Post-treatment mortality after definitive chemoradiotherapy versus resection for esophageal cancer.

In efforts to better characterize incidence and predictors of 30- and 90-day mortality following operative versus nonoperative approaches for locally advanced esophageal cancer (EC), we conducted a novel investigation of a large, contemporary US database. The National Cancer Database was queried for newly-diagnosed T1-3N0-1 squamous cell or adenocarcinoma receiving surgical-based therapy (esophagectomy alone or preceded by chemotherapy and/or radiotherapy) versus definitive chemoradiotherapy (dCRT). Statistics included graphing cumulative incidences of mortality before and following propensity score matching (PSM), based on age-based intervals. Cox regression determined factors independently predictive of 30- and 90-day mortality. Of 15,585 patients, 9,278 (59.5%) received surgical-based therapy and 6,307 (40.5%) underwent dCRT. In the unadjusted population, despite nonsignificant differences at 30 days (3.3% dCRT, 3.6% surgical-based), the dCRT cohort experienced higher 90-day mortality (11.0% vs. 7.5%, P < 0.001). Following PSM, however, dCRT patients experienced significantly lower 30-day mortality (P < 0.001), with nonsignificant differences at 90 days (P = 0.092). Surgical-based management yielded similar (or better) mortality as dCRT in ≤70-year-old patients; however, dCRT was associated with reduced mortality in subjects > 70 years old. In addition to the intervention group, factors predictive for 30- and 90-day mortality included age, gender, insurance status, facility type, comorbidity index, tumor location, histology, and T/N classification. In summary, surgical-based therapy for EC is associated with higher 30-day mortality, which becomes statistically similar to dCRT by 90 days. Differences between surgery and dCRT were most pronounced in patients > 70 years of age. These data may better inform shared decision-making between multidisciplinary providers and patients.

Trimodality therapy for esophageal cancer at high volume facilities is associated with improved postoperative outcomes and overall survival.

Trimodality therapy is the standard of care for locally advanced resectable esophageal cancer (EC) but carries morbidity and mortality risks; thus, therapy at high-volume facilities (HVFs) may offer advantages. This investigation studied postoperative outcomes and overall survival (OS) in EC patients receiving trimodality therapy at HVFs versus lower-volume facilities (LVFs). The National Cancer Data Base was queried for patients with locally advanced EC receiving trimodality therapy. HVFs referred to the 90th percentile of case volume. Multivariate logistic regression determined factors associated with treatment at HVFs, the Kaplan-Meier analysis compared OS between the HVF and LVF groups, and the Cox proportional hazards modeling determined variables associated with OS. Sensitivity analysis evaluated the impact of varying the HVF definition cutoff on OS. A total of 3,229 patients met study criteria, including 330 (10%) treated at HVFs and 2,899 (90%) at LVFs. Treatment at HVFs was associated with decreased 30-day mortality (1.2% vs. 3.3%, P = 0.044) and trends toward lower 90-day mortality (4.8% vs. 7.8%, P = 0.055) and the length of postoperative hospitalization (11.2 vs. 12.3d, P = 0.059). HVF patients experienced higher median OS (55 vs. 36 months, P = 0.004), which also independently correlated on the Cox multivariate analysis (P = 0.001). Sensitivity analysis showed similar results as the HVF/LVF cutoff was decreased until the 80th percentile. This is the first study demonstrating that the trimodality management of EC at HVFs is associated with improved postoperative outcomes and survival. These data have implications for multidisciplinary oncologic providers, in addition to patient counseling by both referring and treating clinicians.

Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer.

A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.

Targeting cellular metabolism to improve cancer therapeutics.

The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer.

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adbetagal, Adbetagal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

Intensity modulated radiation therapy (IMRT) in the management of prostate cancer.

Intensity modulated radiation therapy (IMRT) is gaining widespread use in the radiation therapy community. Prostate cancer is the ideal target for IMRT due to the growing body of literature supporting dose escalation and normal tissue limitations. The need for dose escalation and the limits of conventional radiation therapy necessitate precise patient and prostate localization as well as advanced treatment delivery. The treatment of prostate cancer has been dramatically altered by the introduction of technology that can focus on the target while avoiding normal tissue. IMRT is evolving as the treatment of the future for prostate cancer.

Enhanced therapeutic effect of multiple injections of HSV-TK + GCV gene therapy in combination with ionizing radiation in a mouse mammary tumor model.

PURPOSE: Standard therapies for breast cancer lack tumor specificity and have significant risk for recurrence and toxicities. Herpes simplex virus-thymidine kinase (HSV-tk) gene therapy combined with radiation therapy (XRT) may be effective because of complementary mechanisms and distinct toxicity profiles. HSV-tk gene therapy followed by systemic administration of ganciclovir (GCV) enhances radiation-induced DNA damage by generating high local concentrations of phosphorylated nucleotide analogs that increase radiation-induced DNA breaks and interfere with DNA repair mechanisms. In addition, radiation-induced membrane damage enhances the "bystander effect" by facilitating transfer of nucleotide analogs to neighboring nontransduced cells and by promoting local and systemic immune responses. This study assesses the effect of single and multiple courses of HSV-tk gene therapy in combination with ionizing radiation in a mouse mammary cancer model. METHODS AND MATERIALS: Mouse mammary TM40D tumors transplanted s.c. in syngeneic immunocompetent BALB-c mice were treated with either adenoviral-mediated HSV-tk gene therapy or local radiation or the combination of gene and radiation therapy. A vector consisting of a replication-deficient (E1-deleted) adenovirus type 5 was injected intratumorally to administer the HSV-tk gene, and GCV was initiated 24 h later for a total of 6 days. Radiation was given as a single dose of 5 Gy 48 h after the HSV-tk injection. A metastatic model was developed by tail vein injection of TM40D cells on the same day that the s.c. tumors were established. Systemic antitumor effect was evaluated by counting the number of lung nodules after treating only the primary tumors with gene therapy, radiation, or the combination of gene and radiation therapy. To assess the therapeutic efficacy of multiple courses of this combinatorial approach, one, two, and three courses of HSV-tk + GCV gene therapy, in combination with radiation, were compared to HSV-tk or XRT alone and to sham-treated animals. (Treatments were repeated at 7-day intervals from the HSV-tk injection.) RESULTS: Both single-therapy modalities reduced tumor growth by 11% compared to controls, while the combined therapy resulted in a decrease of 29%. Median survival was 36 days in the combined therapy group, compared to 33 days in the monotherapy groups and 26 days in the control group. In the metastatic model, the number of lung nodules was reduced by 59.5% after HSV-tk gene therapy, whereas radiotherapy had no effect on metastatic growth. Combined therapy led to an additional 66.7% reduction in lung colonization. Compared to controls, local tumor growth was maximally suppressed by three courses of combined therapy (51.5%), followed by two courses of combined therapy (37.2%), and three sessions of XRT alone (35.6%). Median survival was also significantly prolonged to 58 days with the three courses of combined therapy, followed by two courses, to 45 days. All other treatment groups demonstrated median survival times between 26 and 35 days, while controls had a median survival of 24 days. CONCLUSIONS: These results indicate that multiple courses of HSV-tk therapy in combination with radiation improve the therapeutic efficacy of this approach and may provide therapeutic implications for the treatment of human breast cancer and other solid tumors.

Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy.

In an extended phase I/II study we evaluated 36 prostate cancer patients with local recurrence after radiotherapy who received single or repeated cycles of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therapy with respect to serum PSA levels, alterations in immune cells, and numbers of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GCV gene therapy caused a significant prolongation of the mean serum PSA-doubling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the injected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It took a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) value. A repeated cycle of gene therapy failed to significantly extend PSADT but did result in significant increases in PSAR (29.4%) and TR-PSA (10.5 months). Moderately increased serum adenovirus antibody titers were generally observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T cells positive for the HLA-DR marker of activation in peripheral blood (p = 0.0088). Studies using prostate biopsies obtained at the same time point demonstrated that vector DNA was detectable by PCR in most samples yet all patients remained positive for prostate cancer in at least one biopsy core. Further analysis demonstrated a correlation between the level of CD8(+) cells and the number of apoptotic cells in biopsies containing cancer cells (p = 0.042). We conclude that repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to prostate cancer patients who failed radiotherapy and have a localized recurrence. Biological responses to this experimental therapy including increases in PSADT, PSAR, and TR-PSA, and activated CD8(+) T cells present in the peripheral blood, were demonstrated. Interestingly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.

Important prognostic factors in patients with skull base erosion from nasopharyngeal carcinoma after radiotherapy.

PURPOSE: To evaluate the long-term outcome and prognostic factors in patients with skull base erosion from nasopharyngeal carcinoma after initial radiotherapy (RT). METHODS AND MATERIALS: From January 1985 to December 1986, 100 patients (71 males, 29 females) with a diagnosis of nasopharyngeal carcinoma were found on computed tomography (CT) to have skull base erosion. The mean age was 41 years (range 16-66). Ninety-six patients had World Health Organization type III undifferentiated carcinoma, and 4 had type I. The metastatic workup, including chest radiography, liver ultrasound scanning, and liver function test was negative. All patients underwent external beam RT (EBRT) alone to 66-80 Gy during 6-8 weeks. A daily fraction size of 2 Gy was delivered using 60Co or a linear accelerator. No patient received chemotherapy. All patients were followed at regular intervals after irradiation. The median follow-up was 22.3 months (range 2-174). Survival of the cohort was computed by the Kaplan-Meier method. The potential prognostic factors of survival were examined. Multivariate analyses were performed using the Cox regression model. RESULTS: The 1, 2, 5, and 10-year overall survival rate for the cohort was 79%, 41%, 27%, and 13%, respectively. However, the subgroup of patients with both anterior cranial nerve (I-VIII) and posterior cranial nerve (IX-XII) involvement had a 5-year survival of only 7.7%. A difference in the time course of local recurrence and distant metastasis was observed. Both local recurrence and distant metastasis often occurred within the first 2 years after RT. However, local relapse continued to occur after 5 years. In contrast, no additional distant metastases were found after 5 years. The causes of death included local recurrence (n = 59), distant metastasis (n = 21), both local recurrence and distant metastasis (n = 1), and unrelated causes (n = 5). After multivariate analysis, complete recovery of cranial nerve involvement, cranial nerve palsy, and headache after irradiation were found to be independent prognostic factors in this cohort. CONCLUSIONS: We present one of the longest follow-ups of patients with nasopharyngeal carcinoma invading the skull base. Our results demonstrate the importance of cranial nerve involvement, recovery of headache, and cranial nerve palsy. These factors should be carefully evaluated from the history, physical examination, and imaging studies. A subgroup of patients with skull base involvement had long-term survival after RT alone. The findings of this study are important as a yardstick against which more aggressive strategies, such as combined radiochemotherapy and altered fractionation RT can be compared.

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

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

The potential use of intensity modulated radiotherapy (IMRT) in women with pectus excavatum desiring breast-conserving therapy.

The purpose of this study was to determine if intensity modulated radiation therapy (IMRT) offers a better treatment plan compared to conventional radiotherapy for patients with pectus excavatum desiring breast-conserving therapy and to assess the feasibility of simultaneous modulated accelerated radiation therapy (SMART) boost. A patient with pectus excavatum desired breast-conserving therapy for her early stage breast cancer. She underwent lumpectomy and axillary lymph node dissection followed by chemotherapy. She was then referred for radiotherapy. A breast board (Med-Tec) with aquaplast body cast was used to limit the movement of the patient, chest wall, and breasts before planning a computed tomography (CT) scan. IMRT including dose-volume histogram (DVH) was compared to that of the conventional plan using parallel opposed tangential beams with a 15-degree wedge pair. Forty-five gray was prescribed to the whole breast to each plan, while 50 Gy was prescribed to the tumor bed using IMRT with SMART boost in 25 fractions over 5 weeks. The coverage of the whole breast was adequate for both plans. IMRT allowed a more homogeneous dose distribution within the breast at the desired dose range. With IMRT there is less volume of ipsilateral lung receiving the radiation dose that is above the tolerance threshold of 15 Gy when compared to that of the conventional plan. However, there is more volume of surrounding normal tissues (the heart, spinal cord, and contralateral breast and lung) receiving low-dose irradiation when IMRT was employed. SMART boost was feasible, allowing a mean dose of 57 Gy to be delivered to the tumor bed simultaneously along with the rest of the breast in 5 weeks. IMRT is feasible in treating early breast cancer patients with pectus excavatum by decreasing the ipsilateral lung volume receiving high-dose radiation when compared to the conventional method. SMART boost shortens the overall treatment time that may have potential radiobiological benefit.

Enhanced therapeutic effect of HSV-tk+GCV gene therapy and ionizing radiation for prostate cancer.

Standard therapies for prostate cancer including radiation, prostatectomy, and hormone ablation have significant toxicities and recurrence risk. HSV-tk gene therapy may be effective in combination with radiation therapy due to complementary mechanisms and distinct toxicity profiles. Mouse prostate tumors transplanted subcutaneously were treated by either gene therapy involving intratumoral injection of AdV-tk followed by systemic ganciclovir or local radiation therapy or the combination of gene and radiation therapy. Both single-therapy modalities showed a 38% decrease in tumor growth compared to controls. The combined treatment resulted in a decrease of 61%. In addition the combined-therapy group had a mean survival of 22 days versus 16.6 days for single therapy and 13.8 days for nontreated controls. To analyze systemic anti-tumor activity, lung metastases were generated by tail vein injection of RM-1 prostate cancer cells on the same day that they were injected subcutaneously. The primary tumors were treated as before with AdV-tk followed by ganciclovir, radiation, or the combination. The number of lung nodules was reduced by 37% following treatment with AdV-tk, whereas radiotherapy alone had no effect on metastatic growth. The combination led to an additional 50% reduction in lung colonization. Primary tumors that received the combination therapy had a marked increase in CD4 T cell infiltrate. This is the first report showing a dramatic systemic effect following the local combination treatment of radiation and AdV-tk. A clinical study using this strategy has been initiated and patient accrual is ongoing.

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

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

Intensity modulated radiation therapy (IMRT) following prostatectomy: more favorable acute genitourinary toxicity profile compared to primary IMRT for prostate cancer.

PURPOSE: To report our initial experience on postprostatectomy IMRT (PPI), addressing acute genitourinary (GU) toxicity in comparison to primary IMRT (PI) for prostate cancer. METHODS AND MATERIALS: From April 1998 to December 1999, 40 postprostatectomy patients were treated with intensity modulated radiation therapy (IMRT) to a median prescribed dose of 64 Gy (mean dose of 69 Gy). The Radiation Therapy Oncology Group (RTOG) scoring system was used to assess acute GU toxicity. Target volume and maximum and mean doses were evaluated. The mean doses to the bladder and irradiated bladder volume receiving >65 Gy were assessed. These were compared to those of 125 patients treated with PI to a prescribed dose of 70 Gy (mean dose of 76 Gy). RESULTS: The acute GU toxicity profile is more favorable in the PPI group with 82.5% of Grade 0-1 and 17.5% of Grade 2 toxicity compared to 59.2% and 40.8%, respectively, in the PI group (p < 0.001). There was no Grade 3 or higher toxicity in either group. The target volume was larger in the PPI group, while the maximum and mean doses to the target were higher in the PI group. The mean dose delivered to the bladder was higher in the PPI group. The irradiated bladder volume receiving >65 Gy was significantly larger in the PI group (p < 0.001). CONCLUSIONS: PPI can be delivered with acceptable ute GU toxicity. The larger PPI target volume may be related to the difficulty in delineating prostatic fossa. Despite a larger target volume and a higher mean dose to the bladder, PPI produced a more favorable acute GU toxicity profile. This may be related to a combination of lower mean and maximum doses and smaller bladder volumes receiving >65 Gy in the PPI group, as well as urethral rather than bladder irradiation. The findings have implications in the evaluation of IMRT treatment plan for prostate cancer, whereby the irradiated bladder volumes above 65 Gy may be more meaningful than the mean dose to the bladder. Longer term toxicity results are awaited.

Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy.

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

Suicide gene therapy for prostate cancer using a replication-deficient adenovirus containing the herpesvirus thymidine kinase gene.

Current therapies for localized prostate cancer include radical prostatectomy, local radiation therapy, and cryoablation and are associated with a high rate of cure and acceptable morbidity. However, for men who have failed primary curative attempts or have metastatic disease, no effective therapy associated with acceptable morbidity exists. "Suicide" gene therapy delivered alone or in combination with other forms of treatment could potentially provide simultaneous efficacy against localized and systemic disease via the generation of cytotoxic activity and/or systemic immunity to the cancer. In this article we discuss our preclinical and clinical experience with a herpes-simplex-virus thymidine kinase/ganciclovir gene-therapy protocol for prostate cancer.

The use of intensity modulated radiotherapy for the treatment of extensive and recurrent juvenile angiofibroma.

These case series are presented to describe the application and advantages of intensity modulated radiotherapy (IMRT) for the treatment of extensive and/or recurrent juvenile angiofibroma. Two patients were diagnosed with recurrence at 11 and 13 months postoperatively, and one was surgically unresectable. The affected areas included the base of skull, cavernous sinus, pterygopalatine fossa, infratemporal fossa, posterior orbit and nasopharynx. Highly conformal IMRT was delivered with limited radiation doses to the optic nerves, optic chiasm, brainstem, brain, spinal cord, lens, retina, mandible, and parotid. The total dose delivered to the tumor varied from 3400 to 4500 cGy. The tumor shrunk radiographically in all three cases and there was no endoscopic evidence of disease in two cases at 15 months and 40 months. There was no acute toxicity. Late toxicity was limited to one episode of epistaxis and persistent rhinitis in one patient. In conclusion, IMRT provides several advantages over conventional radiotherapy in the treatment of recurrent juvenile angiofibroma.

Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer.

PURPOSE: We assess risks, toxicity and side effects of multiple and repeat in situ suicide gene therapy in patients with localized prostate cancer. MATERIALS AND METHODS: The study population comprised patients with localized prostate cancer receiving multiple and/or repeat intraprostatic injections of a replication deficient adenovirus containing the herpes simplex virus thymidine kinase (HSV-tk) gene. Intravenous ganciclovir or oral valaciclovir was given for 14 days after injection. Patients were recruited from 4 different clinical protocols in studies of toxicity and efficacy of suicide gene therapy, and closely monitored for toxicity and side effects during and after treatment. Toxicity was graded according to the Cancer Therapy Evaluation Program common toxicity criteria published by the National Cancer Institute. RESULTS: A total of 52 patients were treated under these clinical protocols with a total of 76 gene therapy cycles. Toxic events were recorded in 16 of 29 patients (55.2%) who were given multiple viral injections into the prostate, 7 of 20 (35%) who received 2 cycles of "suicide" gene therapy and 3 of 4 (75%) who received a third course of gene therapy. All toxic events after multiple or repeat injections were mild (grades 1 to 2) and resolved completely once the therapy course was terminated. No additive toxicity was noted in patients receiving repeat gene therapy cycles. Mean followup was 12.8 months (range 3 to 34). Preliminary results for 28 patients in 2 clinical protocols indicated a mean decrease of 44% in PSA in 43%. CONCLUSIONS: Direct injection into the prostate of a replication defective adenovirus containing the HSV-tk gene followed by intravenous ganciclovir is safe even in repeat cycles.