Long-term disease-specific and cognitive quality of life after intensity-modulated radiation therapy: a cross-sectional survey of nasopharyngeal carcinoma survivors.

BACKGROUND: There is a lack of data on quality of life in long-term survivors of nasopharyngeal carcinoma (NPC) who have been treated with intensity-modulated radiation therapy (IMRT). We characterized long-term disease-specific and cognitive QoL in NPC survivors after IMRT. METHODS: We conducted a cross-sectional study of surviving patients diagnosed and treated for NPC at our center with curative-intent IMRT, with or without chemotherapy. Patients who were deceased, still undergoing treatment, with known recurrent disease, or treated with RT modality other than IMRT were excluded. QoL was measured by FACT-NP and FACT-Cog. RESULTS: Between May and November 2013, 44 patients completed cognitive (FACT-Cog), general (FACT-G), and NPC-specific (NPCS) QoL assessments. Patients were categorized into 4 cohorts based on duration since IMRT (≤2.5, >2.5-6, >6-10, and >10-16 years). There was no significant difference in age (p = 0.20) or stage ((I/II vs III/IV: p = 0.78) among the cohorts. The 4 cohorts differed overall for all QoL measures (ANOVA: p < 0.02 for each), due to improved scores >2.5-6 years post-IMRT compared with ≤2.5 years post-IMRT (post hoc tests: p ≤ 0.04 for each). No differences were observed between >2.5-6 and >6-10 years post-IMRT, but lower mean FACT-Cog and NPCS scores were observed for >10 years compared to >2.5-6 years post-IMRT (post hoc: p < 0.05 for each). CONCLUSIONS: All QoL measures were low during the initial recovery period (≤2.5 years) and were higher by 6 years post-IMRT. At >10 years post-IMRT, lower scores were observed in the domains of NPC-specific and cognitive QoL. Survivors of NPC, even if treated with IMRT, are at risk for detriment in domain-specific QoL measures at very long-term follow-up.

Evaluation of Heart Dose for Left-Sided Breast Cancer Patients Over an 11-Year Period Spanning the Transition From 2-Dimensional to 3-Dimensional Planning.

INTRODUCTION/BACKGROUND: We evaluated heart dose from left breast radiotherapy with 2-dimensional (2D) versus 3-dimensional (3D) plans. PATIENTS AND METHODS: Treatment plans from patients treated with standard fractionation for left breast cancer from 2003 to 2013 were reviewed, with patients grouped into 3 cohorts: 2003 to 2004 ("2D", with computed tomography scans for dose calculation but fields defined using simulation films; n = 29), 2005 to 2006 ("2D-post," after several influential articles on heart dose were published; n = 31), and 2007 to 2013 ("3D"; n = 256). All patients were treated with free-breathing technique. Heart volumes were retrospectively contoured for the earlier 2 cohorts. Mean heart dose (MHD) and percentage of structure receiving at least 25 Gy (V25 Gy) and percentage of structure receiving at least 5 Gy for the whole heart, left ventricle (LV), right ventricle (RV), and both ventricles were recorded and compared among cohorts. RESULTS: MHD was 345 cGy (2D), 213 cGy (2D-post) and 213 cGy (3D). LV V25 Gy was 6.3%, 1.5%, and 1.1%, respectively. Lower doses were seen over time for all indices (analysis of variance, P < .0001). Post hoc tests indicated significantly higher doses for 2D versus 2D-post or 3D cohorts (P ≤ .001) for all parameters except RV V25 Gy (P = .24). CONCLUSION: Heart doses were higher with 2D versus 3D plans. Cardiac doses and resulting toxicity with modern 3D planning might be lower than those in previous reports.

Sentinel lymph node imaging guided IMRT for prostate cancer: Individualized pelvic radiation therapy versus RTOG guidelines.

PURPOSE/OBJECTIVES: Current Radiation Therapy Oncology Group (RTOG) guidelines for pelvic radiation therapy are based on general anatomic boundaries. Sentinel lymph node (SLN) imaging can identify potential sites of lymph node involvement. We sought to determine how tailored radiation therapy fields for prostate cancer would compare to standard RTOG-based fields. Such individualized radiation therapy could prioritize the most important areas to irradiate while potentially avoiding coverage in areas where critical structures would be overdosed. Individualized radiation therapy could therefore increase the therapeutic index of pelvic radiation therapy. METHODS AND MATERIALS: Ten intermediate or high-risk prostate cancer patients received androgen deprivation therapy with definitive radiation therapy, including an SLN imaging-tailored elective nodal volume (ENV). For dosimetric analyses, the ENV was recontoured using RTOG guidelines (RTOG_ENV) and on SLNs alone (SLN_ENV). Separate intensity modulated radiation therapy (IMRT) plans were optimized using RTOG_ENV and SLN_ENV for each patient. Dosimetric comparisons for these IMRT plans were performed for each patient. Dose differences to targets and critical structures among the different IMRT plans were calculated. Distributions of dose parameters were analyzed using non-parametric methods. RESULTS: Sixty percent of patients had SLNs outside of the RTOG_ENV. The larger volume IMRT plans covering SLN imaging-tailored elective nodal volume exhibited no significant dose differences versus plans covering RTOG_ENV. IMRT plans covering only the SLNs had significantly lower doses to bowel and femoral heads. CONCLUSIONS: SLN-guided pelvic radiation therapy can be used to either treat the most critical nodes only or as an addition to RTOG guided pelvic radiation therapy to ensure that the most important nodes are included.

Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience.

Central neurocytomas are uncommon intraventricular neoplasms whose optimal management remains controversial due to their rarity. We assessed outcomes for a historical cohort of neurocytoma patients and evaluated effects of tumor atypia, size, resection extent, and adjuvant radiotherapy. Progression-free survival (PFS) was measured by Kaplan-Meier and Cox proportional hazards methods. A total of 28 patients (15 males, 13 females) were treated between 1995 and 2014, with a median age at diagnosis of 26 years (range 5-61). Median follow-up was 62.2 months and 3 patients were lost to follow-up postoperatively. Thirteen patients experienced recurrent/progressive disease and 2-year PFS was 75% (95% CI 53-88%). Two-year PFS was 48% for MIB-1 labeling >4% versus 90% for ≤4% (HR 5.4, CI 2.2-27.8, p = 0.0026). Nine patients (32%) had gross total resections (GTR) and 19 (68%) had subtotal resections (STR). PFS for >80% resection was 83 versus 67% for ≤80% resection (HR 0.67, CI 0.23-2.0, p = 0.47). Three STR patients (16%) received adjuvant radiation which significantly improved overall PFS (p = 0.049). Estimated 5-year PFS was 67% for STR with radiotherapy versus 53% for STR without radiotherapy. Salvage therapy regimens were diverse and resulted in stable disease for 54% of patients and additional progression for 38 %. Two patients with neuropathology-confirmed atypical neurocytomas died at 4.3 and 113.4 months after initial surgery. For central neurocytomas, MIB-1 labeling index >4% is predictive of poorer outcome and our data suggest that adjuvant radiotherapy after STR may improve PFS. Most patients requiring salvage therapy will be stabilized and multiple modalities can be effectively utilized.

Intermittent Chemotherapy as a Platform for Testing Novel Agents in Patients With Metastatic Castration-Resistant Prostate Cancer: A Department of Defense Prostate Cancer Clinical Trials Consortium Randomized Phase II Trial of Intermittent Docetaxel With Prednisone With or Without Maintenance GM-CSF.

BACKGROUND: Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: mCRPC patients with ≥ 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same "off chemotherapy" regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR). RESULTS: Of 125 patients enrolled, 52 (42%) experienced ≥ 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13). CONCLUSION: Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer.

Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803.

PURPOSE: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. EXPERIMENTAL DESIGN: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). RESULTS: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. CONCLUSIONS: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men.

Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Uveal melanoma: molecular pattern, clinical features, and radiation response.

PURPOSE: To characterize the clinical spectrum of class 1 and class 2 uveal melanomas and their relationship with intraocular proton radiation response. DESIGN: Masked retrospective case series of uveal melanoma patients with fine needle biopsy-based molecular profiles. METHODS: A total of 197 uveal melanoma patients from a single institution were analyzed for pathology, clinical characteristics, and response to radiation therapy. RESULTS: A total of 126 patients (64%) had class 1 tumors and 71 (36%) had class 2 tumors. Patients with class 2 tumors had more advanced age (mean: 64 years vs 57 years; P = .001), had thicker initial mean ultrasound measurements (7.4 mm vs 5.9 mm; P = .0007), and were more likely to have epithelioid or mixed cells on cytopathology (66% vs 38%; P = .0004). Although mean pretreatment and posttreatment ultrasound thicknesses were significantly different between class 1 and class 2 tumors, there was no difference in the mean change in thickness 24 months after radiation therapy (mean difference: class 1 = -1.64 mm, class 2 = -1.47; P = .47) or in the overall rate of thickness change (slope: P = .64). Class 2 tumors were more likely to metastasize and cause death than class 1 tumors (DSS: P < .0001). CONCLUSIONS: At the time of radiation therapy, thicker tumors, epithelioid pathology, and older patient age are significantly related to class 2 tumors, and class 2 tumors result in higher tumor-related mortality. We found no definitive clinical marker for differentiating class 1 and class 2 tumors.

A phase II study of insulin-like growth factor receptor inhibition with nordihydroguaiaretic acid in men with non-metastatic hormone-sensitive prostate cancer.

Insulin-like growth factor (IGF)-mediated signaling is a newly recognized clinical target in prostate cancer, and it is hypothesized that blockade of the IGF receptor (IGF1R) will impair downstream signaling and slow tumor growth. In this study the efficacy of nordihydroguaiaretic acid (NDGA), a small molecule inhibitor of the IGF-1R, was prospectively evaluated in patients with non-metastatic hormone-sensitive prostate cancer (HSPC). Eligible patients had non-metastatic HSPC with a rising prostate-specific antigen (PSA) and a normal testosterone level. NDGA 2000 mg was given orally daily in 28 day cycles and treatment continued until PSA progression or toxicity. Accrual was stopped early after a pre-planned interim analysis showed no significant PSA declines after 3 cycles of treatment among the first 12 patients enrolled. Median time on treatment was 9 cycles (range 2-19) for 11 patients now off study; 1 patient continues to receive therapy and has been on study for 29 months. Seven patients experienced non-sustained declines in PSA ranging from 1.9 to 15.8% of baseline. PSADT lengthened by a median of 1.4 months for all evaluable patients when compared to pretreatment PSADT (range -6.1 to +19.8 months). Grade 3 events were rare and included nausea/vomiting, syncope due to dehydration, and elevated liver function tests in 1 patient, and cognitive disturbance in another patient. NDGA therapy lengthens median PSADT but does not induce significant PSA declines. Further study may require a placebo-control to determine if changes in PSADT are drug related.

Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study.

BACKGROUND: Insulin-like growth factor (IGF) mediated signaling has been implicated in the growth of many tumor types including prostate cancer, and it is hypothesized that lowering circulating IGF levels in men with castration resistant prostate cancer (CRPC) will slow tumor growth. In this study, the efficacy of depot octreotide acetate was prospectively evaluated in patients with CRPC. METHODS: Eligible patients had progressive non-metastatic CRPC. Octreotide acetate 30 mg was administered intramuscularly every 28 days. Changes in PSA, IGF-1, IGF-2, IGF binding protein-1 (IGFBP-1), and IGFBP-3 were evaluated over time. RESULTS: Accrual was stopped early after a pre-planned interim analysis showed no prostate specific antigen (PSA) declines after 3 cycles of treatment among the first 13 patients enrolled. Median baseline PSA and IGF-1 measurements were 36.2 ng/ml and 162.6 ng/ml, respectively, and median time on treatment was 13 weeks. Radiographic progression occurred in 7 patients, PSA-only progression occurred in 5 patients, and 1 patient was taken off the study due to a grade 3 drug interaction. After 3 cycles of treatment IGF-1 significantly declined with a median -34.5% (P = 0.01) and IGFBP-1 significantly increased with a median 76.3% (P = 0.046). IGF-2 and IGFBP-3 were not significantly changed from baseline. CONCLUSIONS: Octreotide acetate significantly lowers IGF-1 and raises IGFBP-1 levels in patients with non-metastatic CRPC, but does not result in sustained declines in PSA. While treatment with single-agent octreotide may not be warranted, its inclusion in combination regimens directly targeting the IGF-1 receptor on tumor cells may be of interest.

Stereotactic body radiotherapy as monotherapy or post-external beam radiotherapy boost for prostate cancer: technique, early toxicity, and PSA response.

PURPOSE: High dose rate (HDR) brachytherapy has been established as an excellent monotherapy or after external-beam radiotherapy (EBRT) boost treatment for prostate cancer (PCa). Recently, dosimetric studies have demonstrated the potential for achieving similar dosimetry with stereotactic body radiotherapy (SBRT) compared with HDR brachytherapy. Here, we report our technique, PSA nadir, and acute and late toxicity with SBRT as monotherapy and post-EBRT boost for PCa using HDR brachytherapy fractionation. PATIENTS AND METHODS: To date, 38 patients have been treated with SBRT at the University of California-San Francisco with a minimum follow-up of 12 months. Twenty of 38 patients were treated with SBRT monotherapy (9.5 Gy × 4 fractions), and 18 were treated with SBRT boost (9.5 Gy × 2 fractions) post-EBRT and androgen deprivation therapy. PSA nadir to date for 44 HDR brachytherapy boost patients with disease characteristics similar to the SBRT boost cohort was also analyzed as a descriptive comparison. RESULTS: SBRT was well tolerated. With a median follow-up of 18.3 months (range, 12.6-43.5), 42% and 11% of patients had acute Grade 2 gastrourinary and gastrointestinal toxicity, respectively, with no Grade 3 or higher acute toxicity to date. Two patients experienced late Grade 3 GU toxicity. All patients are without evidence of biochemical or clinical progression to date, and favorably low PSA nadirs have been observed with a current median PSA nadir of 0.35 ng/mL (range, <0.01-2.1) for all patients (0.47 ng/mL, range, 0.2-2.1 for the monotherapy cohort; 0.10 ng/mL, range, 0.01-0.5 for the boost cohort). With a median follow-up of 48.6 months (range, 16.4-87.8), the comparable HDR brachytherapy boost cohort has achieved a median PSA nadir of 0.09 ng/mL (range, 0.0-3.3). CONCLUSIONS: Early results with SBRT monotherapy and post-EBRT boost for PCa demonstrate acceptable PSA response and minimal toxicity. PSA nadir with SBRT boost appears comparable to those achieved with HDR brachytherapy boost.

Implications of delayed initiation of radiotherapy: accelerated repopulation after induction chemotherapy for stage III non-small cell lung cancer.

INTRODUCTION: For patients with stage III non-small cell lung cancer treated with induction chemotherapy (ICT), delayed initiation of subsequent radiotherapy (RT) may allow for repopulation in the interval between treatment modalities and during the early phase of RT. We quantified the impact of postinduction RT timing by evaluating the pace of tumor regrowth. METHODS: Institutionally approved retrospective review identified 21 analyzable patients with stage III non-small cell lung cancer who had platinum-based ICT followed by RT+/- chemotherapy from 2002 to 2009. Radiographic response was determined by RECIST criteria and the volume of the single largest tumor mass on the pre-ICT, post-ICT, and RT-planning computed tomography scans. RESULTS: After ICT, the median percent volume change from pre-ICT baseline was -41% (range -86 to +86%). By the RT-planning computed tomography scan, the median percent volume change from the post-ICT timepoint was +40% (range -11 to +311%) and the median volume change was +20 ml (range -4 to 102 ml); these changes were significant (p = 0.0002). Similar results were seen for tumor diameter. A correlation was observed between the amount of delay and degree of regrowth for percent volume (p = 0.0006) and percent diameter change (p = 0.003). A delay greater than 21 days produced greater increases in percent volume change (p = 0.002) and percent diameter (p = 0.055) than lesser delays. CONCLUSIONS: After ICT, tumor regrowth can occur within a few weeks. Radiation treatment planning should begin as soon as possible after the administration of ICT to maximize the benefits of cytoreduction.

A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma.

BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.

Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxel-based therapy: a phase 2 study of the Department Of Defense Prostate Cancer Clinical Trials Consortium.

BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Equivalent biochemical control and improved prostate-specific antigen nadir after permanent prostate seed implant brachytherapy versus high-dose three-dimensional conformal radiotherapy and high-dose conformal proton beam radiotherapy boost.

PURPOSE: Permanent prostate implant brachytherapy (PPI), three-dimensional conformal radiotherapy (3D-CRT), and conformal proton beam radiotherapy (CPBRT) are used in the treatment of localized prostate cancer, although no head-to-head trials have compared these modalities. We studied the biochemical control (biochemical no evidence of disease [bNED]) and prostate-specific antigen (PSA) nadir achieved with contemporary PPI, and evaluated it against 3D-CRT and CPBRT. PATIENTS AND METHODS: A total of 249 patients were treated with PPI at the University of California, San Francisco, and the outcomes were compared with those from a 3D-CRT cohort and the published results of a high-dose CPBRT boost (CPBRTB) trial. For each comparison, subsets of the PPI cohort were selected with patient and disease criteria similar to those of the reference group. RESULTS: With a median follow-up of 5.3 years, the bNED rate at 5 and 7 years achieved with PPI was 92% and 86%, respectively, using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, and 93% using the PSA nadir plus 2 ng/mL definition. Using the ASTRO definition, a 5-year bNED rate of 78% was achieved for the 3D-CRT patients compared with 94% for a comparable PPI subset and 93% vs. 92%, respectively, using the PSA nadir plus 2 ng/mL definition. The median PSA nadir for patients treated with PPI and 3D-CRT was 0.10 and 0.40 ng/mL, respectively (p < .0001). For the CPBRT comparison, the 5-year bNED rate after a CPBRTB was 91% using the ASTRO definition vs. 93% for a similar group of PPI patients. A greater proportion of PPI patients achieved a lower PSA nadir compared with those achieved in the CPBRTB trial (PSA nadir < or =0.5 ng/mL, 91% vs. 59%, respectively). CONCLUSION: We have demonstrated excellent outcomes in low- to intermediate-risk patients treated with PPI, suggesting at least equivalent 5-year bNED rates and a greater proportion of men achieving lower PSA nadirs compared with 3D-CRT or CPBRTB.

Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study.

BACKGROUND: A number of agents, including aspirin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, folic acid, calcium, and vitamins, have been evaluated for their potential in chemoprevention of sporadic colorectal adenomas or cancer. Preclinical data suggest that 5-aminosalicylates also may have a chemopreventive effect. AIM: To investigate chemoprevention of colonic polyps with balsalazide, a 5-aminosalicylate prodrug. METHODS: In this randomized, double-blind, placebo-controlled study, adults diagnosed with small polyps in the rectosigmoid colon were treated with either balsalazide 3 g/d or placebo for 6 months. Follow-up lower endoscopy was performed, and all polyps were measured and analyzed histologically. The primary endpoint was reduction in mean size of the largest polyp per subject. RESULTS: Among 241 participants screened, 86 were randomized to treatment, with 75 subjects evaluable. Balsalazide 3 g/d (n = 38) did not significantly reduce the mean size of the largest colonic polyp or the number of polyps compared with placebo (n = 37). Although not significant, post-hoc analysis revealed that total adenoma burden per subject, calculated as the sum of the volumes of all adenomas in mm3, increased by 55% in the balsalazide group compared with 95% in the placebo group. CONCLUSIONS: Although balsalazide did not have significant chemopreventive effects on established colonic polyps, these results can aid in designing future prospective studies.

Perioperative outcomes comparing patient controlled epidural versus intravenous analgesia in gynecologic oncology surgery.

OBJECTIVES: Our aim was to compare perioperative patient controlled epidural analgesia (PCEA) versus patient controlled intravenous analgesia (PCA) after gynecologic oncology laparotomy. METHODS: This was a prospective cohort study where perioperative pain management was decided through patient-centered discussion by anesthesia and surgical teams. The study was designed to accrue 224 patients, to test for equivalence in pain control on postoperative day 1, defined as less than a 10% difference in the proportion of patients with a visual analog scale pain score of <2 (0-10 scale). RESULTS: Two hundred forty patients were enrolled, with 205 patients evaluable for outcomes: 98 received PCA, while 107 received a thoracic level PCEA. Utilization of PCEA was associated with longer anesthesia time pre-op (means: 60 vs. 44 min, p<0.0001), as well as more likely use of pressors during surgery (78% vs. 57%, p=0.002). Pain control was comparable between groups on postoperative day 1 (mean VAS: 2.4 vs. 2.5, p=0.56), but patients with PCEA tended to require more supplemental pain medications. Time to first ambulation was longer in the PCEA patients (means: 49 vs. 36 h post-op, p=0.03), with no difference in time to tolerating regular diet (means: 89 vs. 77 h post-op, 0.17) and no difference in readiness for discharge (means: 144 vs. 145 h post-op, p=0.95). CONCLUSIONS: In this nonrandomized prospective study, selection of a PCEA for perioperative pain management did not improve pain management for patients undergoing gynecologic oncology surgery.

High-dose-rate brachytherapy for localized prostate adenocarcinoma post abdominoperineal resection of the rectum and pelvic irradiation: Technique and experience.

PURPOSE: Treatment options are limited for patients with localized prostate cancer and a prior history of abdominoperineal resection (APR) and pelvic irradiation. We have previously reported on the successful utility of high-dose-rate (HDR) brachytherapy salvage for prostate cancer failing definitive external beam radiation therapy (EBRT). In this report, we describe our technique and early experience with definitive HDR brachytherapy in patients post APR and pelvic EBRT. PATIENTS AND METHODS: Six men with newly diagnosed localized prostate cancer had a prior history of APR and pelvic EBRT. Sixteen to 18 HDR catheters were placed transperineally under transperineal ultrasound-guidance. The critical first two catheters were placed freehand posterior to the inferior rami on both sides of the bulbar urethra under cystoscopic visualization. A template was used for subsequent catheter placement. Using CT-based planning, 5 men received 36Gy in six fractions as monotherapy. One patient initially treated with EBRT to 30Gy, received 24Gy in four fractions. RESULTS: Median age was 67.5 (56-74) years. At a median followup of 26 (14-60) months, all patients are alive and with no evidence of disease per the Phoenix definition of biochemical failure, with a median prostate-specific antigen nadir of 0.19ng/mL. Three men have reported grade 2 late genitourinary toxicity. There has been no report of grade 3-5 toxicity. CONCLUSION: Transperineal ultrasound-guided HDR brachytherapy using the above technique should be considered as definitive therapy for patients with localized prostate cancer and a prior history of APR and pelvic EBRT.

Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium.

PURPOSE: Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed. PATIENTS AND METHODS: Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity. RESULTS: Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%). CONCLUSION: These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.

Can positron emission tomography (PET) or PET/Computed Tomography (CT) acquired in a nontreatment position be accurately registered to a head-and-neck radiotherapy planning CT?

PURPOSE: To quantify the uncertainties associated with incorporating diagnostic positron emission tomography/CT (PET/CT) and PET into the radiotherapy treatment-planning process using different image registration tools, including automated and manual rigid body registration methods, as well as deformable image registration. METHODS AND MATERIALS: The PET/CTs and treatment-planning CTs from 12 patients were used to evaluate image registration accuracy. The PET/CTs also were used without the contemporaneously acquired CTs to evaluate the registration accuracy of stand-alone PET. Registration accuracy for relevant normal structures was quantified using an overlap index and differences in the center of mass (COM) positions. For tumor volumes, the registration accuracy was measured using COM positions only. RESULTS: Registration accuracy was better with PET/CT than with PET alone. The COM displacements ranged from 3.2 +/- 0.6 mm (mean +/- 95% confidence interval, for brain) to 8.4 +/- 2.6 mm (spinal cord) for registration with PET/CT data, compared with 4.8 +/- 1.7 mm (brain) and 9.9 +/- 3.1 mm (spinal cord) with PET alone. Deformable registration improved accuracy, with minimum and maximum errors of 1.1 +/- 0.8 mm (brain) and 5.4 +/- 1.4 mm (mandible), respectively. CONCLUSIONS: It is possible to incorporate PET and/or PET/CT acquired in diagnostic positions into the treatment-planning process through the use of advanced image registration algorithms, but precautions must be taken, particularly when delineating tumor volumes in the neck. Acquisition of PET/CT in the treatment-planning position would be the ideal method to minimize registration errors.