Adil S. Akthar

Limitations of PET/CT in the Detection of Occult N1 Metastasis in Clinical Stage I(T1-2aN0) Non-Small Cell Lung Cancer for Staging Prior to Stereotactic Body Radiotherapy.

Purpose/Objectives: Patients receiving stereotactic body radiotherapy for stage I non-small cell lung cancer are typically staged clinically with positron emission tomography–computed tomography. Currently, limited data exist for the detection of occult hilar/peribronchial (N1) disease. We hypothesize that positron emission tomography–computed tomography underestimates spread of cancer to N1 lymph nodes and that future stereotactic body radiotherapy patients may benefit from increased pathologic evaluation of N1 nodal stations in addition to N2 nodes. Materials/Methods: A retrospective study was performed of all patients with clinical stage I (T1-2aN0) non-small cell lung cancer (American Joint Committee on Cancer, 7th edition) by positron emission tomography–computed tomography at our institution from 2003 to 2011, with subsequent surgical resection and lymph node staging. Findings on positron emission tomography–computed tomography were compared to pathologic nodal involvement to determine the negative predictive value of positron emission tomography–computed tomography for the detection of N1 nodal disease. An analysis was conducted to identify predictors of occult spread. Results: A total of 105 patients with clinical stage I non-small cell lung cancer were included in this study, of which 8 (7.6%) patients were found to have occult N1 metastasis on pathologic review yielding a negative predictive value for N1 disease of 92.4%. No patients had occult mediastinal nodes. The negative predictive value for positron emission tomography–computed tomography in patients with clinical stage T1 versus T2 tumors was 72 (96%) of 75 versus 25 (83%) of 30, respectively (P = .03), and for peripheral versus central tumor location was 77 (98%) of 78 versus 20 (74%) of 27, respectively (P = .0001). The negative predictive values for peripheral T1 and T2 tumors were 98% and 100%, respectively; while for central T1 and T2 tumors, the rates were 85% and 64%, respectively. Occult lymph node involvement was not associated with primary tumor maximum standard uptake value, histology, grade, or interval between positron emission tomography–computed tomography and surgery. Conclusion: Our results support pathologic assessment of N1 lymph nodes in patients with stage Inon-small cell lung cancer considered for stereotactic body radiotherapy, with the greatest benefit in patients with central and T2 tumors. Diagnostic evaluation with endoscopic bronchial ultrasound should be considered in the evaluation of stereotactic body radiotherapy candidates.

Effect of Endoscopic Bronchial Ultrasound on Outcomes for Stage I Non–Small-Cell Lung Cancer Patients Receiving Hypofractionated Radiotherapy

Micro‐Abstract In this study we retrospectively reviewed 92 clinical stage I non–small‐cell lung cancer patients treated with hypofractionated radiotherapy and found no statistically significant differences in 2‐year freedom from regional failure, disease‐free survival, or overall survival for endoscopic bronchial ultrasound (EBUS)‐staged versus non–EBUS‐staged patients. These results might point to intrinsic limitations of EBUS, competing risks to failure and cancer‐specific death, and effective salvage therapy in patients who had regional disease recurrence. Background: In this study we sought to determine if staging endoscopic bronchial ultrasound (EBUS) improves outcomes in stage I non–small‐cell lung cancer (NSCLC) patients who received hypofractionated radiation therapy (HFRT). Patients and Methods: Patients with stage I NSCLC treated with HFRT from 2008 to 2015 were retrospectively identified from 3 affiliated institutions. All patients underwent positron emission tomography/computed tomography staging and a subset of patients received pretreatment EBUS. Patients with and without pre‐radiation therapy EBUS were compared for baseline characteristics. The log rank test was used to compare Kaplan–Meier estimates. Univariate analysis (UVA) and multivariable analysis (MVA) were used to analyze the effect of factors on disease‐free survival (DFS) and overall survival (OS). Results: Ninety‐two patients met study criteria. Median follow‐up for the entire cohort was 21 months. Two‐year DFS and OS were 63% and 81%, respectively. Two‐year freedom from local, regional, and distant failure were 93%, 87%, and 87%, respectively. Thirty‐seven of 92 patients (40%) received pretreatment EBUS. There were no statistically significant differences in 2‐year freedom from regional failure rates, DFS, or OS for EBUS‐staged versus non–EBUS‐staged patients. On UVA, smaller tumor size (P = .03) and higher performance status (P = .05) were associated with improved OS. On MVA, tumor size retained significance for improved OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19‐0.97; P = .04) and higher performance status showed a trend toward improved OS (HR, 0.51; 95% CI, 0.23‐1.11; P = .09). Conclusion: In this retrospective series, we did not detect a difference in regional failure or survival outcomes among stage I NSCLC patients who received invasive staging with EBUS before HFRT.

Safety and Efficacy of Hypofractionated Radiation Therapy with Capecitabine in Elderly Patients with Urothelial Carcinoma

Background Bladder cancer is commonly diagnosed in patients ineligible for radical cystectomy or chemoradiotherapy (chemo‐RT) with cisplatin or fluorouracil with mitomycin. We assessed tolerability, efficacy, and toxicity of hypofractionated radiotherapy with capecitabine in this challenging population. Patients and Methods Patients with high‐grade urothelial bladder cancer ineligible for radical cystectomy or high‐intensity chemo‐RT underwent maximal transurethral resection of bladder tumor followed by capecitabine (median, 825 mg/m2 per day 2 times a day) and radiation (median, 55 Gy in 2.2 Gy per fraction). Patients underwent surveillance cystoscopy and imaging, and were evaluated for toxicity, freedom from local failure and freedom from distant metastasis, progression‐free survival, and overall survival. Results Eleven patients (median age, 80 years) with localized disease (n = 7), locally advanced disease (n = 3), or local‐only recurrence after cystectomy (n = 1) were treated. Four patients (35%) had an Eastern Cooperative Oncology Group performance status of 2; median Charlson comorbidity index was 5. There was 1 acute grade 3 genitourinary event (9%), 6 acute grade 3 hematologic events (55%) of lymphopenia, and no acute grade 4 or higher events or hospitalizations. Ten patients (91%) completed radiotherapy, while 4 patients (36%) temporarily discontinued capecitabine. The complete response rate in the bladder was 64%. Two patients (18%) experienced late grade 1/2 genitourinary toxicities, and 1 (9%) experienced a transient late grade 4 genitourinary toxicity. With a median follow‐up of 16.6 months, overall survival, progression‐free survival, freedom from local failure, and freedom from distant metastasis at 1 year were 82%, 55%, 100%, and 55%, respectively, and at 2 years were 61%, 41%, 80%, and 55%, respectively. Conclusion Hypofractionated chemo‐RT was well tolerated and was associated with a high rate of local control in this comorbid population, thus providing a treatment option for select bladder cancer patients. Micro‐Abstract Chemoradiotherapy with concurrent capecitabine is a potential treatment option for select elderly or infirm patients with bladder cancer. Eleven patients with poor performance status and comorbidities with a median age of 80 years were treated with this regimen and experienced a favorable toxicity profile with high rates of local control at a median follow‐up of 16 months.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines

Purpose Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. Methods and materials 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. Results With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. Conclusions More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Impact of Endoscopic Bronchial Ultrasound (EBUS) on Outcomes for Stage I Non-Small Cell Lung Cancer (NSCLC) Patients Receiving Hypofractionated Radiotherapy (HFRT)

Micro‐Abstract In this study we retrospectively reviewed 92 clinical stage I non–small‐cell lung cancer patients treated with hypofractionated radiotherapy and found no statistically significant differences in 2‐year freedom from regional failure, disease‐free survival, or overall survival for endoscopic bronchial ultrasound (EBUS)‐staged versus non–EBUS‐staged patients. These results might point to intrinsic limitations of EBUS, competing risks to failure and cancer‐specific death, and effective salvage therapy in patients who had regional disease recurrence. Background: In this study we sought to determine if staging endoscopic bronchial ultrasound (EBUS) improves outcomes in stage I non–small‐cell lung cancer (NSCLC) patients who received hypofractionated radiation therapy (HFRT). Patients and Methods: Patients with stage I NSCLC treated with HFRT from 2008 to 2015 were retrospectively identified from 3 affiliated institutions. All patients underwent positron emission tomography/computed tomography staging and a subset of patients received pretreatment EBUS. Patients with and without pre‐radiation therapy EBUS were compared for baseline characteristics. The log rank test was used to compare Kaplan–Meier estimates. Univariate analysis (UVA) and multivariable analysis (MVA) were used to analyze the effect of factors on disease‐free survival (DFS) and overall survival (OS). Results: Ninety‐two patients met study criteria. Median follow‐up for the entire cohort was 21 months. Two‐year DFS and OS were 63% and 81%, respectively. Two‐year freedom from local, regional, and distant failure were 93%, 87%, and 87%, respectively. Thirty‐seven of 92 patients (40%) received pretreatment EBUS. There were no statistically significant differences in 2‐year freedom from regional failure rates, DFS, or OS for EBUS‐staged versus non–EBUS‐staged patients. On UVA, smaller tumor size (P = .03) and higher performance status (P = .05) were associated with improved OS. On MVA, tumor size retained significance for improved OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19‐0.97; P = .04) and higher performance status showed a trend toward improved OS (HR, 0.51; 95% CI, 0.23‐1.11; P = .09). Conclusion: In this retrospective series, we did not detect a difference in regional failure or survival outcomes among stage I NSCLC patients who received invasive staging with EBUS before HFRT.

Original StudyEffect of Endoscopic Bronchial Ultrasound on Outcomes for Stage I Non–Small-Cell Lung Cancer Patients Receiving Hypofractionated Radiotherapy

Micro‐Abstract In this study we retrospectively reviewed 92 clinical stage I non–small‐cell lung cancer patients treated with hypofractionated radiotherapy and found no statistically significant differences in 2‐year freedom from regional failure, disease‐free survival, or overall survival for endoscopic bronchial ultrasound (EBUS)‐staged versus non–EBUS‐staged patients. These results might point to intrinsic limitations of EBUS, competing risks to failure and cancer‐specific death, and effective salvage therapy in patients who had regional disease recurrence. Background: In this study we sought to determine if staging endoscopic bronchial ultrasound (EBUS) improves outcomes in stage I non–small‐cell lung cancer (NSCLC) patients who received hypofractionated radiation therapy (HFRT). Patients and Methods: Patients with stage I NSCLC treated with HFRT from 2008 to 2015 were retrospectively identified from 3 affiliated institutions. All patients underwent positron emission tomography/computed tomography staging and a subset of patients received pretreatment EBUS. Patients with and without pre‐radiation therapy EBUS were compared for baseline characteristics. The log rank test was used to compare Kaplan–Meier estimates. Univariate analysis (UVA) and multivariable analysis (MVA) were used to analyze the effect of factors on disease‐free survival (DFS) and overall survival (OS). Results: Ninety‐two patients met study criteria. Median follow‐up for the entire cohort was 21 months. Two‐year DFS and OS were 63% and 81%, respectively. Two‐year freedom from local, regional, and distant failure were 93%, 87%, and 87%, respectively. Thirty‐seven of 92 patients (40%) received pretreatment EBUS. There were no statistically significant differences in 2‐year freedom from regional failure rates, DFS, or OS for EBUS‐staged versus non–EBUS‐staged patients. On UVA, smaller tumor size (P = .03) and higher performance status (P = .05) were associated with improved OS. On MVA, tumor size retained significance for improved OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19‐0.97; P = .04) and higher performance status showed a trend toward improved OS (HR, 0.51; 95% CI, 0.23‐1.11; P = .09). Conclusion: In this retrospective series, we did not detect a difference in regional failure or survival outcomes among stage I NSCLC patients who received invasive staging with EBUS before HFRT.

Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus.

Case Report A 30-year-old man presented with a history of progressive shortness of breath for 3 months and fevers and right-sided chest pain for 2 weeks. The patient’s oncologic history was significant for a neuroblastoma at age 6 years that was treated with right nephrectomy, high-dose chemotherapy, 12 Gy total-body irradiation, and autologous stem-cell transplantation. Five years later, he was diagnosed with hepatitis C that was attributed to blood transfusions. Despite treatment with several interferon-based therapies, the hepatitis C persisted and progressed to cirrhosis. This was later complicated by hepatocellular carcinoma (HCC) and end-stage liver disease, for which the patient underwent an orthotopic liver transplantation. He began receiving tacrolimus, a calcineurin inhibitor, for immunosuppression, and surveillance abdominal imaging for the next 5 years was negative for HCC recurrence. The patient subsequently presented with shortness of breath, fevers, and right-sided chest pain. Computed tomography demonstrated a new mediastinal mass and large right-sided pleural effusion. Bronchoscopy with transbronchial fine-needle aspiration of a right paratracheal lymph node showed necrotic cells that were consistent with carcinoma. Sternotomy revealed a retrocaval mass adherent to the superior vena cava, precluding curative resection. Biopsy yielded cytokeratin CAM 5.2–positive necrotic cells. Given the history of HCC and elevated -fetoprotein, these findings were consistent with metastatic HCC. Sorafenib was started, but development of a total-body rash required discontinuation. Because of neutropenia, the patient was not considered a candidate for chemotherapy. The immunosuppression was then changed to the mTOR inhibitor sirolimus at a dose of 1 mg orally once per day and 2 mg orally once every other day to take advantage of its antineoplastic benefits. However, repeat imaging demonstrated progressive mediastinal disease with mass effect on the left brachiocephalic vein. Given the concern with respect to superior vena cava syndrome, the patient elected to proceed with a course of aggressive palliative RT. Sixty Gy in 2-Gy fractions using three-dimensional conformal RT with 6 megavoltage (MV) photon beams was prescribed. Segments and wedges were used to spare critical structures. To adequately cover the target volume, the esophagus (shown in medium blue in Fig 1A) was included in the planning target volume (red color wash) and the 100% isodose line (red). The esophageal mean dose was 19.2 Gy, maximum dose was 62.8 Gy, and volume receiving 60 Gy (V60) was 4.7% (1.1 cm). After receiving 6 Gy, the patient reported symptoms of heartburn. Famotidine 20 mg orally was increased to twice per day. At 16 Gy, the patient reported mild odynophagia, which was consistent with acute grade 1 esophageal toxicity. He was prescribed 10 mL of sucralfate suspension (100 mg/mL) 1 hour before meals and before bedtime, 10 mL of 1:1:1 viscous lidocaine 2%/liquid Maalox (Novartis, Summit, NJ)/diphenhydramine elixir every 6 hours as needed, and pantoprazole 40 mg orally once per day. After receiving 22 Gy, the patient developed severe retrosternal chest pain when swallowing that was consistent with acute grade 3 esophagitis. He was prescribed oxycodone 5 mg orally as needed every 4 to 6 hours and 10 mL of nystatin swish and swallow (100,000 U/mL) four times per day. His symptoms