapy has gained wide acceptance for the treatment of uveal melanoma because of its potential to preserve vision, salvage the globe, and provide good local control. A rigorous analysis of the optimum radiation dose, dose rate, and overall treatment time has not been reported with this technique. METHODS: One hundred fifty patients with uveal melanoma treated with 125I plaques between 1982 and 1990 and included in the uveal melanoma study (UMS) database of the Wills Eye Hospital were analyzed. Mean patient age was 60.7 years (range: 17.7-84.6 years). Initial mean tumor size was 9.7 x 8.5 x 3.7 mm with a range of 4.5 to 21.5 mm in basal dimension and 1.2 to 11.8 mm in height. Mean dose to the tumor apex was 94.77 gray (Gy) (29.5-141 Gy). Mean dose rate to the tumor apex was 92.9 cGy/hr (10-292 cGy/hr); the mean dose to the base was 359 Gy (181-692 Gy); the mean dose rate to the base was 348 cGy/hr (112-893 cGy/hr); and mean duration of treatment was 124.7 hours (range: 28-333 hours) RESULTS: With a median follow-up of 68 months, there have been 33 local failures. Mean time to local failure was 19 months (range: 6-78 months). Actuarial local control is 81% at 5 years. Multivariate analysis demonstrates significant correlation of local failure with larger tumor dimension (P = 0.0046), close proximity to the optic disc (P = 0.0029), lower radiation dose to the tumor apex (P = 0.03), lower radiation dose rate to the tumor apex and base (P = 0.01 and 0.03), and longer overall treatment time (P = < 0.0001). CONCLUSIONS: This retrospective analysis reinforces the importance of dose rate, minimum tumor dose, overall treatment time, maximum tumor basal dimension, and proximity to the optic nerve in the treatment of uveal melanoma.

Final results of a phase II chemoradiation protocol for locally advanced cervical cancer: RTOG 85-15.

BACKGROUND: The lack of improved cure rates for advanced cervical cancer after three decades of megavoltage radiotherapy (RT) has prompted continued efforts in improved treatment delivery. Concurrent chemoradiation (CR) is one of the several avenues being explored to improve these results. METHODS: Sixty women with advanced cervical cancer (30 patients with unfavorable Stage IIB and 30 patients with Stages III and IVA) were treated with CR comprising of a combination of external and intracavitary RT delivering between 7000 to 7500 cGy total to point A and 5890 to 6015 cGy to point B along with one cycle of 5-FU and mitomycin C and a second cycle of 5-FU and cis-platinum. RESULTS: Grade 3 and 4 RT-related toxicities were 15 and 3%, respectively. Chemotherapy-related Grade 3 and 4 toxicities were 9 and 2%, respectively. The 5-year survival for unfavorable Stage IIB patients was 48%; for Stages III and IVA it was 39%. CONCLUSIONS: The toxicity of this particular CR regimen was acceptable and suggests that further qualitative and quantitative intensification of chemoradiation may be attempted. Retrospective comparisons with PCS studies and previous RTOG studies 79-20 and 80-05 suggest that this particular chemoradiation regimen may offer a modest survival advantage over RT alone for Stages III and IVA disease. A CR regimen with higher doses of radiotherapy and a greater number of active chemotherapeutic agents may yet result in acceptable toxicity and further improve cure rates in advanced and poor prognostic featured cervical cancer.

Long term visual outcome of radiated uveal melanomas in eyes eligible for randomisation to enucleation versus brachytherapy.

AIMS: To determine the long term visual outcome of patients who were eligible for randomisation to enucleation versus brachytherapy in a US collaborative ocular melanoma study (COMS) but were treated with either helium ion or 125I radioactive plaque therapy. METHOD: A retrospective analysis was performed of 426 ciliochoroidal melanomas that met COMS inclusion criteria for randomisation to enucleation versus radioactive plaque but were treated with either helium ions or 125I brachytherapy. RESULTS: At 3 years 36.0% of eyes had 6/12 or better visual acuity. The length of visual retention was most dependent on tumour thickness, tumour location with respect to the optic nerve, fovea, or ciliary body, and patient age. In addition to these factors, the retention of 6/12 visual acuity and the time to 6/120 visual acuity were dependent on the preoperative visual acuity. The risk of visual loss was greatest immediately after treatment and decreased with time. The 5 year actuarial metastatic rate was approximately 13%. Patients at the greatest risk of post-radiation visual loss had significantly greater risk of tumour related mortality. CONCLUSIONS: Some patients who would have been eligible for randomisation to either enucleation or radioactive plaque therapy can be irradiated with retention of excellent vision.

31P magnetic resonance spectroscopy after combined hyperthermia and radiation.

Mechanisms of uveal melanoma response to therapy are poorly understood. There are a paucity of changes that have been detected immediately after tumor treatment to differentiate successful from ineffective therapy. In this study we used in vivo 31P magnetic resonance spectroscopy (MRS) to assess intra-tumor treatment alterations. The metabolic consequences of effective and ineffective levels of solitary hyperthermia and combined hyperthermia-radiation were investigated. We have previously noted a characteristic 31P MRS pattern with successful hyperthermia in this intraocular melanoma model. The metabolic response after effective or ineffective combined radiation/hyperthermia therapy was indistinguishable from solitary radiation therapy and opposite to that with successful hyperthermia therapy. In contrast to solitary hyperthermia therapy, early changes in 31P spectral ratios following radiation or combined hyperthermia/radiation therapy of uveal melanoma were not predictive of treatment response. Twenty-four to 48 hours after effective or ineffective radiation or combined treatment the Pi/beta-NTP ratio decreased significantly (delta Pi/beta-NTP = -0.433 +/- 0.08 and -0.478 +/- .13 and .10 +/- 0.2, respectively). There was over a 2.0 thermal enhancement of radiation with heat. The increased tumor cell death after combined therapy was reflected by a two-fold larger decrease in beta-NTP signal-to-noise (S/N).

Irradiation of the cervix uteri: value of unenhanced and contrast-enhanced MR imaging.

PURPOSE: To analyze the value of magnetic resonance (MR) imaging after radiation therapy for cancer of the cervix. MATERIALS AND METHODS: Eighty-nine MR images were retrospectively studied in 69 patients aged 46.3 years +/- 11.5. MR findings of tumor recurrence and irradiation changes were correlated with time after radiation therapy; paracentral radiation dose (dose to point A); and in patients with pretreatment images, primary tumor size and stage. RESULTS: Overall accuracy of MR in diagnosis of tumor recurrence was 78% (positive predictive value, 65%; negative predictive value, 97%). In MR examinations less than 6 months after the beginning of radiation therapy, accuracy (69%) and specificity (46%) were significantly lower than in examinations more than 6 months later (88%, P = .0032; 81%, P = .0166, respectively). Comparison of pre- and posttreatment MR findings and knowledge of stage or initial tumor size did not affect MR results. CONCLUSION: Overall, diagnosis was best with unenhanced T2-weighted images, but in patients with adnexal or pelvic sidewall recurrence and in patients with treatment complications (eg, fistula formation), contrast enhancement did help.

Carcinoma of the cervix: predictive value of clinical and magnetic resonance (MR) imaging assessment of prognostic factors.

PURPOSE: This retrospective study assesses the predictive value of magnetic resonance imaging (MRI) to identify high risk cervical cancer patients. METHODS AND MATERIALS: The MRI evaluation of morphologic risk factors in patients with invasive cervical carcinoma treated with definitive radiation therapy were correlated with clinical factors and with complete tumor regression (CTR) at 6 months, tumor local control (TLC), and patient outcome at 12 months after irradiation. Sixty-six patients, median age 44.5 years, with bulky Stage I or greater disease were included in the study. RESULTS: In univariate analysis, clinical International Federation of Gynecology and Obstetrics (FIGO) stage had significant correlation with patient outcome, but it correlated poorly with complete tumor regression and tumor local control. In contrast, MRI stage showed significant correlation with complete tumor regression, tumor local control, and disease-free survival at 12 months. When each stage was analyzed separately, the greatest difference was demonstrated between clinical and MRI assignment of stage Ib disease. MRI Stage Ib disease significantly correlated with all three categories analyzed, while clinical Stage Ib did not. Superiority of MRI assessment of low stage disease was also evident in the detection of lymph node metastasis. Significant risk for nodal metastasis was related to tumor size greater than 4 cm, invasion of the parametria and urinary bladder, and stage of the disease. CONCLUSION: The multivariate analysis demonstrated that the most related variables in order of significance were the presence of juxta-regional and paraaortic lymph nodes, patient age, tumor size, and MRI tumor stage. This study demonstrates the value of MR imaging as an adjunct to clinical assessment of bulky invasive cervical cancer, rendering more complete assessment of morphologic risk factors important in patient prognosis.