E. Brian Butler

INTENSITY-MODULATED RADIATION THERAPY FOR PEDIATRIC MEDULLOBLASTOMA: EARLY REPORT ON THE REDUCTION OF OTOTOXICITY

PURPOSE The combination of cisplatin chemotherapy and radiation therapy for the treatment of medulloblastoma has been shown to cause significant ototoxicity, impairing a childs cognitive function and quality of life. Our purpose is to determine whether the new conformal technique of intensity-modulated radiation therapy (IMRT) can achieve lower rates of hearing loss by decreasing the radiation dose delivered to the cochlea and eighth cranial nerve (auditory apparatus). PATIENTS AND METHODS Twenty-six pediatric patients treated for medulloblastoma were retrospectively divided into two groups that received either conventional radiotherapy (Conventional-RT Group) or IMRT (IMRT Group). One hundred thirteen pure-tone audiograms were evaluated retrospectively, and hearing function was graded on a scale of 0 to 4 according to the Pediatric Oncology Groups toxicity criteria. Statistical analysis comparing the rates of ototoxicity was performed using Fishers exact test with two-tailed analysis. RESULTS When compared to conventional radiotherapy, IMRT delivered 68% of the radiation dose to the auditory apparatus (mean dose: 36.7 vs. 54.2 Gy). Audiometric evaluation showed that mean decibel hearing thresholds of the IMRT Group were lower at every frequency compared to those of the Conventional-RT Group, despite having higher cumulative doses of cisplatin. The overall incidence of ototoxicity was lower in the IMRT Group. Thirteen percent of the IMRT Group had Grade 3 or 4 hearing loss, compared to 64% of the Conventional-RT Group (p < 0.014). CONCLUSION The conformal technique of IMRT delivered much lower doses of radiation to the auditory apparatus, while still delivering full doses to the desired target volume. Our findings suggest that, despite higher doses of cisplatin, and despite radiotherapy before cisplatin therapy, treatment with IMRT can achieve a lower rate of hearing loss.

Prediction of Response to Salvage Radiation Therapy in Patients With Prostate Cancer Recurrence After Radical Prostatectomy

PURPOSE To identify factors predictive of local recurrence as defined by a complete response to salvage radiation therapy in patients whose disease recurs after radical prostatectomy. PATIENTS AND METHODS Ninety-five patients with recurrence after radical prostatectomy who were evaluated by prostatic fossa biopsies, and a subset of 49 of these patients treated with radiation for control of presumed or biopsy-proven local recurrence, were studied. RESULTS Biopsies were positive in 40 (42%) of the 95 biopsied patients. Multivariate analysis revealed that prebiopsy prostate-specific antigen (PSA) level, postrecurrence PSA doubling time, and positive digital rectal examination (DRE) of the prostatic fossa were all statistically significant predictors of a positive biopsy. For the 49 patients subsequently treated with salvage radiation therapy, the overall actuarial 3- and 5-year PSA relapse-free probabilities were 43% and 24%, respectively. Univariate analysis showed no differences in the PSA relapse-free probabilities associated with any pathologic features of the radical prostatectomy specimen, biopsy confirmation of local recurrence, or DRE of the prostatic fossa. In multivariate analysis, controlling for all other variables, preradiation PSA and postrecurrence PSA doubling time measured before radiation were the only statistically significant predictors of outcome. CONCLUSION DRE of the prostatic fossa, prebiopsy PSA, and postrecurrence PSA doubling time predict which patients will have biopsy-proven local recurrence. However, response to salvage radiation therapy is associated with postrecurrence PSA doubling time and with preradiation PSA level only. DRE of the prostatic fossa and biopsy confirmation of local recurrence are not associated with salvage radiation outcome.

Malignant meningioma: An indication for initial aggressive surgery and adjuvant radiotherapy

Malignant meningiomas constitute a rare subset of meningiomas and display a marked propensity for post-surgical recurrence. This retrospective study evaluates the various parameters which alter the recurrence rate. The records of all malignant meningioma patients treated from 1984 through 1992 were reviewed, and the time to recurrence or current patient status was determined, and the influence of various patient and disease parameters were analyzed. Thirty-eight patients were treated with 48 malignant meningioma resections performed (28 total and 20 subtotal), 25 at initial presentation and 23 for recurrent disease; 19 patients received postoperative radiotherapy. Subtypes included 32 anaplastic meningioma, 11 hemangiopericytoma, 2 meningiosarcoma, and 3 papillary meningioma. Followup ranged from 3 to 144 months, with five patients excluded from analysis. Actuarial disease free/progression free survival (DFS) at 5 years was 39% following total resection versus 0% after subtotal resection (p=0.001). For all totally excised lesions, the 5-yr DFS was improved from 28% for surgery alone to 57% with adjuvant radiotherapy (p=NS). Adjuvant irradiation following initial resection increased the 5-yr DFS rates from 15% to 80% (p=0.002). When administered for recurrent lesions, adjuvant radiotherapy improved the 2-yr DFS from 50% to 89% (p=0.015), but had no impact on 5-yr DFS. Multivariate analysis indicates extent of resection, adjuvant radiotherapy, and recurrence status are independent prognostic factors. Malignant meningiomas display a tendency for post surgical recurrence, with recurrence significantly increased for multicentric and recurrent disease. Complete surgical resection and the administration of adjuvant irradiation following initial resection are crucial to long-term control.

Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose–volume analysis

PURPOSE To report acute toxicity and to evaluate the relationship between dose-volume effects and acute toxicity in patients with localized prostate cancer, treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS Acute toxicity (both lower gastrointestinal [GI] and genito-urinary [GU]) in 100 patients treated with IMRT definitively to a prescribed dose of 70 Gy were assessed using RTOG scoring criteria. A rectal balloon was used for prostate immobilization. Mean doses to seminal vesicles, prostate, bladder, and rectum were recorded. Average irradiated bladder and rectal volumes above 65, 70, and 75 Gy were assessed. A relationship between dose volume and clinical toxicity was evaluated. All patients completed the full duration of acute toxicity assessment. RESULTS Mean doses to the prostate and seminal vesicles were 75.8 and 73.9 Gy. This represents a moderate dose escalation. Acute GI toxicity profile was very favorable. Eleven percent and 6% of the patients had grade 1 and 2 GI toxicity, respectively, while 83% had no GI complaint. For GU complaints, 38% and 35% had grade 1 and 2 toxicity, respectively, while 27% had no complaints. There was no grade 3 or higher acute GI or GU toxicity. Mean doses to the bladder were 22.8, 23.4, and 26.1 Gy for grade 0, 1, and 2 GU toxicity, respectively (p = 0.132). There is no statistically significant relationship between acute GU toxicity and the bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. In evaluating acute GI toxicity, there are very few grade 1 and 2 events. No relationship was found between acute rectal toxicity and mean rectal dose or irradiated rectal volumes receiving more than 65, 70, and 75 Gy. CONCLUSION The findings are important with regard to the safety of IMRT, especially in reducing acute GI toxicity. Dose escalation with IMRT using a prostate immobilization technique is feasible. The findings are also important because they contribute to the clinical and dosimetric correlation aspect in the use of IMRT to treat prostate cancer. A larger cohort may be needed to determine if there is a relationship between acute GU toxicity and (a) mean bladder dose and (b) irradiated bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. A larger cohort of patients treated to a higher dose may be needed to show a relationship between dose volume and acute GI toxicity.

Treatment of acoustic neuroma: stereotactic radiosurgery vs. microsurgery

PURPOSE Two major treatment options are available for patients with acoustic neuroma, microsurgery and radiosurgery. Our objective was to compare these two treatment modalities with respect to tumor growth control, hearing preservation, development of cranial neuropathies, complications, functional outcome, and patient satisfaction. METHODS AND MATERIALS To compare radiosurgery with microsurgery, we analyzed 96 patients with unilateral acoustic neuromas treated with Leksell Gamma Knife or microsurgery at Memorial Hermann Hospital, Houston, Texas, between 1993 and 2000. Radiosurgery technique involved multiple isocenter (1-30 single fraction fixed-frame magnetic resonance imaging) image-based treatment with a mean dose prescription of 14.5 Gy. Microsurgery included translabyrinthine, suboccipital, and middle fossa approaches with intraoperative neurophysiologic monitoring. Preoperative patient characteristics were similar except for tumor size and age. Patients undergoing microsurgery were younger with larger tumors compared to the radiosurgical group. The tumors were divided into small <2.0 cm, medium 2.0-3.9 cm, or large >4.0 cm. Median follow-up of the radiosurgical group was longer than the microsurgical group, 48 months (3-84 months) vs. 24 months (3-72 months). RESULTS There was no statistical significance in tumor growth control between the two groups, 100% in the microsurgery group vs. 91% in the radiosurgery group (p > 0.05). Radiosurgery was more effective than microsurgery in measurable hearing preservation, 57.5% vs. 14.4% (p = 0.01). There was no difference in serviceable hearing preservation between the two groups. Microsurgery was associated with a greater rate of facial and trigeminal neuropathy in the immediate postoperative period and at long-term follow-up. The rate of development of facial neuropathy was significantly higher in the microsurgical group than in the radiosurgical group (35% vs. 0%, p < 0.01 in the immediate postsurgical period and 35.3% vs. 6.1%, p = 0.008, at long-term follow-up). Similarly, the rate of trigeminal neuropathy was significantly higher in the microsurgical group than in the radiosurgical group (17% vs. 0% in the immediate postoperative period, p < 001, and 22% vs. 12.2%, p = 0.009, at long-term follow-up). There was no significant difference in exacerbation of preoperative tinnitus, imbalance, dysarthria, dysphagia, and headache. Patients treated with microsurgery had a longer hospital stay (2-16 days vs. 1-2 days, p < 0.01) and more perioperative complications (47.8% vs. 4.6%, p < 0.01) than did patients treated with radiosurgery. There was no correlation between the microsurgical approach used and postoperative symptoms. There was no difference in the postoperative functioning level, employment, and overall patient satisfaction. There was no correlation between the radiation dose, tumor size, number of isocenters used, and postoperative symptoms in the radiosurgical group. CONCLUSION Radiosurgical treatment for acoustic neuroma is an alternative to microsurgery. It is associated with a lower rate of immediate and long-term development of facial and trigeminal neuropathy, postoperative complications, and hospital stay. Radiosurgery yields better measurable hearing preservation than microsurgery and equivalent serviceable hearing preservation rate and tumor growth control.

High dose rate intracoronary radiation for inhibition of neointimal formation in the stented and balloon-injured porcine models of restenosis : Angiographic, morphometric, and histopathologic analyses

PURPOSE We examined the effects of intracoronary irradiation delivered at a high dose rate on neointimal hyperplasia after injury induced by two methods: balloon overstretch injury, and stent implantation in a porcine model of coronary restenosis. METHODS AND MATERIALS In 34 Hanford miniature swine, a segment of each coronary artery was targeted for injury and treatment. The artery segments were treated with 192Ir at doses of 10 Gy over 4 min (eight animals), 15 Gy over 6 min (nine animals), 25 Gy over 10 min (nine animals) or control (simulation wire only; eight animals). The treated segments were subjected to stent implantation (left anterior descending and right coronary artery) or balloon overstretch (circumflex) injury. Twenty-eight days later, repeat coronary angiography and sacrifice were done. Quantitative coronary angiography, morphometry, and extensive histopathologic analyses were carried out in a blinded fashion. RESULTS The change in minimal lumen diameter from postinjury to presacrifice in the stent-injured left anterior descending was -0.79 +/- 0.34 (mean: +/- SD) mm in the control group, compared to -0.43 +/- 0.35 mm in the 15 Gy (p = 0.04) and -0.21 +/- 0.50 mm in the 25 Gy (p = 0.01) groups; and in the balloon-injured circumflex was -0.31 +/- 0.22 mm in the control group compared to -0.03 +/- 0.18 mm in the 10 Gy (p = 0.05) and 0.00 +/- 0.33 in the 15 Gy (p = 0.01) groups. Percent area stenosis in the left anterior descending was 36 +/- 9% in the control group compared to 18 +/- 12% in the 15 Gy (p = 0.003) and 11 +/- 11% in the 25 Gy (p < 0.001) groups; and in the circumflex was 16 +/- 10% in the control groups, compared to 5 +/- 5% in the 15 Gy (p = 0.02) and 2 +/- 2% in the 25 Gy (p = 0.009) groups. Histopathology showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels. Other radiation effects were stromal fibrin exudate, thinning of the media, and adventitial fibrosis and leukocyte infiltration in the radiated arterial segments. CONCLUSIONS High dose rate intracoronary irradiation with 192Ir effectively inhibits intimal proliferation after stent-induced as well as balloon-overstretch injury. This shorter treatment time (4 to 10 min) may provide a clinically practical approach to the prevention of restenosis after angioplasty.

Initial experience using intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma

PURPOSE To report our initial experience on the feasibility, toxicity, and tumor control using intensity-modulated radiotherapy (IMRT) for retreatment of recurrent nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS A total of 49 patients with locoregional recurrent carcinoma in the nasopharynx were treated with IMRT between January 2001 and February 2002 at the Sun Yat-Sen University Cancer Center, Guangzhou, China. The average time to the nasopharyngeal recurrence was 30.2 months after initial conventional RT. The median isocenter dose to the nasopharynx was 70 Gy (range 60.9-78.0) for the initial conventional RT. All patients were restaged at the time of recurrence according to the 1992 Fuzhou, China staging system on NPC. The number of patients with Stage I, II, III and IV disease was 4, 9, 10, and 26, respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively. Invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the base of the skull was found in 8, 1, 3, 8, 15, and 20 patients, respectively. The gross tumor volume (GTV) was contoured according to the International Commission on Radiation Units and Measurements (ICRU) Report 62 guidelines. The critical structures were contoured, and the doses to critical structures were constrained according to ICRU 50 guidelines. The GTV in the nasopharynx and positive lymph nodes in the neck received a prescription dose of 68-70 Gy and 60 Gy, respectively. All patients received full-course IMRT. Three patients who had positive lymph nodes were treated with five to six courses of chemotherapy (cisplatin + 5-fluorouracil) after IMRT. RESULTS The treatment plans showed that the percentage of GTV receiving 95% of the prescribed dose (V(95-GTV)) was 98.5%, and the dose encompassing 95% of GTV (D(95-GTV)) was 68.1 Gy in the nasopharynx. The mean dose to the GTV was 71.4 Gy. The average doses of the surrounding critical structures were much lower than the tolerable thresholds. At a median follow-up of 9 months (range 3-13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen at the completion of IMRT, but had achieved a complete response at follow-up. Three patients developed metastases at a distant site: two in the bone and one in the liver and lung at 13 months follow-up. Acute toxicity (skin, mucosa, and xerostomia) was acceptable according to the Radiation Therapy Oncology Group criteria. Tumor necrosis was seen toward the end of IMRT in 14 patients (28.6%). CONCLUSION The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial conventional RT. This is the first large series using IMRT to reirradiate local recurrent NPC after initial RT failed. The treatment-related toxicity profile was acceptable. The initial tumor response/local control was also very encouraging. In contrast to primary NPC, recurrent NPC reirradiated with high-dose IMRT led to the shedding of tumor necrotic tissue toward the end of RT. More patients and longer term follow-up are warranted to evaluate late toxicity and treatment outcome.

Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme

PURPOSE A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. METHODS AND MATERIALS Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of >/=70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. RESULTS Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. CONCLUSION This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.

INTENSITY-MODULATED RADIATION THERAPY (IMRT) FOR MENINGIOMA

PURPOSE To assess the safety and efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of intracranial meningioma. METHODS AND MATERIALS Forty patients with intracranial meningioma (excluding optic nerve sheath meningiomas) were treated using IMRT with the NOMOS Peacock system between 1994 and 1999. Twenty-five patients received IMRT after surgery either as adjuvant therapy for incomplete resection or for recurrence, and 15 patients received definitive IMRT after presumptive diagnosis based on imaging. Thirty-two patients had skull base lesions, and 8 had nonskull base lesions. The prescribed dose ranged from 40 to 56 Gy (median 50.4 Gy) at 1.71 to 2 Gy per fraction, and the volume of the primary target ranged from 1.55 to 324.57 cc (median 20.22 cc). The mean dose to the target ranged from 44 to 60 Gy (median 53 Gy). Follow-up ranged from 6 to 71 months (median 30 months). Acute and chronic toxicity were assessed using Radiation Therapy Oncology Group (RTOG) morbidity criteria and tumor response was assessed by patient report, examination, and imaging. Overall survival, progression-free survival, and local control were calculated using the Kaplan-Meier method. RESULTS Cumulative 5-year local control, progression-free survival, and overall survival were 93%, 88%, and 89%, respectively. Two patients progressed after IMRT, one locally and one distantly. Each was treated with IMRT after multiple recurrences of benign meningioma over many years. Both were found to have malignant meningioma at the time of relapse after IMRT, and it is likely their tumors had already undergone malignant change by the time IMRT was given. Defined normal structures generally received a significantly lower dose than the target. The most common acute central nervous system (CNS) toxicity was mild headache, usually relieved with steroids. One patient experienced RTOG Grade 3 acute CNS toxicity, and 2 experienced Grade 3 or higher late CNS toxicity, with one possible treatment-related death. No toxicity was observed with mean doses to the optic nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy. CONCLUSION IMRT is a promising new technology that is safe and efficacious in the primary and adjuvant treatment of intracranial meningiomas. A history of local aggression may indicate malignant degeneration and predict a poorer outcome. Toxicity data are encouraging, but the potential for serious side effects exists, as demonstrated by one possible treatment-related death. Larger cohort and longer follow-up are needed to better define efficacy and late toxicity of IMRT.

Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report.

PURPOSE To report the preliminary results of a Phase I/II study combining radiotherapy and in situ gene therapy (adenovirus/herpes simplex virus thymidine kinase gene/valacyclovir) with or without hormonal therapy in the treatment of prostate cancer. METHODS AND MATERIALS Arm A: low-risk patients (T1-T2a, Gleason score <7, pretreatment PSA <10) were treated with combined radio-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated radiotherapy. Arm B: high-risk patients (T2b-T3, Gleason score >or=7, pretreatment PSA >or=10) were treated with combined radio-gene therapy and hormonal therapy. Hormonal therapy was comprised of a 4-month leuprolide injection and 2-week use of flutamide. Arm C: Stage D1 (positive pelvic lymph node) patients received the same regimen as Arm B, with the additional 45 Gy to the pelvic lymphatics. Treatment-related toxicity was assessed using Cancer Therapy Evaluation Program common toxicity score and Radiation Therapy Oncology Group (RTOG) toxicity score. RESULTS Thirty patients (13 in Arm A, 14 in Arm B, and 3 in Arm C) completed the trial. Median follow-up was 5.5 months. Eleven patients (37%) developed flu-like symptoms (Cancer Therapy Evaluation Program Grade 1) of fatigue and chills/rigors after gene therapy injection but recovered within 24 h. Four patients (13%) and 2 patients (7%) developed Grade 1 and 2 fever, respectively. There was no patient with weight loss. One patient in Arm B developed Grade 3 elevation in liver enzyme, whereas 11 and 2 patients developed Grade 1 and 2 abnormal liver function tests. There was no Grade 2 or above hematologic toxicity. Three patients had transient rise in creatinine. There was no RTOG Grade 3 or above lower gastrointestinal toxicity. Toxicity levels were as follows: 4 patients (13%), Grade 2; 6 patients (20%), Grade 1; and 20 patients (67%), no toxicity. There was 1 patient with RTOG Grade 3 genitourinary toxicity, 12 patients (40%) with Grade 2, 8 patients (27%) with Grade 1, and 9 patients (30%) with no toxicity. No patient dropped out from the trial or had to withhold treatment because of severe toxicity. CONCLUSIONS This is the first trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of radiotherapy by combining in situ gene therapy. Initial experience has demonstrated the safety of this approach. There is no added toxicity to each therapy used alone. Long-term follow-up and larger cohort studies are warranted to evaluate long-term toxicity and efficacy.