Percutaneous Cryoablation: Safety and Efficacy for Pain Palliation of Metastases to Pleura and Chest Wall.

PURPOSE: To assess safety and efficacy of percutaneous cryoablation for pain palliation of metastases to pleura and chest wall. MATERIALS AND METHODS: This retrospective single-center cohort study included 22 patients (27% female, mean age 63 y ± 11.4) who underwent 25 cryoablation procedures for pain palliation of 39 symptomatic metastases measuring 5.1 cm ± 1.9 (range, 2.0-8.0 cm) in pleura and chest wall between June 2012 and December 2017. Pain intensity was assessed using a numerical scale (0-10 points). Statistical tests t test, χ2, and Wilcoxon signed rank were performed. RESULTS: Patients were followed for a median of 4.1 months (interquartile range [IQR], 2.3-10.1; range, 0.1-36.7 mo) before death or loss to follow-up. Following cryoablation, pain intensity decreased significantly by a median of 4.5 points (IQR, 2.8-6; range, 0-10 points; P = .0002 points, Wilcoxon signed rank). Pain relief of at least 3 points was documented following 18 of 20 procedures. Pain relief occurred within a median of 1 day following cryoablation (IQR, 1-2; range, 1-4 d) and lasted for a median of 5 weeks (IQR, 3-17; range, 1-34 wk). Systemic opioid requirements decreased in 11 of 22 patients (50%) by an average of 56% ± 34. Difference in morphine milligram equivalents was not significant (P = .73, Wilcoxon signed rank). No procedure-related complications occurred despite previous radiation of 7 tumors. Of 25 procedures, 22 (88%) were performed on an outpatient basis. CONCLUSIONS: Percutaneous cryoablation for metastases to pleura and chest wall can safely provide significant pain relief within days following a single session.

Management and outcomes of women diagnosed with primary breast lymphoma: a multi-institution experience.

PURPOSE: Primary breast lymphoma (PBL) comprises < 1% of breast malignancies, leading to a paucity of data to guide management. We evaluated PBL recurrence patterns across two academic hospitals in the era of modern systemic-therapy and radiotherapy. METHODS: Patients diagnosed with PBL between October 1994 and June 2016 were identified. Demographic/clinical variables were assessed via primary chart review. Local control (LC) was estimated using the cumulative incidence function and overall survival (OS) using the Kaplan-Meier method. RESULTS: Thirty-five patients were identified. Median follow-up 5.8 years (range 0.3-17.8 years). Median age at diagnosis 66 years (range 35-86 years). Indolent versus aggressive lymphoma represented 57% (n = 20) and 43% (n = 15) of the cohort, respectively. All patients with aggressive lymphoma received systemic therapy. Thirty patients (86%) received radiotherapy (RT). Breast-only RT was used in 57% (n = 20); 23% (n = 7) received regional nodal irradiation (RNI), and 6% (n = 2) received limited-field RT. Local recurrences were observed in 3% (n = 1), contralateral breast 9% (n = 3), CNS 6% (n = 2), distant non-CNS 30% (n = 10), both local and distant 3% (n = 1). There were no regional nodal recurrences. The 6-year LC rate was 95% for indolent and 81% for aggressive subtypes. The 6-year OS rate was 87% for indolent and 70% for aggressive subtypes. CONCLUSIONS: The majority of patients in this PBL cohort received breast-only RT with no nodal relapses, suggesting that prophylactic RNI may be unnecessary. Given the prevalence of contralateral breast involvement at diagnosis and at recurrence, vigilant surveillance of bilateral breasts may be warranted. The role of CNS prophylaxis requires further investigation.

Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study.

Introduction: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population. Methods: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis. Results: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021). Conclusions: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.

Determining if pretreatment PSA doubling time predicts PSA trajectories after radiation therapy for localized prostate cancer.

INTRODUCTION: To determine if pretreatment PSA doubling time (PSA-DT) can predict post-radiation therapy (RT) PSA trajectories for localized prostate cancer. MATERIALS AND METHODS: Three hundred and seventy-five prostate cancer patients treated with external beam RT without androgen deprivation therapy (ADT) were identified with an adequate number of PSA values. We utilized a linear mixed model (LMM) analysis to model longitudinal PSA data sets after definitive treatment. Post-treatment PSA trajectories were allowed to depend on the pre-RT PSA-DT, pre-RT PSA (iPSA), Gleason score (GS), and T-stage. RESULTS: Pre-RT PSA-DT had a borderline impact on predicting the rate of PSA rise after nadir (p=0.08). For a typical low risk patient (T1, GS6, iPSA 10), the predicted PSA-DT post-nadir was 21% shorter for pre-RT PSA-DT<24month compared to pre-RT PSA-DT>24month (19month vs. 24month). Additional significant predictors of post-RT PSA rate of rise included GS (p<0.0001), iPSA (p<0.0001), and T-stage (p=0.02). CONCLUSIONS: We observed a trend between rapidly rising pre-RT PSA and the post-RT post-nadir PSA rise. This effect appeared to be independent of iPSA, GS, or T-stage. The results presented suggest that pretreatment PSA-DT may help predict post-RT PSA trajectories.

Androgen deprivation therapy for patients with prostate carcinoma and Parkinson's disease: case report and review of literature.

We report a case history of a patient with Parkinson's disease (PD) treated with androgen deprivation therapy (ADT) and external beam radiation for prostate cancer, who developed severe deterioration of his PD during ADT.

Combined permanent implant and external-beam radiation therapy for prostate cancer.

A number of series have been published examining the utility of combining low-dose rate permanent interstitial implants with external-beam radiation (CMT). However, the data show conflicting results. Comparisons of these studies are confounded by the lack of similar biochemical failure definitions, inequities in risk groups between compared arms, variable implant quality, and differences in implant margins and techniques. Despite these limitations, the literature does suggest that CMT may help spare patients the need for androgen deprivation, overcome adverse pathologic factors, and correct for poor implant quality. We present the recent innovation and potential benefits of using implant dose-adjusted intensity-modulated radiation therapy.

In patients experiencing biochemical failure after radiotherapy, pretreatment risk group and PSA velocity predict differences in overall survival and biochemical failure-free interval.

PURPOSE: To characterize the demographics and survival outcomes of localized prostate cancer patients who developed biochemical failure (BF) according to a prostate-specific antigen (PSA) nadir plus 2 ng/mL. METHODS AND MATERIALS: We identified 375 prostate cancer patients who had undergone external beam radiotherapy without androgen deprivation therapy but with sufficient PSA data to study PSA kinetics. Of these patients, we identified 82 with BF. The pretreatment PSA velocity was calculated for each patient. RESULTS: For the BF cohort, 26% were low-risk and 74% were intermediate- or high-risk patients. Of the 82 BF patients, 16 (20%) were noted to have both low-risk disease and a pretreatment low PSA velocity of < or =2 ng/mL/y (termed "low-risk low-velocity" [LRLV]). The remaining BF patients had either intermediate- or high-risk features or a high PSA velocity >2 ng/mL/y (termed "higher risk" [HR]). For patients who had BF, the LRLV group had a delayed median time to BF of 55 months compared with 33 months for the HR patients (p = 0.04). With a median clinical follow-up of 112 months, the 5-year overall survival rate was 100% for the LRLV BF patients vs. 84% for the HR patients (p = 0.02). CONCLUSIONS: We observed that LRLV BF patients represent a sizeable proportion of all patients with treatment failure. However, when comparing LRLV BF with HR BF patients, the former had significantly better overall survival and a longer interval to BF. This suggests that not all BF events are equivalent and emphasizes the challenges associated with using BF alone as a surrogate for a survival endpoint.

Correlation between pretreatment FDG-PET biological target volume and anatomical location of failure after radiation therapy for head and neck cancers.

BACKGROUND AND PURPOSE: To assess whether the pretreatment FDG-PET-defined biologic target volume (PET-BTV) correlates with the anatomical sites of loco-regional failure (LRF) after RT for head and neck cancer (HNC). MATERIALS AND METHODS: We retrospectively identified 61 HNC patients treated definitively with either 3-D CRT or IMRT who had a pre-therapy PET/CT. The GTV and high-risk CTV(1) definitions included composite data obtained from diagnostic CT, PET/CT, physical examination, and MRI when available. The median CTV(1) dose was 70Gy. 95% received chemotherapy. For patients with LRF, a recurrence volume (V(r)) was identified and was mapped to the pretreatment planning CT and pretreatment PET scan. RESULTS: At a median follow-up of 22 months, 15% (9/61) patients had LRF. For patients with a LRF, 100% (9/9) of failures were inside the GTV. One of nine [11% (95% CI: 3-45%)] had V(r) which mapped outside of the pretreatment PET-BTV, while 8/9 patients had V(r) within the PET-BTV. Predictors of LRF in our series included GTV volume (p=0.003), but not mean SUV (p=0.13) or max SUV (p=0.25). CONCLUSIONS: Following treatment in which the GTV was defined based on the composite of imaging and physical examination, the majority, but not all, LRF occurred within the PET-BTV. These results support an important, but not exclusive, role of FDG-PET in defining the GTV.

Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves treatment outcomes in high-risk patients.

PURPOSE: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes. METHODS AND MATERIALS: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS. RESULTS: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty-four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p < 0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients. CONCLUSIONS: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients.

No effect of statins on biochemical outcomes after radiotherapy for localized prostate cancer.

OBJECTIVES: To examine the effect of concurrent statin use during definitive radiotherapy (RT) on the biochemical outcomes for localized prostate cancer. METHODS: A total of 968 patients treated with RT had information about medication use available. Of these, 23% had been taking using statins during RT. Progression-free survival (PFS) was determined by a biochemical failure definition of prostate-specific antigen nadir plus 2 ng/mL, clinical failure, start of androgen deprivation therapy, or death. RESULTS: The mean patient age was 68 years. The median radiation dose was 76 Gy. Of the patients, 29% underwent androgen deprivation therapy. The 5-year overall survival rate was 83%. The median PFS time was 7.8 years versus 6.4 years, and the 5-year PFS rate was 70% versus 59% in favor of the statin users (P = 0.03). The analysis by risk group demonstrated no significant statin effect in any of the three risk strata. Stratification by hydrophilic versus hydrophobic statin agents revealed similar results. Multivariate analysis revealed that T stage (P <0.0001), pretreatment prostate-specific antigen level (P <0.0001), and Gleason score (P = 0.0026) were significant predictors of PFS; however, statin use (P = 0.48), androgen deprivation therapy (P = 0.95), pelvic RT (P = 0.96), radiation dose (P = 0.13), age (P = 0.19), and year of treatment (P = 0.07) were not. CONCLUSIONS: Statin use did not affect PFS after adjusting for differences in treatment year and multiple prognostic factors. However, T stage, baseline prostate-specific antigen level, and Gleason score were critical determinants of prostate-specific antigen failure. These results did not differ when hydrophilic pravastatin was excluded.

Combined-modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: long-term results of a phase I trial.

PURPOSE: A Phase I trial of twice-weekly gemcitabine and concurrent radiation therapy (RT) was performed in patients with muscle-invasive bladder cancer. We present the final analysis of bladder-intact survival (BIS), disease-specific survival (DSS), and overall survival (OS). METHODS AND MATERIALS: Eligible patients had muscle-invasive transitional cell carcinoma (cT2-3) and were candidates for cystectomy. Patients underwent maximal transurethral resection of bladder tumor followed by twice-weekly gemcitabine with concurrent RT to the bladder (total of 60 Gy over 6 weeks). Gemcitabine doses ranged from 10 to 33 mg/m(2). RESULTS: Median follow-up was 5.6 years (range, 0.6-9.5 years). Twenty-three of 24 patients were evaluable for response. All patients were clinical stage T2. Locoregional failure occurred in seven patients (30%), which were successfully salvaged by radical cystectomy (n = 5) or intravesical therapy (n = 2). Four local failures occurred > 5 years after therapy. Most local failures were noninvasive tumors (Ta or Tis, n = 6). Ten patients (43%) experienced optimal outcome (no failures and bladder intact). The 5-year actuarial estimates of survival are BIS 62%, OS 76%, and DSS 82%. CONCLUSION: Twice-weekly gemcitabine with concurrent RT is well tolerated and provides rates of survival and bladder preservation that are comparable to the existing literature. All locoregional failures were successfully salvaged by either radical cystectomy or intravesical therapy. Given the high proportion of late local failures, we recommend long-term monitoring when using this regimen. Future studies comparing the safety and efficacy of gemcitabine- vs. platinum-based bladder preservation protocols are pending.

Impact of common iliac nodal treatment on radiation outcomes in localized prostate cancer.

OBJECTIVES: The Radiation Therapy Oncology Group 9413 trial has shown an improvement in progression-free survival (PFS) with external beam radiotherapy that included the pelvic nodes. In clinical practice, two pelvic field size designs are in use. We examined the effect of differences in the level of pelvic nodal coverage using three-dimensional conformal radiotherapy on biochemical failure-free survival (BFFS) and PFS in early-stage prostate cancer. METHODS: The patients were identified retrospectively who had undergone whole pelvis (WP) or minipelvis (MP) three-dimensional conformal radiotherapy. Biochemical failure was defined as the nadir prostate-specific antigen (PSA) level plus 2 ng/mL. RESULTS: Of the 669 patients identified, 384 had undergone MP (57%) and 285 WP (42%) treatment, with a median PSA follow-up of 56 months. Of the 669 patients, 11%, 35%, and 54% were at low, intermediate, and high risk, respectively. The median dose was 75 Gy for the MP and 71 Gy for the WP groups. Of the MP and WP groups, 52% and 36% underwent hormonal therapy. The median BFFS and 5-year BFFS rate was 128 months and 73% for the MP group and 96 months and 58% for the WP group. The median PFS and 5-year PFS rate was 128 months and 72% for the MP group and 83 months and 56% for the WP group. Multivariate analysis revealed no difference between MP and WP treatment. However T stage, pretreatment PSA level, and Gleason score were significant predictors of BFFS and PFS. CONCLUSIONS: We observed no difference in outcomes between patients undergoing WP versus MP using three-dimensional conformal radiotherapy. Therefore, the exclusion of the common iliac lymph nodes in the treatment of patients with high-risk prostate cancer might be acceptable.

Predicting biochemical failure and overall survival through intratherapy PSA changes during definitive external beam radiotherapy.

PURPOSE: To determine whether intratherapy prostate-specific antigen (itPSA) changes during radiotherapy (RT) predict prostate cancer outcomes. METHODS AND MATERIALS: We retrospectively identified patients treated with definitive external beam RT without hormonal therapy who had at least two itPSA measurements. We calculated the adjusted ratio of rise (ARR) in itPSA relative to the pretreatment baseline PSA for each patient. This was defined as ln(maximal itPSA + 1)/ln(baseline PSA + 1). We stratified patients according to an ARR of <1 vs. >1.1. This corresponded to an approximately <30% vs. >30% increase in PSA during RT. Univariate and multivariate analyses were performed examining for biochemical failure-free survival (BFFS) and overall survival (OS). RESULTS: At a median follow-up of 74 months, we identified 307 patients who met our criteria. Univariate analysis revealed that patients with an ARR of <1.1 (n = 182) had statistically significant inferior BFFS and OS compared with those with an ARR of >1.1 (n = 125). The median BFFS and OS for these two groups was 51 vs. 101 months (p = 0.001) and 96 vs. 128 months (p = 0.01), respectively. On multivariate analysis, the effect of ARR on the risk of biochemical failure for patients with an ARR of <1.1 was significant (p = 0.03) only during the first year after RT. In contrast, the effect of the ARR on OS remained significant for a full 5 years (p = 0.05). CONCLUSION: The results of our study have shown that an ARR of <1.1 predicts for inferior BFFS and OS in patients treated with RT alone. PSA measurement during RT is a novel clinical tool that could be used to identify patients who might warrant more aggressive therapeutic intervention.

Limited-stage extrapulmonary small cell carcinoma: outcomes after modern chemotherapy and radiotherapy.

BACKGROUND: The purpose of this study was to determine the clinical outcomes and patterns of failure of limited-stage extrapulmonary small cell carcinoma (EPSCC) treated with modern chemotherapy and radiation (RT). METHODS: We retrospectively identified 18 patients with limited-stage EPSCC treated definitively with three-dimensional conformal RT or intensity modulated radiation therapy and chemotherapy. Patients were treated between November 1987 and May 2006. Primary sites of disease included head and neck (n = 7), genitourinary (n = 7), gynecologic (n = 3), and gastrointestinal (n = 1). Chemotherapy consisted of combined platinum and etoposide in 88% of patients. The median number of chemotherapy cycles was 4 (range 3-6), and the median RT dose was 62 Gy (range 32.4-85 Gy). No patient received prophylactic cranial radiation. RESULTS: With a median follow-up for all patients of 14 months (range 4-42 months), the median overall survival was 17 months, and median disease-free survival was 6 months. Eleven percent (2 of 18) of patients had a locoregional failure, and 78% (14 of 18) had a distant failure. One of these patients had a brain failure. There were no significant differences between the overall survival for patients with gynecologic, head and neck, and genitourinary disease. CONCLUSIONS: Despite modern chemotherapy and RT, patients with limited-stage EPSCC do poorly. Consistent with previous findings the majority of the first failures are distant. Brain failures in this series were uncommon despite no prophylactic cranial radiation. These findings support the need for further studies in an attempt to improve systemic therapies for this disease.

Signaling pathways in NSCLC as a predictor of outcome and response to therapy.

The 5-year survival rate for patients with stage III non-small cell lung cancer (NSCLC) is 10%. A number of genetic alterations are associated with this disease including mutations and amplifications of EGFR (70%) and Ras (20-30%), both of which are upstream of PI3K. Our previous data show that these regulate tumor radiation sensitivity. Here we ask whether the activation of this pathway has prognostic relevance in NSCLC. Two series of patients were retrospectively analyzed. The first series consisted of 23 Stage III NSCLC patients treated preoperatively with a chemo/radiation protocol. The second consisted of 12 Stage III NSCLC patients treated with chemo/ radiation without surgery who had survived more than 2 years. Expression levels of EGFR and Her-2 were assessed by immunohistochemical staining. PI3K signaling was evaluated by staining for phosphorylated Akt (P-Akt), a downstream target of PI3K. The staining for EGFR, Her-2, and P-Akt were related to outcome in the two groups. Additionally, the importance of PI3K signaling was evaluated in 3 NSCLC cell lines using a pharmacological blockade of PI3K by LY294002. In the first series of patients, 43% were positive for EGFR, 5% for Her-2, and 82.6% for P-Akt. Of the survivors, 25% were positive for EGFR, 0% for Her-2, and 42% for P-Akt. For P-Akt, this difference had a probability calculation of 0.003. The three NSCLC cell lines that we tested were found to have high levels of P-Akt. Pharmacologically inhibiting PI3K led to decreased Akt phosphorylation and radio sensitization of all three cell lines. The finding that NSCLC survivors treated by radiation have lower levels of PI3K and Akt signaling is consistent with the idea that inhibition of Akt leads to radio sensitization. This further suggests that Akt might be a useful target for sensitization of NSCLC to radiation.