Pulmonary diseases in patients with classical Hodgkin lymphoma relative to a matched background population: A Danish national cohort study.

Late toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin-containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population-based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age- and sex-matched comparators from the background population. Median follow-up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30-3.68]), with a 10-year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35-26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43-2.76]), with a 10-year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43-1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B-symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work-up of pulmonary symptoms.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

A systematic review on clinical adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) patients' anatomy may undergo significant changes during radiotherapy (RT). This potentially affects dose distribution and compromises conformity between planned and delivered dose. Adaptive radiotherapy (ART) is a promising technique to overcome this problem but requires a significant workload. This systematic review aims to estimate the clinical and dosimetric benefits of ART using prospective data. MATERIAL AND METHODS: A search on PubMed and Web of Science according to the PRISMA guidelines was made on Feb 6, 2023. Search string used was: 'adaptive radiotherapy head neck cancer'. English language filter was applied. All studies were screened for inclusion on title and abstract, and the full text was read and discussed in the research group in case of uncertainty. Inclusion criteria were a prospective ART strategy for HNC investigating clinical or dosimetric outcomes. RESULTS: A total of 1251 articles were identified of which 15 met inclusion criteria. All included studies were published between 2010 and 2023 with a substantial diversity in design, endpoints, and nomenclature. The number of patients treated with ART was small with a median of 20 patients per study (range 4 to 86), undergoing 1-2 replannings. Mean dose to the parotid glands was reduced by 0.4-7.1 Gy. Maximum dose to the spinal cord was reduced by 0.5-4.6 Gy. Only five studies reported clinical outcome and disease control was excellent. Data on toxicity were ambiguous with some studies indicating reduced acute toxicity and xerostomia, while others found reduced quality of life in patients treated with ART. CONCLUSION: The literature on clinical ART in HNC is limited. ART is associated with small reductions in doses to organs at risk, but the influence on toxicity and disease control is uncertain. There is a clear need for larger, prospective trials with a well-defined control group.

A comparison of loco-regional relapse pattern in HPV positive vs negative oropharyngeal cancers following radiotherapy; relation to pretreatment FDG-PET and radiotherapy target volumes.

BACKGROUND: Previous studies have shown that a large proportion of relapses in head-and neck squamous cell carcinoma (HNSCC) following radiotherapy (RT) occur in the pretreatment FDG-PET avid volume (GTV-PET). The aim of the current work was to see if this was valid also in an oropharynx squamous cell carcinoma (OPSCC) only population, and to compare the loco-regional relapse pattern between HPV positive and HPV negative patients. MATERIAL AND METHODS: Among 633 OPSCC patients treated between 2009 and 2017, 46 patients with known HPV (p16) status and isolated loco-regional relapse were included. Oncologists contoured relapse volumes (RV) on relapse scans (PET/CT, CT or MR), which were thereafter deformed to match the anatomy of the planning CTs. The point of origin (center of volume) of the deformed RVs were determined and analyzed in relation to the RT target volumes (GTV-PET, GTV and CTVs). The relapse pattern was compared between HPV positive and HPV negative patients using Fischer's exact test. RESULTS: Sixty RVs were contoured in the 46 patients. 55% (95% CI 44-67%) of relapses originated in GTV-PET, while the other RT volumes harbored 12% (5-20%) (GTV), 18% (9-28%) (high risk CTV) and 5% (0-11%) (low risk CTV) of relapses. Six relapses were found outside the RT target volumes. No significant difference in relapse pattern between HPV positive and HPV negative patients was found (p = .95). CONCLUSION: There were no signs of difference in loco-regional relapse pattern between HPV positive and HPV negative patients. In agreement with previous findings, GTV-PET was the most frequent RT target volume of relapse.

Personalised therapy in follicular lymphoma - is the dial turning?

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed.

Reappraisal of the role of radiation therapy in lymphoma treatment.

Radiation therapy (RT) for lymphomas has improved dramatically with modern imaging and treatment techniques, encompassing only the necessary volume with minimal doses to normal structures. Prescribed radiation doses are reduced, and fractionation schedules are under revision. With effective systemic treatment only initial macroscopic disease is irradiated. With no or less effective systemic treatment, possible microscopic disease is also included. Risks of long-term side effects of RT have diminished dramatically and should be weighed against risks from more systemic treatment or increased risk of relapse. Lymphoma patients are often elderly, they tolerate modern limited RT very well. Lymphomas refractory to systemic treatments often remain radioresponsive, and brief, mild RT may offer effective palliation. New roles for RT are emerging with immune therapies. RT for "bridging," keeping the lymphoma under control while waiting for immune therapy, is well established. Enhancement of the immune response to lymphomas, so-called "priming," is being intensively researched.

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma: Lessons Learned.

PURPOSE: Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. METHODS AND MATERIALS: A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. RESULTS: Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. CONCLUSIONS: The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.

Increased incidence rates of positive blood cultures shortly after chemotherapy compared to radiotherapy among individuals treated for solid malignant tumours.

BACKGROUND: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated. METHODS: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated. FINDINGS: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified. INTERPRETATION: PBCs are not common, but when they occur, mortality is high.

Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial.

PURPOSE: The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979). METHODS: BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD. RESULTS: Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; P < .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively. CONCLUSION: BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.

Cardiovascular risk factors, radiation therapy, and myocardial infarction among lymphoma survivors.

BACKGROUND: Mediastinal radiation is associated with increased risk of myocardial infarction (MI) among non-Hodgkin lymphoma (NHL) survivors. OBJECTIVE: To evaluate how preexisting cardiovascular risk factors (CVRFs) modify the association of mediastinal radiation and MI among a national population of NHL survivors with a range of CVRFs. MATERIAL AND METHODS: Using Danish registries, we identified adults diagnosed with lymphoma 2000-2010. We assessed MI from one year after diagnosis through 2016. We ascertained CVRFs (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at lymphoma diagnosis. We used multivariable Cox regression to test the interaction between preexisting CVRFs and receipt of mediastinal radiation on subsequent MI. RESULTS: Among 3151 NHL survivors (median age 63, median follow-up 6.5 years), 96 were diagnosed with MI. Before lymphoma, 32% of survivors had ≥1 CVRF. 8.5% of survivors received mediastinal radiation. In multivariable analysis, we found that mediastinal radiation (HR = 1.96; 95% CI = 1.09-3.52), and presence of ≥1 CVRF (HR = 2.71; 95% CI = 1.77-4.15) were associated with an increased risk of MI. Although there was no interaction on the relative scale (p = 0.14), we saw a clinically relevant absolute increase in risk for patients with CVRF from 10-year of MI of 10.5% without radiation to 29.5% for those undergoing radiation. CONCLUSION: Patients with CVRFs have an importantly higher risk of subsequent MI if they have mediastinal radiation. Routine evaluation of CVRFs and optimal treatment of preexisting cardiovascular disease should continue after receiving cancer therapy. In patients with CVRFs, mediastinal radiation should only be given if oncologic benefit clearly outweighs cardiovascular harm.

Patterns of relapse and long-term outcome in patients treated with a curative intent for advanced Hodgkin lymphoma.

BACKGROUND: Consolidation radiotherapy for advanced Hodgkin lymphoma (AHL) is controversial. Precise knowledge of the most likely relapse location is crucial for radiotherapy planning. We performed detailed patterns of relapse analyses and evaluated if initial bulky disease, initial 18F-fluoro-deoxy-glucose (FDG)-avidity and/or a residual mass on computed tomography (CT)-scan after chemotherapy are sites with a high risk of relapse. This information could provide guidance for optimal use of radiotherapy in AHL. MATERIAL AND METHODS: We included 133 patients treated with curatively intended chemotherapy for AHL. 23 patients received consolidation radiotherapy. For relapsed patients, imaging from diagnosis, response evaluation, relapse, and any radiotherapy planning, were retrieved and co-registered to determine the exact site(s) of relapse relative to initial site(s), residual mass(es) and to any irradiated volumes. Size and FDG-avidity of initial sites with later relapse, and residual CT-abnormalities after chemotherapy in these sites were registered. Survival analyses were done using the Kaplan-Meier method. RESULTS: Nine (6.8%) patients relapsed, eight in initially involved sites. One relapse was in an initially irradiated site (as well as other sites). Initial bulky disease, high initial FDG-uptake, and/or residual masses on CT-scan after chemotherapy did not predict sites with a high risk of relapse. Overall survival was 79.6% (95% CI, 72.7-86.5%) and 70.6% (95% CI, 62.4-78.8%) at 5 and 10 years, respectively. Time to progression analysis showed 91.8% (95% CI, 86.9-96.7%) and 90.7% (95% CI, 85.4-96.0%) without progression at 5 and 10 years, respectively. CONCLUSION: Current treatment strategies for AHL provide excellent disease control. Neither initial bulk, high initial FDG-uptake, nor a residual CT-abnormality post-chemotherapy seem to indicate sites with a high risk of relapse.

A phase 2 trial of deep-inspiration breath hold in radiotherapy of gastric lymphomas.

Background and purpose: Radiotherapy (RT) is an important part in the treatment of gastric lymphomas and the prognosis after radiotherapy is very good with a good chance of long-term survival, so prevention of long-term adverse effects is important. In patients with gastric lymphomas cardiac late effects are of most concern. The aim of this study was to assess if the dose to the heart could be reduced with deep inspiration breath-hold (DIBH) without compromising the dose to the target or increasing the risk of other late effects. Methods and patients: Fifteen patients with gastric lymphoma were included. RT plans were made using DIBH and Free breathing (FB) scans. Clinical target volume (CTV) was the stomach plus 1 cm margin. The heart and surrounding organs at risk (OAR) were contoured. Two sets of plan comparisons were made, one with 1 cm CTV to planning target volume (PTV) margin in both DIBH and FB and one set with an additional 5 mm CTV to PTV margin in cranio-caudal direction with FB. Datasets were analysed with Wilcoxon signed rank test for non-parametric paired data. Results: All patients tolerated the procedures and were treated with volumetric arc therapy technique in DIBH. Target coverage was kept equal between FB and DIBH, while a statistically significant reduction of the estimated does to the heart was seen with DIBH. Median mean heart dose was reduced from 7.1 Gy (5.7-12) to a median of 3.2 Gy (1.2-7.0) and heart V20 from a median of 54 (17-106) cm3 to 15. (0.0-78) cm3. The estimated mean doses to the liver, duodenum, pancreas and spinal cord were at the same level. Conclusion: This clinical trial of RT with DIBH for gastric lymphomas showed that the heart dose could be reduced without compromising PTV coverage. The doses to abdominal OARs were similar with FB and DIBH.

Response Evaluation Following Radiation Therapy With 18F-FDG PET/CT: Common Variants of Radiation-Induced Changes and Potential Pitfalls.

Radiation therapy (RT) is one of the cornerstones in cancer treatment and approximately half of all patients will receive some form of RT during the course of their cancer management. Response evaluation after RT and follow-up imaging with 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can be complicated by RT-induced acute, chronic or consequential effects. There is a general consensus that 18F-FDG PET/CT for response evaluation should be delayed for 12 weeks after completing RT to minimize the risk of false-positive findings. Radiation-induced late side effects in normal tissue can take years to develop and eventually cause symptoms that on imaging can potentially mimic recurrent disease. Imaging findings in radiation induced injuries depend on the normal tissue included in the irradiated volume and the radiation therapy regime including the total dose delivered, dose per fraction and treatment schedule. The intent for radiation therapy should be taken in consideration when evaluating the response on imaging, that is palliative vs curative or neoadjuvant vs adjuvant RT. Imaging findings can further be distorted by altered anatomy and sequelae following surgery within the radiation field. An awareness of common PET/CT-induced changes/injuries is essential when interpreting 18F-FDG PET/CT as well as obtaining a complete medical history, as patients are occasionally scanned for an unrelated cause to previously RT treated malignancy. In addition, secondary malignancies due to carcinogenic effects of radiation exposure in long-term cancer survivors should not be overlooked. 18F-FDG PET/CT can be very useful in response evaluation and follow-up in patients treated with RT, however, variants and pitfalls are common and it is important to remember that radiation-induced injury is often a diagnosis of exclusion.

Risk of Bacterial, Viral, and Fungal Infections in Patients With Solid Malignant Tumors Treated With Curative Intent Radiation Therapy.

Purpose: The incidence, etiology, and association of infections with radiation therapy (RT)-induced lymphopenia in patients with solid tumors is not well elucidated. Methods and Materials: We identified possible, probable, and definite infections caused by bacteria, fungi, and viruses, combining data on medication, microbiology, and diagnoses. Definite infections had either a diagnosis or a positive microbiological isolation. We analyzed the incidence and adjusted incidence-rate ratio of infections in the year after the start of RT among patients who received RT plus chemotherapy and RT monotherapy, by type of infection and according to the degree of RT-induced lymphopenia. Results: A total of 4450 of 6334 (70.3%) patients experienced 11264 infections overall; 1424 (22.5%) patients developed 2104 definite infections in the first year after RT. Infections were more frequent among patients who received RT plus chemotherapy (2590 of 3469; incidence: 16.5 [95% confidence interval {CI}, 16.1-17.0], per 100 patient-years) compared with patients who received RT monotherapy (1860 of 2865; incidence: 12.7 [95% CI, 12.3-13.2]). The incidence of infection was highest in the first 3 months overall (28.2 vs 18.0 in patients who received RT plus chemotherapy compared with those who received RT monotherapy) and for definite infections (4.7 vs 3.8). The proportion of specific bacterial infections were similar among patients who received RT plus chemotherapy versus those who received RT monotherapy. Urinary tract infections were the most frequent (51.2% vs 56.2%), followed by pneumonias (24.1% vs 22.4%). Viral and fungal infections were more frequent among patients who received RT plus chemotherapy, but they were uncommon. In multivariable analyses, patients who received RT plus chemotherapy with a lymphopenia grade of 1-2 or ≥3 versus no lymphopenia at end of RT had an increased risk of bacterial infections 0 to 3 months after RT (incidence rate ratio, 1.45 [95% CI, 1.06-1.97] and 1.71 [95% CI, 1.26-2.34], respectively). Limiting to definite bacterial infections, the incidence rate ratio for lymphopenia grade ≥3 versus no lymphopenia was 2.66 (95% CI, 1.40-5.03). Conclusions: The incidence of bacterial infections 0 to 3 months after RT plus chemotherapy for solid tumors was high, especially among patients with RT-induced lymphopenia grade 1-2 and ≥3.

Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma.

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5-10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days followingRT/CRT initiation. METHODS: Patients with HNSCC treated with RT/CRT, including postoperative RT/CRT, at Rigshospitalet or Herlev Hospitals between 2010-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. Predictor variables included age, stage, performance status, tumor subsite including p16 status, comorbidity, postoperative status, smoking and pre-treatment albumin levels. The 180-day non-HNSCCmortality risk was estimated by combining cause-specific Cox regression models. RESULTS: We included 2209 patients. The 180-day non-HNSCCmortality rate was 4.4% and almostone third (31.6%) of non-HNSCCdeathswere caused by pneumonia.After internal model validation, the area under the receiver operating curve was 0.74 (95% CI: 0.66-0.81) and calibration was good for risk predictions ranging from 0% to 20%. CONCLUSION: We developed a prediction tool to estimate the 180-day non-HNSCC mortality risk. This tool can be used to select high-risk patients for supportive interventions aiming to improve survival rates, and is availablefor interactive use at https://emriskpred.shinyapps.io/EMNED_App/.

Intraglandular Off-the-Shelf Allogeneic Mesenchymal Stem Cell Treatment in Patients with Radiation-Induced Xerostomia: A Safety Study (MESRIX-II).

No effective therapy exists for the most common long-term side effect of radiation therapy for head and neck cancer (HNC)-xerostomia. The objective was to evaluate safety and provide proof of concept for efficacy of allogeneic adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) injected into the major salivary glands of irradiated patients. This open-label, first-in-human, phase 1b, and single-center trial was conducted with repeated measurements days 0, 1, 5, and 30 and 4 months. Eligible patients with objective and subjective signs of radiation-induced salivary gland damage after treatment of oropharyngeal squamous cell carcinoma stages I-II (UICC 8) were enrolled. Twenty-five million cryopreserved AT-MSCs were injected into each submandibular and 50 million AT-MSCs into each parotid gland. Data were collected on adverse events, unstimulated and stimulated whole saliva (UWS and SWS) flow rates and saliva composition, patient-reported outcomes (EORTC QLQ-H&N35 and Xerostomia Questionnaire [XQ]), blood samples and salivary gland scintigraphy. Data were analyzed using repeated measures linear mixed models. Ten patients (7 men, 3 women, 59.5 years [range: 45-70]) were treated in 4 glands. No treatment-related serious adverse events occurred. During 4 months, UWS flow rate increased from 0.13 mL/minute at baseline to 0.18 mL/minute with a change of 0.06 (P = .0009) mL/minute. SWS flow rate increased from 0.66 mL/minute at baseline to 0.75 mL/minute with a change of 0.09 (P = .017) mL/minute. XQ summary score decreased by 22.6 units (P = .0004), EORTC QLQ-H&N35 dry mouth domains decreased by 26.7 (P = .0013), sticky saliva 23.3 (P = .0015), and swallowing 10.0 (P = .0016). Our trial suggests treatment of the major salivary glands with allogenic AT-MSCs is safe, warranting confirmation in larger trials.

Long-term Safety of Treatment with Autologous Mesenchymal Stem Cells in Patients with Radiation-Induced Xerostomia: Primary Results of the MESRIX Phase I/II Randomized Trial.

PURPOSE: Mesenchymal stem/stromal cell therapy may reduce radiation-induced xerostomia. We investigated the long-term safety of autologous adipose tissue-derived mesenchymal stem/stromal cell (ASC) injections into the submandibular glands. EXPERIMENTAL DESIGN: An investigator-initiated, randomized, single-center, placebo-controlled trial. Previous patients with oropharyngeal squamous cell carcinoma with radiation-induced xerostomia were randomly (1:1) allocated to receive a 2.8 million ASCs/cm3 injection or placebo in both submandibular glands and followed for a minimum of 2 years. The primary endpoint was number of serious adverse events (SAE). Secondary endpoints included whole saliva flow rates and xerostomia-related symptoms. Data analysis was based on the intention-to-treat population using repeated measures mixed-effects linear models. RESULTS: Thirty-three patients were randomized; 30 patients were treated (ASC group, n = 15; placebo group, n = 15). Long-term safety data were collected from all 30 patients. During follow-up, 6 of 15 (40%) of the ASC-treated patients versus 5 of 15 (33%) of the placebo patients experienced an SAE; no SAEs appeared to be treatment related. Unstimulated whole saliva flow rate increased to 0.20 and 0.16 mL/minute in the ASC and placebo group, respectively, yielding a 0.05 mL/minute (95% confidence interval: 0.00-0.10; P = 0.051) difference between groups. Patient-reported xerostomia symptoms diminished according to a decreased xerostomia questionnaire summary score of 35.0 and 45.1, respectively [-10.1 (-18.1 to -2.2); P = 0.013]. Three of the visual analog scale xerostomia measures indicated clinical benefit following use of ASC. CONCLUSIONS: Our data show that ASC therapy is safe with a clinically relevant effect on xerostomia-related symptoms. Confirmation in larger randomized controlled trials is warranted.