Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation.

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

Pre-treatment neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are prognostic of progression in early stage classical Hodgkin lymphoma.

To determine whether pre-treatment neutrophil/lymphocyte (NLR) or platelet/lymphocyte ratios (PLR) are predictive for progression in early-stage classical Hodgkin lymphoma (cHL), we derived NLR and PLR values for 338 stage I/II cHL patients and appropriate cut-off point values to define progression. Two-year freedom from progression (FFP) for patients with NLR ≥6·4 was 82·2% vs. 95·7% with NLR <6·4 (P < 0·001). Similarly, 2-year FFP was 84·3% for patients with PLR ≥266·2 vs. 96·1% with PLR <266·2 (P = 0·003). On univariate analysis, both NLR and PLR were significantly associated with worse FFP (P = 0·001). On multivariate analysis, PLR remained a significant, independent prognostic factor (P < 0·001).

Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone?

Early-stage classical Hodgkin lymphoma (HL) patients are evaluated by an end-of-chemotherapy positron emission tomography-computed tomography (eoc-PET-CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc-PET-CT 5-point score (5PS). Secondarily, we assessed whether patients with a positive eoc-PET-CT (5PS of 4-5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I-II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30·6 Gy. Five-year FFP was 97%. Five-year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1-2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0·001). Patients with positive eoc-PET-CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a 'bounce' in ≥1 PET-CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc-PET-CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone.

A PET Radiomics Model to Predict Refractory Mediastinal Hodgkin Lymphoma.

First-order radiomic features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are associated with disease progression in early-stage classical Hodgkin lymphoma (HL). We hypothesized that a model incorporating first- and second-order radiomic features would more accurately predict outcome than MTV or TLG alone. We assessed whether radiomic features extracted from baseline PET scans predicted relapsed or refractory disease status in a cohort of 251 patients with stage I-II HL who were managed at a tertiary cancer center. Models were developed and tested using a machine-learning algorithm. Features extracted from mediastinal sites were highly predictive of primary refractory disease. A model incorporating 5 of the most predictive features had an area under the curve (AUC) of 95.2% and total error rate of 1.8%. By comparison, the AUC was 78% for both MTV and TLG and was 65% for maximum standardize uptake value (SUVmax). Furthermore, among the patients with refractory mediastinal disease, our model distinguished those who were successfully salvaged from those who ultimately died of HL. We conclude that our PET radiomic model may improve upfront stratification of early-stage HL patients with mediastinal disease and thus contribute to risk-adapted, individualized management.

Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL.

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.

Chemotherapy Response Assessment by FDG-PET-CT in Early-stage Classical Hodgkin Lymphoma: Moving Beyond the Five-Point Deauville Score.

PURPOSE: In early-stage classical Hodgkin lymphoma, fluorodeoxyglucose positron emission tomography (PET)-computed tomography (CT) scans are performed routinely after chemotherapy, and the 5-point Deauville score is used to report the disease response. We hypothesized that other PET-CT parameters, considered in combination with Deauville score, would improve risk stratification. METHODS AND MATERIALS: Patients treated for stage I to II Hodgkin lymphoma from 2003 to 2013, who were aged ≥18 years and had analyzable PET-CT scans performed before and after chemotherapy, were eligible. The soft tissue volume (STV), maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis were recorded from the PET-CT scans before and after chemotherapy. Reductions were defined as 1 - (final PET-CT value)/(corresponding initial PET-CT value). The primary endpoint was freedom from progression (FFP). RESULTS: For 202 patients treated with chemotherapy with or without radiation therapy, the 5-year FFP was 89% (95% confidence interval 85%-93%). All PET-CT parameters were strongly associated with the Deauville score (P<.001) and FFP (P<.0001) on univariate analysis. The Deauville score was highly predictive of FFP (C-index 0.89) but was less discriminating in the Deauville 1 to 4 subset (C-index 0.67). Therefore, we aimed to identify PET-CT parameters that would improve risk stratification for this subgroup (n=187). STV reduction was predictive of outcome (C-index 0.71) and was dichotomized with an optimal cutoff of 0.65 (65% reduction in STV). A model incorporating the Deauville score and STV reduction predicted FFP more accurately than either measurement alone in the Deauville 1 to 4 subset (C-index 0.83). The improvement in predictive accuracy of this composite measure compared with the Deauville score alone met statistical significance (P=.045). CONCLUSIONS: The relative reduction in tumor size is an independent predictor of outcome. Combined with the Deauville score, it might improve risk stratification and contribute to response-adapted individualization of therapy.

Accelerated partial breast irradiation: advances and controversies.

The management of localized breast cancer has changed dramatically over the past three to four decades. Breast-conserving therapy, which involved lumpectomy followed by adjuvant irradiation, is now widely considered the standard of care in women with early-stage breast cancer. Accelerated partial breast irradiation (APBI), which involves focal irradiation of the lumpectomy cavity over a short period of time, has developed over the past two decades as an alternative to whole breast irradiation (WBI). Multiple APBI modalities have been developed including brachytherapy, external beam irradiation, and intraoperative irradiation. These new techniques have provided early-stage breast cancer patients with shorter treatment duration and more focused irradiation, delivering very high biological doses to the region at a high risk of failures over a much shorter treatment course as compared with conventional radiotherapy. However, the advantages of APBI over conventional radiotherapy are controversial, including a higher risk of complications reported in retrospective literature and shorter follow-up duration in the intraoperative APBI trials. Nevertheless, APBI presents a valuable alternative to WBI for a selected population of women with early-stage breast cancer.

Chemotherapy in non-small cell lung cancer: opportunities for advancement.

Locally advanced non-small cell lung cancer (NSCLC) continues to be a challenging disease to treat. With high rates of both local and distant failures, there is significant interest in finding more biologically active chemotherapy regimens that can contribute to reduce both failures. The phase III PROCLAIM trial, recently published in the Journal of Clinical Oncology entitled "PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer", compared two different chemotherapy regimens given concurrently with radiotherapy in patients with stage III non-squamous lung cancer: pemetrexed plus cisplatin versus cisplatin plus etoposide. Both groups received consolidation chemotherapy. After enrolling 598 of planned 600 patients, the study was stopped early due to futility as no difference was seen in the primary end-point of overall survival. Since PROCLAIM was designed as a superiority trial, these results suggest that pemetrexed regimens do not offer a clinical advantage over standard cisplatin plus etoposide. There are some subpopulations who might still benefit from pemetrexed, especially if clinicians are concerned about myelosuppression-related adverse events. Future trials are needed to investigate novel biologic agents and irradiation techniques that can result in more durable local and distant disease control in locally advanced NSCLC.

Clinical outcomes, toxicity, and cosmesis in breast cancer patients with close skin spacing treated with accelerated partial breast irradiation (APBI) using multi-lumen/catheter applicators.

PURPOSE: Accelerated partial breast irradiation (APBI) using a single-lumen device is associated with better cosmetic outcomes if the spacing between the applicator and skin is > 7 mm. However, there are no reports addressing the late toxicity and clinical outcomes in patients treated with single-entry multi-lumen/catheter applicators who had close skin spacing (7 mm or less). We undertook this study to report clinical outcome, acute and late toxicity as well as cosmesis of early stage breast cancer patients with close skin spacing treated with APBI using multi-lumen or multi-catheter devices. MATERIAL AND METHODS: This is a retrospective study of all breast cancer patients who had undergone APBI using single-entry multi-lumen/catheter devices in a single institution between 2008 to 2012. The study was limited to those with ≤ 7 mm spacing between the device and skin. RESULTS: We identified 37 patients and 38 lesions with skin spacing of ≤ 7 mm. Seven lesions (18%) had spacing of ≤ 3 mm. Median follow-up was 47.5 months. There was one case of ipsilateral breast recurrence and one ipsilateral axillary recurrence. Based on RTOG criteria, 22 treated lesions experienced grade 1 and 9 lesions experienced grade 2 toxicity. Twenty-one lesions experienced late grade 1 toxicity. One patient had to undergo mastectomy due to mastitis. Twenty-four treated breasts showed excellent and 11 had good cosmetic outcome. Overall cosmesis trended towards a significant correlation with skin spacing. However, all patients with ≤ 3 mm skin spacing experienced acute and late toxicities. CONCLUSIONS: Accelerated partial breast irradiation can be safely performed in patients with skin spacing of ≤ 7 mm using single-entry multi-lumen/catheter applicators with excellent cosmetic outcomes and an acceptable toxicity profile. However, skin spacing of ≤ 3 mm is associated with acute and late toxicity and should be avoided if possible.

Primary cutaneous B-cell lymphoma (non-leg type) has excellent outcomes even after very low dose radiation as single-modality therapy.

Primary cutaneous B cell lymphomas (PCBCL) are rare; although data on outcomes and treatment are limited, traditionally they have been treated with radiation doses in excess of 24 Gy. We retrospectively identified and reviewed all cases of PCBCL treated at our institution from 2002-2014. Thirty-nine patients with PCBCL (42 lesions) were identified. Radiation was the only treatment for most patients. All lesions had a complete response and none had in-field failures; seven patients had out-of-field relapses, three of which were salvaged with radiation therapy. No differences in PFS or OS were found for patients given low-dose (≤ 12 Gy) versus high-dose (> 12 Gy) radiation. PCBCL is an indolent entity with a long clinical course and excellent response to radiation therapy and successful salvage of recurrent disease, even when doses are as low as 4 Gy. Given the above findings, we recommend the initial use of low-dose irradiation for PCBCL.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation.

PURPOSE: The German Hodgkin Study Group HD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). METHODS AND MATERIALS: We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. RESULTS: The median follow-up time was 5.0 years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6 year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. CONCLUSIONS: Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

PURPOSE: Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. METHODS AND MATERIALS: We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. RESULTS: A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. CONCLUSIONS: The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

Long-term outcome of accelerated partial breast irradiation using a multilumen balloon applicator in a patient with existing breast implants.

PURPOSE: Accelerated partial breast irradiation is now an accepted component of breast-conserving therapy. However, data regarding long-term outcomes of patients treated with multilumen catheter systems who have existing breast implants are limited. METHODS AND MATERIALS: We report the treatment and outcome of our patient who had existing bilateral silicone subpectoral implants at the time of presentation. Ultrasound-guided core needle biopsy of the right breast showed infiltrating mucinous carcinoma. Right breast lumpectomy revealed an 8 mm area of infiltrating ductal carcinoma with mucinous features and nuclear grade 1. A 4-5 cm Contura (Bard Biopsy Systems, Tempe, AZ) device was placed, and she was treated over the course of 5 days twice daily to a dose of 34 Gy using a high-dose-rate iridium-192 source. RESULTS: The planning target volume for evaluation was 73.9 cc. The percentage of the planning target volume for evaluation receiving 90%, 95%, and 100% of the prescribed dose was 99.9%, 99.3%, and 97.8%, respectively. The total implant volume was 234.5 cc and received a mean dose of 15.4 Gy and a maximum dose of 72.8 Gy. The percentage of implant volume receiving 50%, 75%, 100%, and 200% of the prescribed dose was 31.1%, 16.5%, 8.6%, 2.0%, and 0%, respectively. Maximum skin dose was 97% of the prescribed dose. With a followup of nearly 5 years, she continues to be cancer free with minimal late toxicities and good to excellent cosmetic outcome. CONCLUSIONS: Accelerated partial breast irradiation using a multilumen balloon applicator in patients with existing breast implants can safely be performed with excellent long-term cosmetic outcome. Further studies are needed to establish the absolute dosimetric tolerance of breast implants.

Dosimetric considerations and early clinical experience of accelerated partial breast irradiation using multi-lumen applicators in the setting of breast augmentation.

PURPOSE: Accelerated partial breast irradiation (APBI) is an accepted treatment option in breast-conserving therapy for early stage breast cancer. However, data regarding outcomes of patients treated with multi-lumen catheter systems who have existing breast implants is limited. The purpose of this study was to report treatment parameters, outcomes, and possible dosimetric correlation with cosmetic outcome for this population of patients at our institution. MATERIAL AND METHODS: We report the treatment and outcome of seven consecutive patients with existing breast implants and early stage breast cancer who were treated between 2009 and 2013 using APBI following lumpectomy. All patients were treated twice per day for five days to a total dose of 34 Gy using a high-dose-rate (192)Ir source. Cosmetic outcomes were evaluated using the Harvard breast cosmesis scale, and late toxicities were reported using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity schema. RESULTS: After a mean follow-up of 32 months, all patients have remained cancer free. Six out of seven patients had an excellent or good cosmetic outcome. There were no grade 3 or 4 late toxicities. The average total breast implant volume was 279.3 cc, received an average mean dose of 12.1 Gy, and a maximum dose of 234.1 Gy. The average percentage of breast implant volume receiving 50%, 75%, 100%, 150%, and 200% of the prescribed dose was 15.6%, 7.03%, 4.6%, 1.58%, and 0.46%, respectively. Absolute volume of breast implants receiving more than 50% of prescribed dose correlated with worse cosmetic outcomes. CONCLUSIONS: Accelerated partial breast irradiation using a multi-lumen applicator in patients with existing breast implants can safely be performed with promising early clinical results. The presence of the implant did not compromise the ability to achieve dosimetric criteria; however, dose to the implant and the irradiated implant volume may be related with worse cosmetic outcomes.

Incidence and predictors of Lhermitte's sign among patients receiving mediastinal radiation for lymphoma.

PURPOSE: To prospectively examine the risk of developing Lhermitte's sign (LS) in patients with lymphoma treated with modern-era chemotherapy followed by consolidation intensity-modulated radiation therapy. METHODS: We prospectively interviewed all patients with lymphoma who received irradiation to the mediastinum from July 2011 through April 2014. We extracted patient, disease, and treatment-related variables from the medical records of those patients and dosimetric variables from treatment-planning systems and analyzed these factors to identify potential predictors of LS with Pearson chi-square tests. RESULTS: During the study period 106 patients received mediastinal radiation for lymphoma, and 31 (29 %) developed LS. No correlations were found between LS and any of the variables examined, including total radiation dose, maximum point dose to the spinal cord, volume receiving 105 % of the dose, and volumes receiving 5 or 15 Gy. CONCLUSION: In this group of patients, treatment with chemotherapy followed by intensity-modulated radiation therapy led to 29 % developing LS; this symptom was independent of radiation dose and seemed to be an idiosyncratic reaction. This relatively high incidence could have resulted from prospective use of a structured interview.

Outcomes After Chemotherapy Followed by Radiation for Stage IIB Hodgkin Lymphoma With Bulky Disease.

BACKGROUND: Treatment of stage IIB bulky Hodgkin lymphoma (HL) is controversial, with treatment varying by institution. We evaluated patients with IIB bulky disease treated with combined-modality therapy at our institution by describing their long-term outcomes. PATIENTS AND METHODS: We identified 149 consecutive patients with stage IIB bulky HL treated between 1971 and 2012. Clinical, pathologic, and treatment characteristics were extracted from medical records. Actuarial overall survival (OS) and relapse-free survival (RFS) were calculated by the Kaplan-Meier method. Independent factors associated with these outcomes were identified by a multivariate Cox regression model. Outcomes were further compared against comparison groups of both advanced-stage and stage IIB patients treated between 1971 and 2009. RESULTS: The 8-year OS rate for patients with stage IIB bulky disease who received combined-modality ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and radiation was 88.8%; the 8-year RFS rate was 76.8%. On multivariate analysis, age < 40 years (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.14-0.57; P = .001), receipt of ABVD (vs. MOPP [mechlorethamine, vincristine, procarbazine, prednisone]; HR, 0.32; 95% CI, 0.10-0.88; P = .028), and radiation dose ≥ 30.1 Gy (HR, 0.25; 95% CI, 0.11-0.65; P = .006) were associated with improved OS. Cardiac events (n = 11) and secondary malignancies (n = 11) only occurred in patients treated before 1995. A subgroup analysis demonstrated significantly improved survival in IIB bulky versus advanced-stage patients (8-year OS, 73.4% vs. 57.4%; P = .008). Improved outcomes in patients with in IIB bulky disease were especially evident in the modern era (> 1995; P = .004). CONCLUSION: Patients with stage IIB bulky HL had excellent outcomes after combined-modality therapy. Treatment strategies have changed substantially over time, with concomitant improvements in disease outcomes and long-term toxicities.

Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma.

PURPOSE: Few studies to date have evaluated factors associated with the development of radiation pneumonitis (RP) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), especially in patients treated with contemporary radiation techniques. These patients represent a unique group owing to the often large radiation target volumes within the mediastinum and to the potential to receive several lines of chemotherapy that add to pulmonary toxicity for relapsed or refractory disease. Our objective was to determine the incidence and clinical and dosimetric risk factors associated with RP in lymphoma patients treated with intensity modulated radiation therapy (IMRT) at a single institution. METHODS AND MATERIALS: We retrospectively reviewed clinical charts and radiation records of 150 consecutive patients who received mediastinal IMRT for HL and NHL from 2009 through 2013. Clinical and dosimetric predictors associated with RP according to Radiation Therapy Oncology Group (RTOG) acute toxicity criteria were identified in univariate analysis using the Pearson χ(2) test and logistic multivariate regression. RESULTS: Mediastinal radiation was administered as consolidation therapy in 110 patients with newly diagnosed HL or NHL and in 40 patients with relapsed or refractory disease. The overall incidence of RP (RTOG grades 1-3) was 14% in the entire cohort. Risk of RP was increased for patients who received radiation for relapsed or refractory disease (25%) versus those who received consolidation therapy (10%, P=.019). Several dosimetric parameters predicted RP, including mean lung dose of >13.5 Gy, V20 of >30%, V15 of >35%, V10 of >40%, and V5 of >55%. The likelihood ratio χ(2) value was highest for V5 >55% (χ(2) = 19.37). CONCLUSIONS: In using IMRT to treat mediastinal lymphoma, all dosimetric parameters predicted RP, although small doses to large volumes of lung had the greatest influence. Patients with relapsed or refractory lymphoma who received salvage chemotherapy and hematopoietic stem cell transplantation were at higher risk for symptomatic RP.

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice.

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe⁻/⁻ mice fed a chow or Western- type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1⁻/⁻ mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1- and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe⁻/⁻ mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.