Positron Emission Tomography-Guided Bone Marrow-Sparing Radiation Therapy for Locoregionally Advanced Cervix Cancer: Final Results From the INTERTECC Phase II/III Trial.

PURPOSE: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS. RESULTS: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P = .048) and in the combined cohort (13% vs 35%, χ2P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group. CONCLUSIONS: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

Failure of IVIG in steroid-responsive autoimmune glial fibrillary acidic protein astrocytopathy: A case report.

OBJECTIVE: To advocate for high-dose steroids, not intravenous immunoglobulins (IVIG), as first-line treatment for Anti-glial fibrillary acidic protein (GFAP) associated meningoencephalomyelitis. BACKGROUND: A novel IgG antibody against GFAP was associated with relapsing autoimmune meningoencephalomyelitis. DESIGN/METHODS: Here, we present an investigational case report to highlight continuing challenges in diagnosing and managing Anti-GFAP associated meningoencephalomyelitis. RESULTS: Our 45-year-old Asian female presented to the emergency department with an acute onset low-grade fever and back pain associated with headaches, intermittent confusion, vision changes, and hand tremors. A review of systems identified no inciting factors. Past medical history was significant only for chronic Hepatitis B without significant viral load. Neurological exam was significant for decreased visual acuity, high-frequency hand tremor, and gait imbalance. Serum labs were within normal limits. Video electroencephalogram captured tremors without electrographical correlates. Cerebrospinal fluid analysis revealed lymphocytic leukocytosis, elevated protein, and reduced glucose. A wide range of infectious studies including bacterial, viral, and fungal cultures were negative. MRI brain and spine showed leptomeningeal enhancement. CT chest abdomen pelvis were negative. Patient continued to decline clinically, working diagnosis was possible paraneoplastic syndrome with pending laboratory results. She was given a five-day course of intravenous immunoglobulin as a therapeutic trial,hh however, her symptoms did not improve. A broader investigation with repeat lumbar puncture, imaging and serum laboratory failed to provide any additional information. She was treated symptomatically with minimal benefit. A trial of steroids was given with clinical improvement and continued stability. Paraneoplastic panels returned positive for high levels of Anti-GFAP antibody for confirmation of diagnosis. CONCLUSIONS: Autoimmune GFAP astrocytopathy is a rare cause of meningoencephalomyelitis that remains difficult to diagnose despite emerging laboratory studies. Our case adds to the limited literature by proposing that high-dose steroids, not IVIG, should be the first-line treatment. Further investigations are underway to assess implications of this finding in disease pathophysiology and management.

Risk of Pelvic Fracture With Radiation Therapy in Older Patients.

PURPOSE: Older patients undergoing radiation therapy (RT) for pelvic malignancies are at increased risk for pelvic fracture, which is associated with significant morbidity and mortality. RT techniques such as brachytherapy or intensity modulated RT (IMRT) allow for more conformal dose distributions, but it is not known whether the risk for pelvic fracture varies by RT modality. METHODS AND MATERIALS: This observational cohort study involved 28,354 patients ≥65 years old, treated with RT for pelvic malignancies. We evaluated the relative risk of pelvic fracture by type of RT when accounting for baseline factors. To test for nonspecific effects, we also evaluated risk of nonpelvic fractures in the same population. RESULTS: The 5-year incidence of pelvic fractures was 12.7% (95% confidence interval [CI], 11.6%-13.8%), 11.8% (10.8%-12.8%), and 3.7% (3.4%-4.0%) for patients with gastrointestinal, gynecologic, and prostate cancer, respectively. On multivariable analysis, being treated with IMRT (hazard ratio, 0.85; 95% CI, 0.73-0.99) or brachytherapy therapy alone (hazard ratio, 0.43; 95% CI, 0.34-0.54) was associated with a reduced hazard for pelvic fractures compared with 3D conformal radiation therapy in female patients. In contrast, there was no association with RT modality and the hazard for nonpelvic fractures among females. There was no significant association between pelvic fractures and IMRT or brachytherapy for male patients. White race, advanced age, and higher comorbidity were associated with an increased hazard for pelvic fracture. CONCLUSIONS: IMRT and brachytherapy were associated with a reduced risk of pelvic fractures in older women undergoing RT for pelvic malignancies. Pelvic insufficiency fracture risk should be considered when treating with pelvic RT.

Comparison of Hematologic Toxicity and Bone Marrow Compensatory Response in Head and Neck vs. Cervical Cancer Patients Undergoing Chemoradiotherapy.

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m2. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 103 per µL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.

Phase 1 Trial of Concurrent Gemcitabine and Cisplatin with Image Guided Intensity Modulated Radiation Therapy for Locoregionally Advanced Cervical Carcinoma.

PURPOSE: The use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC. METHODS AND MATERIALS: We conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%. RESULTS: Between February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level. CONCLUSIONS: IG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing.

A Matched Case-Control Analysis of Clinical Outcomes for Patients With Inflammatory Bowel Disease and Rectal Cancer Treated With Pelvic Radiation Therapy.

PURPOSE: Inflammatory bowel disease (IBD) is a known risk factor for rectal cancer, and RT is often an important part of therapy for these patients. Previously published studies have raised concerns for increased rates of RT toxicity in patients with IBD. We performed a matched case-control analysis to assess RT-related toxicity in a large sample of U.S. veterans afflicted with IBD and rectal cancer. METHODS AND MATERIALS: We identified 186 veterans with rectal cancer (71 Patients with IBD treated with RT, 71 matched controls without IBD treated with RT, and 44 nonmatched controls with IBD treated without RT) diagnosed between 2000 and 2015. We analyzed short- and long-term toxicity and mortality in multivariable logistic regression, Fine-Gray, and frailty models, adjusting for potential confounders. RESULTS: When comparing patients with and without IBD treated with RT there were no differences in RT breaks (adjusted odds ratio [aOR], 1.70; 95% confidence interval [CI], 0.38-4.76; P = .49) or the need for antidiarrheal medication during RT (aOR, 1.53; 95% CI, 0.70-3.35; P = .29). There was a trend toward higher risk of hospital admission during RT for RT + patients with IBD (aOR, 2.69; 95% CI, 0.88-8.22; P = .08). There were higher rates of small bowel obstruction (OR, 15; 95% CI, 1.9-115; P = .009) and a trend toward higher rates of abdominopelvic adhesions (OR, 3.6; 95% CI, 0.98-13; P = .05) in the RT + IBD cohort. However, compared with a nonmatched cohort of patients with IBD treated without RT there were no differences in long-term complications. No differences were found in other acute or long-term toxicities. Rectal cancer-specific mortality appeared similar across all cohorts. CONCLUSIONS: RT does not appear to increase the rates of acute or long-term toxicity in patients with IBD and should be considered a standard part of therapy when otherwise indicated.