Multiple Primary Lung Cancers: Treatment Outcomes After Stereotactic Body Radiotherapy (SBRT).

PURPOSE/OBJECTIVES: Patients with lung cancer sometimes present with multiple primary lung cancers (MPLCs), either simultaneously (synchronous) or after treatment of an initial lesion (metachronous). Although open surgery remains a treatment mainstay for patients with stage I-II non-small-cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) is an acceptable alternative for patients who are medically unfit for or who refuse surgery. In this study, we retrospectively examine the outcome among patients with early-stage MPLCs treated at our institution with SBRT. MATERIALS/METHODS: Patients at our institution receiving SBRT for MPLC between June 2011 and March 2020 were reviewed retrospectively. Prior to undergoing definitive SBRT, the imaging, and pathology for every patient were reviewed in a multi-disciplinary thoracic/pulmonary tumor board. Dose and fractionation varied with the most common prescriptions being 50 Gy/5 fractions, 56 Gy/4 fractions, and 55 Gy/5 fractions. RESULTS: A total of 38 patients with a total of 80 MPLCs were treated, among which 68 were T1 lesions and 12 were T2 lesions. Median follow-up was 25.9 months, with local control (LC) rates calculated per lesion to be 98.6%, 93.3%, and 88.2% at one, two, and three years. Median overall survival (OS) was 43.5 months; 83.6%, 67.8%, and 52.3% at one, two, and three years, respectively. Sixty-two of the 80 (77.5%) treated lesions were not associated with any subsequent acute or late toxicity. The 18 (22.5%) lesions associated with toxicity included nine acute and nine late events. All toxicity was either grade 1 (13 of 18) or grade 2 (five of 18). CONCLUSIONS: SBRT for early-stage MPLC achieves high control rates with limited toxicity. MPLC patients deemed unfit for open surgical management should be considered for definitive SBRT.

Early detection of mandible osteoradionecrosis risk in a high comorbidity veteran population.

OBJECTIVE: Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively. STUDY DESIGN: Retrospective analysis of prospective cohort. SETTING: Tertiary care Veterans Health Administration (VHA) medical center. METHODS: Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who received definitive or adjuvant EBRT (2016-2020). RESULTS: Most patients were dentate and 80 % underwent dental extractions prior to EBRT of which 16 (16 %) had complications. The rate of ORN was 3.7 % for oral cavity SCC patients and 8.1 % for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start. CONCLUSION: ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication.

Three-dimensional (3D) anatomic location, extension, and timing of severe osteoradionecrosis of the mandible.

Background: The purpose of this study was to describe the topography, extension (volume), and timing of severe osteoradionecrosis (ORN) that required mandible resection in patients previously treated for head and neck cancer at a high-volume Veterans Affairs Medical Center. Materials and methods: The records from a reference hyperbaric oxygen clinic were retrospectively analyzed (n = 50, 2018-2021). Inclusion criteria were: I) severe ORN defined as progressive ORN that required resection; II) pathologic confirmation of ORN; and III) availability of pre-operative CT-imaging. Using a radiotherapy (RT) imaging software, we performed a detailed volumetric (3D) analysis of the bone involvement by ORN. Time intervals from RT to surgery for ORN and from surgery to the last follow-up were calculated. Results: All patients that met inclusion criteria (n = 10) were male with significant smoking history (median 47.5 pack-years) and a median age of 57 years old at the time of RT. The primary tumors were: oropharynx (n = 6), oral cavity (n = 3) and nasopharynx (n = 1). The median time from RT to ORN surgery was 8 years. The most common ORN location was the posterior lateral body (molar) and six patients had associated fractures. The mean ORN volume was 3.6 cc (range: 0.6-8.3), corresponding to a mean 6.3% (range: 0.7-14) of the total mandibular volume. After a median follow-up of 13.5 months, no recurrence of ORN occurred. Three patients died of non-cancer and non-ORN-recurrence related causes (1 y OS 77.1%). Conclusion: Severe ORN occurred after a median of 8 years from the previous RT and usually affected the posterior lateral body. Surgical resection achieved excellent ORN control.

Early glottic cancer in a veteran population: Impact of race on management and outcomes.

OBJECTIVES: Multiple population studies have shown racial discrepancies in head and neck cancer treatment and outcomes. We sought to characterize the impact of race on clinical outcomes for patients with early glottic squamous cell carcinoma (SCC) in a tertiary institution which provides equivalent access to care. METHODS: We retrospectively reviewed all early glottic (T1-T2) squamous cell carcinoma at a single institution, the Michael E. DeBakey Veterans' Administration Medical Center (MEDVAMC). Data collected included demographic information, primary and adjuvant treatment modalities, time to diagnosis, time to treatment, recurrences, recurrence treatment modality, secondary malignancies, recurrence-free survival (RFS), and overall survival (OS). RESULTS: One hundred seventeen patients with a primary diagnosis of T1-T2 glottic squamous cell carcinoma were included. Black and white patients demonstrated equivalent rates of recurrence, RFS, and OS. There was no significant difference in treatment delivery by race for all recorded parameters. T1b tumors were associated with an increased risk of recurrence which did not translate into a statistically significant decrease in RFS or OS. Surgical treatment was associated with increased recurrence but similar RFS and OS compared to radiation-based treatment. Secondary malignancies were common; 12% of patients were diagnosed with a second primary lung cancer during the study period. CONCLUSION: At our institution, race did not impact survival when access to care, treatment selection, and delivery are equivalent for early glottic SCC. Secondary lung cancer is a critical risk factor for mortality in this patient group and requires long-term surveillance and monitoring. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1733-1739, 2020.

Long-term outcome of a moderately hypofractionated, intensity-modulated radiotherapy approach using an endorectal balloon for patients with localized prostate cancer.

BACKGROUND: Technical advances in radiotherapy delivery have simultaneously enabled dose escalation and enhanced bladder and rectal sparing. However, the optimal radiation fractionation regimen for localized prostate cancer is unclear. Laboratory and clinical evidence suggest that hypofractionation may improve the therapeutic ratio of radiotherapy. We report our institutional outcomes using moderately hypofractionated, intensity-modulated radiotherapy (IMRT), and an endorectal balloon, with emphasis on long-term biochemical control and treatment-related adverse events in patients with localized prostate cancer. METHODS: Between January 1997 and April 2004, 596 patients with cT1-T3 prostate cancer underwent IMRT using a moderate hypofractionation regimen (76.70 Gy at 2.19 Gy/fraction) with an endorectal balloon. Using D'Amico classification, 226 (37.9%), 264 (44.3%), and 106 (17.8%) patients had low-, intermediate-, or high-risk disease, respectively. The majority of intermediate- and high-risk patients received androgen deprivation therapy. Biochemical relapse-free survival (bRFS) was evaluated using 2005 Phoenix criteria and estimated using the Kaplan-Meier method. RESULTS: The median follow-up was 62 months. Overall 5- and 10-year bRFS rates were 92.7% and 87.7%. For low-, intermediate-, and high-risk patients, the 5-year bRFS rates were 96.9%, 93.3%, and 82.0%, respectively; the 10-year bRFS rates were 91.4%, 89.3%, and 76.2%, respectively. Prostate-specific antigen, Gleason score, and T stage were significant predictors of bRFS (all P < 0.01). The 5-year rates of severe (≥ Grade 3) adverse events were very low: 1.2% for gastrointestinal events and 1.1% for genitourinary events. CONCLUSIONS: Long-term outcomes after moderately hypofractionated IMRT are encouraging. Moderate hypofractionation represents a safe, efficacious, alternative regimen in the treatment of localized prostate cancer.

Video-assisted thoracoscopic lobectomy is associated with greater recurrence-free survival than stereotactic body radiotherapy for clinical stage I lung cancer.

OBJECTIVE: Stereotactic body radiotherapy is the standard treatment for medically inoperable early-stage non-small cell lung cancer. Recent data suggest that in operable patients, stereotactic body radiotherapy produces outcomes comparable to those of surgical resection. In veterans with early non-small cell lung cancer, we compared the outcomes of stereotactic body radiotherapy and video-assisted thoracoscopic lobectomy. METHODS: We retrospectively reviewed data from 183 patients (94.0% male) with clinical stage I non-small cell lung cancer who underwent stereotactic body radiotherapy (n = 56) or video-assisted thoracoscopic lobectomy (n = 127) from 2009 to 2014. Propensity matching was used to produce more comparable groups. Primary end points were tumor control and overall, recurrence-free, and lung-cancer-specific survival, as estimated by Kaplan-Meier actuarial analysis. Multivariable analysis was used to identify independent predictors. RESULTS: In the overall cohort, the patients who received stereotactic body radiotherapy were older than the patients who received video-assisted thoracoscopic lobectomy (median age, 79.5 vs 64 years) and had more comorbidities. In the 37 propensity-matched pairs, the 3-year actuarial tumor control rate was 54.3% after stereotactic body radiotherapy and 90.6% after video-assisted thoracoscopic lobectomy (P = .0038). Actuarial lung cancer-specific 3-year survival was 78.1% (stereotactic body radiotherapy) versus 93.6% (video-assisted thoracoscopic lobectomy) (P = .055). One-year overall, 3-year overall, and 3-year recurrence-free survivals were 89.2%, 52.9%, and 38.5% after stereotactic body radiotherapy and 94.6%, 85.7%, and 82.8% after video-assisted thoracoscopic lobectomy (P < .005 for all), respectively. In multivariable analysis, stereotactic body radiotherapy independently predicted recurrence and poorer survival. CONCLUSIONS: In veteran patients with early-stage non-small cell lung cancer, video-assisted thoracoscopic lobectomy resulted in better disease control and survival than stereotactic body radiotherapy. Although prior reports suggest that stereotactic body radiotherapy is a suitable alternative to surgery in early-stage lung cancer, a prospective randomized trial is needed. Nevertheless, stereotactic body radiotherapy remains a suitable option for medically inoperable patients.

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.

The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo.

BACKGROUND: Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo. METHODS: Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo. RESULTS: In vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups. CONCLUSIONS: Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies.

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.

Radiosensitization by inhibiting STAT1 in renal cell carcinoma.

PURPOSE: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. METHODS AND MATERIALS: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. RESULTS: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10(-8) for clear cell; and p = 3.6 x 10(-4) for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. CONCLUSION: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

[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.