Salvage intensity modulated radiotherapy using endorectal balloon after radical prostatectomy: clinical outcomes.

OBJECTIVES: To evaluate biochemical non-evidence of disease and adverse events of salvage intensity-modulated radiotherapy using an endorectal balloon for prostate cancer patients after radical prostatectomy. METHODS: Data of 107 patients (median age 65 years) with persistent (>0.1 ng/mL) or rising prostate-specific antigen after radical prostatectomy were retrospectively analyzed. The mean dose to clinical target volume was 70 Gy in 32 fractions (the equivalent dose in 2 Gy fraction is 73.2 Gy based on α:ß = 2). Biochemical non-evidence of disease and predictive factors were assessed. Genitourinary toxicity and gastrointestinal toxicity were also evaluated using the Radiation Therapy Oncology Group toxicity criteria. RESULTS: The median follow up was 37 months (range 6-126 months). A total of 48 patients developed biochemical recurrence. The 3- and 5-year biochemical non-evidence of disease rates of all patients were 52.6% and 48.8%, respectively. The Gleason score (≥4 + 3, ≤3 + 4) and pre-intensity-modulated radiotherapy prostate-specific antigen level (≥0.5 ng/mL, <0.5 ng/mL) were significant predictive factors for biochemical non-evidence of disease in univariate analysis. In multivariate analysis, only the Gleason score was detected as a significant variable. The highest late genitourinary toxicities were grade 2 in 13% and grade 3 in 6% of patients. The highest late gastrointestinal toxicities were grade 2 in 6% and grade 3 in 3% of patients. CONCLUSION: Despite a relatively high radiation dose, intensity-modulated radiotherapy with an endorectal balloon can be delivered with acceptable toxicity and efficacy for patients developing biochemical recurrence after radical prostatectomy.

Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy.

AIMS: To analyse the outcomes and to evaluate the prognostic factors involved in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: A retrospective analysis of 239 NPC patients with local recurrence who were re-irradiated with IMRT between 2001 and 2008 was conducted. The distribution of disease re-staging was 5.4% for stage I, 18.4% for stage II, 29.7% for stage III and 46.4% for stage IV. Cisplatin-based chemotherapy was administered to 117 patients (49.0%) in addition to the IMRT. RESULTS: The mean D(95) and the V(95) of the gross tumour volume (GTV) were 66.78 Gy and 98.61%, respectively. The mean dose to the GTV was 70.04 Gy (61.73-77.54 Gy). The 5 year overall survival, local recurrence-free survival, distant metastasis-free survival and disease-free survival were 44.9, 85.8, 80.6 and 45.4%, respectively. In a univariate analysis, patient age, recurrent T (rT), recurrent N (rN), recurrent stage, tumour volume, mean dose and mean fractional dose of the GTV were significant prognostic factors for overall survival. In a multivariate analysis, only patient age, rN stage, recurrent stage, mean fractional dose and tumour volume remained significant for overall survival. CONCLUSIONS: Re-irradiation using IMRT is available to improve local tumour control and to prolong patients' survival. A smaller tumour volume, higher fractional dose, younger patient ages, lower rN(0) stage and early recurrent stage are all independent prognostic factors for overall survival of recurrent NPC. It is of clinical importance to select the appropriate recurrent NPC cases for salvage re-irradiation by IMRT.

Endoscopic microwave coagulation therapy for early recurrent T1 nasopharyngeal carcinoma.

The result of reirradiation in recurrent T1 (rT1) nasopharyngeal carcinoma (NPC) is unsatisfactory. We sought to study the efficacy and complications of endoscopic microwave coagulation therapy (MCT) in salvaging rT1 NPC after primary radiotherapy. Between August 1994 and April 2005, 55 patients with rT1 NPC were treated with endoscopic MCT. With a median follow-up of 102.1 months, 52 of 55 patients are still alive. Five patients had local failure after retreatment. The overall survival and local progression-free survival were 100% (95% CI, 99.4% to 100%) and 94.5% (95% CI, 94.1% to 94.9%) at 2 years, respectively, and 93.6% (95% CI, 93.5% to 94.4%) and 90.7% (95% CI, 90.2% to 91.2%) at 5 years. The common complications of endoscopic MCT were mild postoperative pain and headache. Nasopharyngeal necrosis was transient in one patient and subsided in 1 month. Endoscopic MCT achieved significant survival and tumour control without severe complications in selective rT1 NPC.

[Endoscopic microwave coagulation therapy for locally recurrent nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Management of locally recurrent nasopharyngeal carcinoma (NPC) is difficult. External beam re-irradiation could cure some patients but might cause severe radiation injury. This study was to evaluate the clinical value of endoscopic microwave coagulation therapy as salvage treatment for locally recurrent NPC. METHODS: Between Aug. 1994 and Apr. 2005, 55 patients with locally recurrent NPC (stage rT1) were treated with endoscopic microwave coagulation therapy. Local progression-free and overall survival were observed. RESULTS: The median follow-up was 102.1 months (range, 22.4-153.9 months). The median time from last irradiation to recurrence was 22.1 months (range, 6.5-125.6 months). Five patients had local failure. The 5-year local progression-free and overall survival rates were 90.7% and 93.6%, respectively. No patient had intraoperative complications. One patient had nasopharyngeal necrosis after operation, and was healed after one month. CONCLUSIONS: Endoscopic microwave coagulation therapy is effective without severe complications in locally recurrent NPC patients. It is a minimally invasive therapy for recurrent NPC.

Preliminary report of the effect of high-dose adjuvant intensity modulated radiation therapy on the sural nerve graft for cavernosal nerve sacrifice after radical prostatectomy.

PURPOSE: A sural nerve graft may replace a killed cavernosal nerve. The effect of intensity-modulated radiation therapy (IMRT) on function of the graft has not been reported. MATERIALS AND METHODS: Between 1998 and 2001, 8 patients (9 nerve grafts) were treated with postoperative IMRT (mean dose, 70 Gy). Two patients had neoadjuvant Lupron 30 mg 2 months prior to radiation. Potency was defined as ability to achieve spontaneous erection sufficient for vaginal penetration. Median follow-up was 31.6 months. RESULTS: Five patients (62.5%) who had erectile function after prostatectomy preserved spontaneous erectile function after radiation. Of these, 3 patients had both nerves resected (two receiving unilateral grafts and one receiving bilateral grafts) and 2 others had one graft and one nerve preserved. The impotent patients were impotent after surgery. CONCLUSION: High-dose postprostatectomy IMRT does not place sural nerve grafts at greater risk for failure. Larger numbers of patients are needed to confirm these encouraging, preliminary findings.

Radiation proctopathy in the treatment of prostate cancer.

PURPOSE: To compile and review data on radiation proctopathy in the treatment of prostate cancer with respect to epidemiology, clinical manifestations, pathogenesis, risk factors, and treatment. METHODS: Medical literature databases including PubMed and Medline were screened for pertinent reports, and critically analyzed for relevance in the scope of our purpose. RESULTS: Rectal toxicity as a complication of radiotherapy has received attention over the past decade, especially with the advent of dose-escalation in prostate cancer treatment. A number of clinical criteria help to define acute and chronic radiation proctopathy, but lack of a unified grading scale makes comparing studies difficult. A variety of risk factors, related to either radiation delivery or patient, are the subject of intense study. Also, a variety of treatment options, including medical therapy, endoscopic treatments, and surgery have shown varied results, but a lack of large randomized trials evaluating their efficacy prevents forming concrete recommendations. CONCLUSION: Radiation proctopathy should be an important consideration for the clinician in the treatment of prostate cancer especially with dose escalation. With further study of possible risk factors, the advent of a standardized grading scale, and more randomized trials to evaluate treatments, patients and physicians will be better armed to make appropriate management decisions.

Long-term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins.

PURPOSE: The benefit of adjuvant radiotherapy after prostatectomy for patients with pathological risk factors but with an undetectable postoperative PSA remains controversial. In this retrospective study we define the benefits of elective postoperative radiotherapy in this setting. MATERIALS AND METHODS: A total of 44 patients received elective postoperative radiotherapy at a single institution in the PSA era (1989 to 1995) for positive surgical margins and undetectable postoperative PSA. Radiotherapy was delivered to a median dose of 60 Gy. Clinical target volume included the prostate bed. Pelvic nodes were not treated. The four-field box technique with customized blocking of bladder, rectum and small bowels was used and defined the planning target volume. The patients were then compared to a contemporaneous group of 189 patients with positive surgical margins who underwent radical prostatectomy without any adjuvant therapy. Failure was defined as biochemical (PSA) recurrence and was timed from first detectable PSA. RESULTS: The 5 and 10-year biochemical no evidence of disease was 90.9% and 90.9% for the elective postoperative radiotherapy group, and 66.4% and 54.5% for the observation group, respectively (p = 0.0012). Median time to biochemical failure was also longer in the elective postoperative radiotherapy group (88.6 months) compared to the observation group (43.5 months) (p <0.001). Risk factors for biochemical recurrence on multivariate analysis were Gleason score greater than 7 (p = 0.017), established extracapsular extension (p = 0.002) and lack of elective postoperative radiation (p = 0.001). CONCLUSIONS: This is one of the longest followup studies showing that elective postoperative radiation therapy is associated with improved bNED and prolonged time to recurrence. Combined radical prostatectomy and elective postoperative radiotherapy should be considered in the management of high risk prostate cancer, especially in the presence of positive surgical margins despite undetectable PSA.

Sustained long-term immune responses after in situ gene therapy combined with radiotherapy and hormonal therapy in prostate cancer patients.

PURPOSE: To explore long-term immune responses after combined radio-gene-hormonal therapy. METHODS AND MATERIALS: Thirty-three patients with prostate specific antigen 10 or higher or Gleason score of 7 or higher or clinical stage T2b to T3 were treated with gene therapy that consisted of 3 separate intraprostatic injections of AdHSV-tk on Days 0, 56, and 70. Each injection was followed by 2 weeks of valacyclovir. Intensity-modulated radiation therapy was delivered 2 days after the second AdHSV-tk injection for 7 weeks. Hormonal therapy was initiated on Day 0 and continued for 4 months or 2.3 years. Blood samples were taken before, during, and after treatment. Lymphocytes were analyzed by fluorescent antibody cell sorting (FACS). RESULTS: Median follow-up was 26 months (range, 4-48 months). The mean percentages of DR+CD8+ T cells were increased at all timepoints up to 8 months. The mean percentages of DR+CD4+ T cells were increased later and sustained longer until 12 months. Long-term (2.3 years) use of hormonal therapy did not affect the percentage of any lymphocyte population. CONCLUSIONS: Sustained long-term (up to 8 to 12 months) systemic T-cell responses were noted after combined radio-gene-hormonal therapy for prostate cancer. Prolonged use of hormonal therapy does not suppress this response. These results suggest the potential for sustained activation of cell-mediated immune responses against cancer.

Tolerance of endorectal balloon in 396 patients treated with intensity-modulated radiation therapy (IMRT) for prostate cancer.

PURPOSE: To report patient tolerance and acute anorectal toxicity of an endorectal balloon used for prostate immobilization during 35 daily fractions. MATERIALS AND METHODS: The records of 396 patients treated for prostate cancer from October 1997 to November 2001 were reviewed. Patients were treated with intensity modulated radiation therapy (IMRT). Endorectal balloon catheter was inserted daily, inflated with 100 mL of air for immobilizing the prostate gland. Patient and treatment factors were analyzed. Patients received a mean dose of 77 Gy/35 fractions/7 weeks with no rectal block. RESULTS: None of the 396 patients halted treatment because of associated ano-rectal toxicity. No patient stated that he would decline to be treated again with rectal balloon. Three of 396 (0.8%) patients required a reduction in the volume of the balloon to 50 mL. Seventeen of 396 (4.3%) patients required Lidocaine jelly with the insertion of balloon. Radiation Therapy Oncology Group (RTOG) grades 1 and 2 rectal toxicity occurred in 55/396 (13.9%) and 73/396 (18.4%), respectively. No RTOG grade 3 or 4 toxicities occurred. Topical anal medications were prescribed for 46 of 396 (11.6%) patients and antidiarrhea medication for 27 of 396 (6.8%) patients. Of patients with pretreatment anorectal disease, 50% developed rectal toxicities over the 7 weeks. Rectal toxicity occurred most frequently in the third, fourth, fifth, or sixth week; 19.5%, 20.8%, 18.2%, and 16.9%, respectively. The duration of the toxicity measured lasted 1 week, 35.2%; 2 weeks, 31.0%; 3 weeks, 15.5%; 4 weeks, 11.3%; 5 weeks, 4.2%; and 6 weeks, 2.8%. CONCLUSION: Most of the patients, 393/396 (99.2%), tolerated a 100 mL endorectal immobilization balloon for IMRT. The rate of acute anorectal toxicity was acceptable with no grade 3 or 4 toxicities. Duration of the toxicities typically was 1 to 2 weeks. Patients with pre-existing anorectal disease are at higher risk of developing acute anorectal toxicity with the use of an endorectal balloon.

Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.

The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.

Rectal wall sparing by dosimetric effect of rectal balloon used during intensity-modulated radiation therapy (IMRT) for prostate cancer.

The use of an air-filled rectal balloon has been shown to decrease prostate motion during prostate radiotherapy. However, the perturbation of radiation dose near the air-tissue interfaces has raised clinical concerns of underdosing the prostate gland. The aim of this study was to investigate the dosimetric effects of an air-filled rectal balloon on the rectal wall/mucosa and prostate gland. Clinical rectal toxicity and dose-volume histogram (DVH) were also assessed to evaluate for any correlation. A film phantom was constructed to simulate the 4-cm diameter air cavity created by a rectal balloon. Kodak XV2 films were utilized to measure and compare dose distribution with and without air cavity. To study the effect in a typical clinical situation, the phantom was computed tomography (CT) scanned on a Siemens DR CT scanner for intensity-modulated radiation therapy (IMRT) treatment planning. A target object was drawn on the phantom CT images to simulate the treatment of prostate cancer. Because patients were treated in prone position, the air cavity was situated superiorly to the target. The treatment used a serial tomotherapy technique with the Multivane Intensity Modulating Collimator (MIMiC) in arc treatment mode. Rectal toxicity was assessed in 116 patients treated with IMRT to a mean dose of 76 Gy over 35 fractions (2.17-Gy fraction size). They were treated in the prone position, immobilized using a Vac-Loktrade mark bag and carrier-box system. Rectal balloon inflated with 100 cc of air was used for prostate gland immobilization during daily treatment. Rectal toxicity was assessed using modifications of the Radiation Therapy Oncology Group (RTOG) and late effects Normal Tissue Task Force (LENT) scales systems. DVH of the rectum was also evaluated. From film dosimetry, there was a dose reduction at the distal air-tissue interface as much as 60% compared with the same geometry without the air cavity for 15-MV photon beam and 2x2-cm field size. The dose beyond the interface recovered quickly and the dose reductions due to air cavity were 50%, 28%, 11%, and 1% at 2, 5, 10, and 15 mm, respectively, from the distal air-tissue interface. Evaluating the dose profiles of the more clinically relevant situation revealed the dose at air-tissue interface was approximately 15% lower in comparison to that without an air cavity. The dose built up rapidly so that at 1 and 2 mm, there was only an 8% and 5% differential, respectively. The dosimetric coverage at the depth of the posterior prostate wall was essentially equal with or without the air cavity. The median follow-up was 31.3 months. Rectal toxicity profile was very favorable: 81% (94/116) patients had no rectal complaint while 10.3% (12/116), 6.9% (8/116), and 1.7% (2/116) had grade 1, 2, and 3 toxicity, respectively. There was no grade 4 rectal toxicity. DVH analysis revealed that none of the patients had more than 25% of the rectum receiving 70 Gy or greater. Rectal balloon has rendered anterior rectal wall sparing by its dosimetric effects. In addition, it has reduced rectal volume, especially posterior and lateral rectal wall receiving high-dose radiation by rectal wall distension. Both factors may have contributed to decreased rectal toxicity achieved by IMRT despite dose escalation and higher than conventional fraction size. The findings have clinical significance for future very high-dose escalation trials whereby radiation proctitis is a major limiting factor.

Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.

PURPOSE: In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or valacyclovir (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial. METHODS AND MATERIALS: The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs. RESULTS: The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p < 0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035). CONCLUSIONS: This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.

Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data.

PURPOSE: There 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 MATERIALS: This 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. RESULTS: Fifty-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. CONCLUSION: This 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.

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.

Dosimetric predictors of xerostomia for head-and-neck cancer patients treated with the smart (simultaneous modulated accelerated radiation therapy) boost technique.

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.

IMRT for prostate cancer: defining target volume based on correlated pathologic volume of disease.

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.

Predictors of extracapsular extension and its radial distance in prostate cancer: implications for prostate IMRT, brachytherapy, and surgery.

PURPOSE: Tightly constricted isodose lines are generated using brachytherapy or intensity-modulated radiation therapy (IMRT) treatment planning systems for prostate cancer. Definition of margins that encompass subclinical disease extension is important to maximize dose escalation while attemptingto adhere to normal tissue dose tolerances. In this study, we attempted to find predictors of extracapsular extension (ECE) and its radial distance. MATERIALS AND METHODS: Pathological assessment of ECE and its radial distance was performed on 712 radical prostatectomy specimens. Preoperative data (initial prostate-specific antigen, clinical stage, ultrasound volume, and biopsy Gleason score) were evaluated for their ability to predict the presence of ECE and its radial distance. RESULTS: Measurable disease was noted outside the prostatic capsule in 185 of 712 (26.0%) specimens. All preoperative parameters except ultrasound volume were able to predict the presence of ECE. However, none of them was predictive of the radial ECE distance. In this group, the median and the range of the maximum depth of invasion (radial extension from the capsule) were 2.00 and 0.5-12.00 mm, respectively. The mean radial distance from the capsule was 2.93 mm, SD +/- 2.286 mm. All subgroups had some patients with radial extension ranging from 0-2 mm, 2-5 mm, to > 5 mm. Only patients with a prostate-specific antigen of 0-4 ng/mL had no extension > 5 mm. CONCLUSIONS: This is the largest series in the literature thus far that quantitatively assesses radial extracapsular extension. Coverage of subclinical disease must be addressed carefully before successful implementation of intensity-modulated radiation therapy, brachytherapy, or prostatectomy in order to avoid geographical miss.

The use of rectal balloon during the delivery of intensity modulated radiotherapy (IMRT) for prostate cancer: more than just a prostate gland immobilization device?

PURPOSE: The purpose of this study was to investigate the role of a rectal balloon for prostate immobilization and rectal toxicity reduction in patients receiving dose-escalated intensity-modulated radiotherapy for prostate cancer. PATIENTS AND METHODS: Patients with localized prostate cancer who were undergoing intensity-modulated radiotherapy were treated in a prone position, immobilized with a customized Vac-Lok bag (MED-TEC, Orange City, IA). A rectal balloon with 100 cc of air was used to immobilize the prostate. The prostate displacements were measured using computed tomography (CT)-CT fusion on 10 patients who received radioactive seed implant before intensity-modulated radiotherapy. They were scanned twice weekly during 5 weeks of intensity-modulated radiotherapy, and breathing studies were also performed. Rectal toxicity was evaluated by use of Radiation Therapy Oncology Group scoring in 100 patients. They were treated to a mean dose of 76 Gy over 35 fractions (2.17-Gy fraction size). Dose-volume histogram of the rectum was assessed. A film phantom was constructed to simulate the 4-cm diameter air cavity that was created by the rectal balloon. Kodak XV2 films (Rochester NY) were used to measure and compare dose distribution with and without the air cavity. A fraction of 1.25 Gy was delivered to the phantom at isocenter with 15-MV photons by use of the NOMOS Peacock system and the MIMiC treatment delivery system (Sewickley, PA). RESULTS: The anterior-posterior and lateral prostate displacements were minimal, on the order of measurement uncertainty (approximately 1 mm). The standard deviation of superior-inferior displacement was 1.78 mm. Breathing studies showed no organ displacement during normal breathing when the rectal balloon was in place. The rectal toxicity profile was very favorable: 83% (83/100) patients had no rectal complaint, and 11% and 6% had grade 1 and 2 toxicity, respectively. Dose-volume histogram analysis revealed that in all of the patients, no more than 25% of the rectum received 70 Gy or greater. As visualized by film dosimetry, the dose at air-tissue interface was approximately 15% lower than that without an air cavity. The dose built up rapidly so that at 1 and 2 mm, the differential was approximately 8% and 5%, respectively. The dosimetric coverage at the depth of the posterior prostate wall was essentially equal, with or without the air cavity. DISCUSSION: The use of a rectal balloon during intensity-modulated radiotherapy significantly reduces prostate motion. Prostate immobilization thus allows a safer and smaller planning target volume margin. It has also helped spare the anterior rectal wall (by its dosimetric effects) and reduced the rectal volume that received high-dose radiation (by rectal wall distension). All these factors may have further contributed to the decreased rectal toxicity achieved by intensity-modulated radiotherapy, despite dose escalation and higher-than-conventional fraction size.

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.