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: PurposeThere is an evolving role for combining radiotherapy (RT) with gene therapy in the management of prostate cancer. However, the clinical results of this combined approach are much needed. The preliminary results addressing the safety of this Phase I-II study combining RT and gene therapy (adenovirus/herpes simplex virus-thymidine kinase gene/valacyclovir with or without hormonal therapy) in the treatment of prostate cancer have been previously reported. We now report the prostate-specific antigen (PSA) response and biopsy data.: Methods and materialsThis trial was composed of three separate arms. Arm A consisted of low-risk patients (Stage T1-T2a, Gleason score <7, pretreatment PSA <10 ng/mL) treated with combined RT-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated RT. They also received adenovirus/herpes simplex virus-thymidine kinase/valacyclovir gene therapy. Arm B consisted of high-risk patients (Stage T2b-T3, Gleason score >6, pretreatment PSA level >10 ng/mL) treated with combined RT-gene therapy and hormonal therapy (luteinizing hormone-releasing hormone agonist [30-mg Lupron, 4-month depot] and an antiandrogen [flutamide, 250 mg t.i.d. for 14 days]). Arm C consisted of patients with Stage D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition of 45 Gy to the pelvic lymphatics. PSA determination and biopsy were performed before, during, and after treatment. The American Society for Therapeutic Radiology and Oncology consensus definition (three consecutive rises in PSA level) was used to denote PSA failure.: ResultsFifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in Arm C) completed the trial. The median age was 68 years (range, 39–85 years). The median follow-up for the entire group was 13.5 months (range, 1.4–27.8 months). Only Arm A patients were observed to have an increase in PSA on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B (median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the RT portal. Six to twelve prostate biopsies performed in these 3 patients revealed no evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% (18 of 27), 92.3% (24 of 26), 91.7% (11 of 12), 100% (8 of 8), and 100% (6 of 6) at 6 weeks, 4 months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, no evidence of carcinoma on biopsy was noted in 96% (24 of 25), 90.5% (19 of 21), 100% (14 of 14), 100% (7 of 7), and 100% (2 of 2), respectively, in the same interval after treatment.: ConclusionThis is the first reported trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of RT by combining it with in situ gene therapy. The initial transient PSA rise in the Arm A patients may have been a result of local immunologic response or inflammation elicited by in situ gene therapy. Additional investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. The biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control. [Copyright &y& Elsevier]

: PurposeA 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 materialsTwenty 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.: ResultsOf 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.: ConclusionThis 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. [Copyright &y& Elsevier]

: PurposeTo 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 materialsA 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.: ResultsThe treatment plans showed that the percentage of GTV receiving 95% of the prescribed dose (V95-GTV) was 98.5%, and the dose encompassing 95% of GTV (D95-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%).: ConclusionThe 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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Purpose: The advent of widespread prostate-specific antigen screening has resulted in more younger, potent men being diagnosed with early-stage, organ-confined prostate cancer amenable to definitive surgery. Nerve-sparing prostatectomy is a relatively new surgical advance in the treatment of prostate cancer. Very few data exist on the effect of postoperative radiotherapy (RT) on erectile function after nerve-sparing prostatectomy. They are based on conventional techniques using moderate doses of radiation, 45–54 Gy. Intensity-modulated RT (IMRT) is becoming more widespread because it allows dose escalation with increased sparing of the surrounding normal tissue. We investigated the effect of postprostatectomy, high-dose IMRT on patients’ erectile function.Methods and Materials: A review of patient records found 51 patients treated between April 1998 and December 2000 with IMRT after unilateral or bilateral nerve-sparing prostatectomy. The pathologic disease stage in these patients was T2 in 47.4% and T3 in 52.6%. Postoperatively, 4 patients received hormonal ablation consisting of one injection of Lupron Depot (30 mg) 2 months before RT. The median age was 65 years (range 46–77) at the time of RT. The prescribed dose was 64 Gy (range 60–66). The mean dose was 69.6 Gy (range 64.0–72.3). Erectile function was assessed before and after RT by questionnaires. Sexual potency was defined as erectile rigidity adequate for vaginal penetration.Results: Of the 51 patients, 18 (35.3%) maintained their potency and 33 (64.7%) became impotent after nerve-sparing prostatectomy. Patients who underwent bilateral nerve-sparing prostatectomy had higher rates of postoperative potency than did those who underwent unilateral nerve-sparing surgery (72.2% vs. 27.8%; p = 0.025). The follow-up for the entire group was 19.5 months. All 18 patients (100%) who were potent postoperatively remained potent after RT. The median follow-up for the 18 potent patients was 27.2 months, significantly longer than that of the impotent group, 13.0 months (p <0.001).Conclusion: This is the first report on the effects of dose-escalated IMRT on men who have undergone nerve-sparing prostatectomy. Despite the high dose (mean dose 69.6 Gy) to the prostate bed and nerves, postoperative IMRT had no negative effect on erectile function for the patients who remained potent after nerve-sparing prostatectomy. Longer term follow-up and a larger cohort of patients are warranted to confirm these findings. [Copyright &y& Elsevier]

The implementation of intensity-modulated radiation therapy (IMRT) is the result of advances in imaging, radiotherapy planning technologies, and computer-controlled linear accelerators. IMRT allows both conformal treatment of tumors and conformal avoidance of the surrounding normal structures. The first patient treated with Peacock IMRT at Baylor College of Medicine took place in March 1994. To date, more than 1500 patients have been treated with IMRT; more than 700 patients were treated for prostate cancer. Our experience in treating prostate cancer with IMRT was reviewed. Patient and prostate motions are important issues to address in delivering IMRT. The Vac-Lok bag-and-box system, as well as rectal balloon for immobilization of patient and prostate gland, respectively, are employed. Treatment planning also plays a very important role. IMRT as a boost after conventional external beam radiotherapy is not our treatment strategy. To derive maximal benefits with this new technology, all patients received full course IMRT. Three separate groups of patients receiving (1) primary IMRT, (2) combined radioactive seed implant and IMRT, and (3) post-prostatectomy IMRT were addressed. Overall, toxicity profiles in these patients were very favorable. IMRT has the potential to improve treatment outcome with dose escalation while minimizing treatment-related toxicity. [Copyright &y& Elsevier]

Purpose: The combination of cisplatin chemotherapy and radiation therapy for the treatment of medulloblastoma has been shown to cause significant ototoxicity, impairing a child’s 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 Group’s toxicity criteria. Statistical analysis comparing the rates of ototoxicity was performed using Fisher’s 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. [Copyright &y& Elsevier]

Objective. The presence of nodal metastases is the most important prognostic factor in cervical cancer. To adjust our therapy based on the true extent of the patient''s disease, we performed an extraperitoneal lymph node dissection (EPLND) in all patients with cervical cancer prior to radiotherapy (RT) or radical hysterectomy.Methods. Thirty-three patients with carcinoma of the cervix underwent EPLND. The value of this procedure as a diagnostic tool for monitoring the extension of the disease was determined. Additionally, EPLND/RT-associated treatment complications were monitored.Results. The combined treatment approach of EPLND with RT or chemotherapy/RT was without major complications. Nineteen patients showed a temperature elevation, but only one patient had a fever of greater than 39.0°C. Fourteen (48.3%) of 29 patients experienced some degree of proctitis or diarrhea and 3 (10.3%) experienced cystitis during the course of RT. No grade 3 or 4 acute or late genitourinary or gastrointestinal toxicities were noted. EPLND changed the clinical management for 6 patients from a radical hysterectomy to RT and for 7 patients from standard-field RT to extended-field RT. Without EPLND these 7 patients would have received RT with standard pelvic fields that would not have treated involved lymph node areas at high risk for subsequent failure.Conclusion. Thirteen (44.8%) of 29 patients received a different treatment than would otherwise have been administered with standard treatment planning. Therefore, we suggest that EPLND should be performed in all patients with cervical cancer prior to radical surgery or RT. [Copyright &y& Elsevier]

Purpose: To evaluate the predictors of xerostomia in the treatment of head-and-neck cancers treated with intensity-modulated radiation therapy (IMRT), using the simultaneous modulated accelerated radiation therapy (SMART) boost technique. Dosimetric parameters of the parotid glands are correlated to subjective salivary gland function., Materials and Methods: Between January 1996 and June 2000, 30 patients with at least 6 months follow-up were evaluated for subjective xerostomia after being treated definitively for head-and-neck cancer with the SMART boost technique. Threshold limits for the ipsilateral and contralateral parotid glands were 35 Gy and 25 Gy, respectively. Dosimetric parameters to the parotid glands were evaluated. The median follow-up time was 38.5 months (mean 39.9 months). The results of the dosimetric parameters and questionnaire were statistically correlated., Results: Xerostomia was assessed with a 10-question subjective salivary gland function questionnaire. The salivary gland function questionnaire (questions 1, 2, 3, 4, 6, and 9) correlated significantly with the dosimetric parameters (mean and maximum doses and volume and percent above tolerance) of the parotid glands. These questions related to overall comfort, eating, and abnormal taste. Questions related to thirst, difficulty with speech or sleep, and the need to carry water daily did not correlate statistically with the dosimetric parameters of the parotid glands., Conclusions: Questions regarding overall comfort, eating, and abnormal taste correlated significantly with the dosimetric parameters of the parotid glands. Questions related to thirst, difficulty with speech or sleep, and the need to carry water daily did not correlate statistically with the dosimetric parameters of the parotid glands. Dosimetric sparing of the parotid glands improved subjective xerostomia. IMRT in the treatment of head-and-neck cancer can be exploited to preserve the parotid glands and decrease xerostomia. This is feasible even with an accelerated treatment regimen like the SMART boost. More patients need to be evaluated using IMRT to identify relevant dosimetric parameters.

Purpose: The intensity-modulated radiation therapy (IMRT) treatment planning system generates tightly constricted isodose lines. It is very important to define the margins that are acceptable in the treatment of prostate cancer to maximize the dose escalation and normal tissue avoidance advantages offered by IMRT. It is necessary to take into account subclinical disease and the potential for extracapsular spread. Organ and patient motion as well as setup errors are variables that must be minimized and defined to avoid underdosing the tumor or overdosing the normal tissues. We have addressed these issues previously. The purpose of the study was twofold: to quantify the radial distance of extracapsular extension in the prostatectomy specimens, and to quantify differences between the pathologic prostate volume (PPV), CT-based gross tumor volume (GTV), and planning target volume (PTV)., Materials and Methods: Two related studies were undertaken. A total of 712 patients underwent prostatectomy between August 1983 and September 1995. Pathologic assessment of the radial distance of extracapsular extension was performed. Shrinkage associated with fixation was accounted for with a linear shrinkage factor. Ten patients had preoperative staging studies including a CT scan of the pelvis. The GTV was outlined and volume determined from these CT scans. The PTV, defined as GTV with a 5-mm margin in all dimensions, was then calculated. The Peacock inverse planning system (NOMOS Corp., Sewickley, PA) was used. The PPV, GTV, and PTV were compared for differences and evaluated for correlation., Results: Extracapsular extension (ECE) (i.e., prostatic capsular invasion level 3 [both focal and established]) was found in 299 of 712 patients (42.0%). Measurable disease extending radially outside the prostatic capsule (i.e., ECE level 3 established) was noted in 185 of 712 (26.0%). The median radial extension was 2.0 mm (range 0.50-12.00 mm) outside the prostatic capsule. As a group, 20 of 712 (2.8%) had extracapsular extension of more than 5 mm. In the volumetric comparison and correlation study of the GTV and PTV to the PPV, the average GTV was 2 times larger than the PPV. The average PTV was 4.1 times larger than the PPV., Conclusions: This is the largest series in the literature quantitatively assessing prostatic capsular invasion (i.e., the radial extracapsular extension). It is the first report of a comparison of PPV to CT-planned GTV and PTV. Using patient and prostate immobilization, 5 mm of margin to the GTV in this study provided sufficient coverage of the tumor volume based on data gathered from 712 patients. In the absence of prostate immobilization, additional margins of differing amounts depending on the technique employed would have to be placed to account for target, patient, and setup uncertainties. The large mean difference between CT-based estimates of the tumor volume and target volume (GTV+PTV) and PPV added further evidence for adequacy of tumor coverage. Target immobilization, setup error, and coverage of subclinical disease must be addressed carefully before successful implementation of IMRT to maximize its ability to escalate dose and to spare normal tissue simultaneously and safely.

Purpose: The combination of cisplatin chemotherapy and radiation therapy for the treatment of medulloblastoma has been shown to cause significant ototoxicity, impairing a child's 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 Group's toxicity criteria. Statistical analysis comparing the rates of ototoxicity was performed using Fisher's 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.