Long-Term Survival in Human Epidermal Growth Factor Receptor 2-Positive Bone-Only Metastatic Breast Cancer: Trastuzumab, Denosumab, and Potential Synergistic Effects.

Breast cancer is the second most common cancer worldwide. There are four main subtypes of breast cancer, one of which involves positivity for human epidermal growth factor receptor 2 (HER2). Here, we present a case series of unusually long survival in three patients with HER2-positive metastatic breast cancer. All cases involved post-menopausal women with bone-only metastases undergoing treatment with the HER2-targeted therapy trastuzumab and the receptor activator of nuclear factor kappa-Β ligand (RANK-L) inhibitor denosumab. Our three patients survived for 17, 13, and 11 years, respectively, from the time of metastasis. The patients who survived for 17 and 13 years both presented with metastatic disease at diagnosis, while the patient who survived for 11 years with metastatic disease was known to have non-metastatic breast cancer for four years prior. We also report the development of foot fractures from minor trauma, as low as walking, despite a bone density reported as normal in the patient with 17 years of treatment. These unusually long survival times and the unusual location of the fractures are questioned to be secondary to the long duration of treatment with HER2-targeted therapy and RANK-L inhibitor therapy. Our case series is the first to describe the use of trastuzumab and denosumab in HER2-positive metastatic breast cancer. All three reported cases had no clinical or radiographic disease progression at the time of reporting. Furthermore, our case of survival for 17 years represents the longest survival time reported yet, raising the possibility of a synergistic relationship between RANK-L inhibitors and HER2-targeted therapy in the long-term control of HER2-positive metastatic breast cancer. This manuscript discusses evidence from primary studies on HER2 and receptor activator of nuclear factor kappa-Β (RANK) signalling and drug responses and hypothesizes on possible mechanisms of synergism. Given that treatment of HER2-positive breast cancer has historically not involved RANK-L inhibition, this study may outline future areas of research in improving treatment algorithms, especially for bone-only metastatic disease.

Toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer: A secondary analysis of the LUSTRE randomized trial.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) carries potentially higher risks for ultracentral (UC) NSCLC with limited prospective data to guide decision making. We conducted a secondary analysis from a randomized trial of SBRT and conventionally hypofractionated radiation (CRT) to assess these risks. MATERIALS AND METHODS: Patients (n = 233) with medically inoperable stage I NSCLC were recruited from 2014 to 2020. Patients with UC targets directly overlapping the proximal bronchial tree (PBT) were identified. The primary objective was the occurrence of related grade 3-5 toxicity > 3 months following radiation. Secondary endpoints included local control, survival, and evaluation of PBT dose and its association with late toxicity. RESULTS: Thirty UC tumors were identified (23 - SBRT 60 Gy/8 fractions, 7 - CRT 60 Gy/15 fractions). Median age was 72 years, and median tumor size was 2.8 cm. Most patients (67 %) had histologically confirmed NSCLC. At a median follow-up of 2.9 years, 3 and 1 patients developed grade 3 and 5 toxicity respectively (all SBRT). 3-year local control was 85 %. Mean PBT dose (converted to 2 Gy dose equivalents) was higher in patients with grade ≥ 3 toxicity, particularly for 4 cc (105.5 vs 51.8 Gy, p = 0.0004), 5 cc (84 vs 46.1 Gy, p = 0.003), and volumetric doses (V65 - V100Gy). The patient with grade 5 toxicity had the highest 5 cc dose (117 Gy), V90Gy (8.2 cc), and V100Gy (7 cc). CONCLUSIONS: SBRT for UC NSCLC provides good local control but carries a high rate of late grade 3-5 toxicity. An apparent association between toxicity and PBT volumetric dose was observed, which should be considered if SBRT is offered.

Stereotactic vs Hypofractionated Radiotherapy for Inoperable Stage I Non-Small Cell Lung Cancer: The LUSTRE Phase 3 Randomized Clinical Trial.

Importance: Stereotactic body radiotherapy (SBRT) is widely used for stage I medically inoperable non-small cell lung cancer (NSCLC), yet varied results from randomized clinical trials (RCTs) and concerns in treating centrally located tumors persist. Objective: To examine whether SBRT would improve local control (LC) compared with hypofractionated conventional radiotherapy (CRT). Design, Setting, and Participants: This phase 3 RCT was conducted in 16 Canadian centers. Patients with medically inoperable stage I (≤5 cm) NSCLC were randomized 2:1 to SBRT of 48 Gy in 4 fractions (peripheral NSCLC) or 60 Gy in 8 fractions (central NSCLC) vs CRT of 60 Gy in 15 fractions. Data were collected from May 2014 to January 2020, and data were analyzed from July 2022 to July 2023. Interventions: SBRT or CRT. Main Outcomes and Measures: The primary objective was to determine the effectiveness of SBRT compared with CRT based on LC at 3 years. Secondary outcomes included event-free survival, overall survival, and toxic effects. All radiation plans were subject to real-time/final review. Local failures were centrally adjudicated. The study was designed to detect a 3-year LC improvement of SBRT from 75% to 87.5%. The target sample size was 324 patients. Results: Of 233 included patients, 119 (51.1%) were male, and the mean (SD) age was 75.4 (7.7) years; the median (IQR) follow-up was 36.1 (26.4-52.8) months. A total of 154 patients received SBRT and 79 received CRT. The 3-year LC was 87.6% (95% CI, 81.9%-93.4%) for SBRT and 81.2% (95% CI, 71.9%-90.5%) for CRT (hazard ratio [HR], 0.61; 95% CI, 0.31-1.20; P = .15). The HR was 1.02 (95% CI, 0.72-1.45; P = .87) for event-free survival and 1.18 (95% CI, 0.80-1.76; P = .40) for overall survival. Minimal acute toxic effects were observed. Among those randomized to SBRT, late grade 3 or 4 toxic effects occurred in 5 of 45 (11%) with central NSCLC and 2 of 109 (1.8%) with peripheral NSCLC; among those randomized to CRT, in 1 of 19 (5%) with central NSCLC and 1 of 60 (2%) with peripheral NSCLC. One patient who received SBRT for an ultracentral lesion (target overlapping proximal bronchus) experienced a possible treatment-related grade 5 event (hemoptysis). Conclusions and Relevance: This RCT compared lung SBRT with hypofractionated CRT that included central/ultracentral tumors. No difference was detected in LC between groups. Severe toxic effects were limited, including patients with central tumors. The trial provides important prospective data evaluating SBRT; however, further research is necessary to determine if SBRT is more effective than CRT for peripheral and central NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03924869.

Adjuvant Chemotherapy and Radiotherapy in Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Clinical Practice Guideline.

Pancreatic cancer is the seventh leading cause of cancer deaths worldwide, accounting for 4.7% of all cancer deaths, and is expected to climb significantly over the next decade. The purpose of this systematic review and guidance document was to synthesize the evidence surrounding the role of adjuvant treatment (chemotherapy and chemoradiation therapy [CRT], and stereotactic body radiation therapy [SBRT]) in resected pancreatic ductal adenocarcinoma (PDAC). Systematic literature searches of MEDLINE, EMBASE, and 11 guideline databases were conducted. Both direct and indirect comparisons indicate adjuvant chemotherapy offers a survival advantage over surgery alone. The optimal regimens recommended are mFOLFIRINOX with alternative options of gemcitabine plus capecitabine, gemcitabine alone, or S-1 (which is not available in North America). Trials comparing a CRT strategy to modern chemotherapy regimens are lacking. However, current evidence demonstrates that the addition of CRT to chemotherapy does not result in a survival advantage over chemotherapy alone and is therefore not recommended. Trials evaluating SBRT in PDAC are also lacking. SBRT should only be used within a clinical trial or multi-institutional registry.

Early-Stage Non-Small Cell Lung Cancer Stereotactic Body Radiation Therapy Outcomes in a Single Institution.

Introduction The gold standard treatment of stage I non-small cell lung cancer (NSCLC) is surgical resection. For medically inoperable patients, stereotactic body radiation therapy (SBRT) can provide comparable local control (LC) and overall survival (OS). The objectives of this study are to determine the three-year LC and OS for SBRT compared to early-stage NSCLC patients treated with alternative radiation modalities at our institution. Materials and methods This retrospective study included a total of 139 consecutive patients who were diagnosed with stage I (T1-2 N0 M0) NSCLC and treated with radiation therapy at our institution between 2015 and 2020. Patient demographics and clinical data were obtained from chart reviews. Treatment subgroups were: SBRT (48Gy/4 or 60Gy/8), hypofractionation (60Gy/15), conventional fractionation (60Gy/30 or 50Gy/20), and palliative radiation (20Gy/5, 30Gy/10, or 40Gy/15). Kaplan-Meier curves were plotted for LC and OS. We also performed Cox's proportional hazard regression analysis. Results The median patient age was 74 (range 52-91). The numbers of patients in each treatment subgroup were: SBRT (44), hypofractionation (78), conventional fractionation (8), and palliative (9). Differences in age, gender, and histopathological cell type between subgroups were not statistically significant. Metastatic progression was the most common outcome amongst treatment failures, followed by local recurrence and regional spread. Median post-treatment follow-up in months for each subgroup was: SBRT (20.2), hypofractionated (20.7), conventional fractionation (13.9), and palliative (14.4). Post-treatment three-year LC was found to be significantly better with SBRT (94%) versus hypofractionation (71%), conventional fractionation (80%), and palliative (71%). OS at three years were SBRT (67%), hypofractionation (59%), conventional fractionation (66%), and palliative (44%). As a whole, 72% (100/139) of patients had biopsy-proven NSCLC. Analysis showed biopsy status had no statistical significance with regards to LC or OS. Every 20 years of age had a 3.2x risk of death (95% CI: 1.425-7.268). Concerning the treatment modalities, there were significant differences for the hazard of death compared to SBRT: hypofractionation had 2.58x increased risk while palliative had 5.83x increased risk. The proportion of patients who experienced post-treatment radiation pneumonitis or dermatitis were: SBRT (7%, 2%), hypofractionation (8%, 3%), conventional fractionation (13%, 25%), and palliative (0%, 0%), respectively. No patients who experienced grade III or higher toxicities were observed as defined by Common Terminology Criteria for Adverse Events (CTCAE).  Conclusion Our experience confirms SBRT can provide durable three-year local control with a comparable rate of post-treatment complications versus other radiation modalities for early-stage NSCLC. SBRT appears to be non-inferior to hypofractionation with regards to three-year LC.

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Survival of patients with pancreatic cancer treated with varied modalities: A single-centre study.

The present retrospective chart review examined the overall survival (OS) of patients with pancreatic ductal adenocarcinoma based on the disease stage in a sample of 296 patients with pancreatic cancer. Secondary outcome measurements included OS in chemotherapy vs. supportive treatment groups among metastatic patients, OS based on response to chemotherapy among metastatic patients, and OS and disease free survival (DFS) in surgically resected disease with vs. without adjuvant therapy. Data were analyzed using Kaplan-Meier and multivariate cox-regression analyses based on a 95% confidence interval (CI) or an α-value of 0.05. OS was significantly different based on the disease stage, with 3.63 (95% CI, 2.84-4.43), 6.57 (95% CI, 4.06-9.08) and 15.57 (95% CI, 11.79-19.35) months in the advanced, locally advanced, and localized disease groups, respectively. OS was higher in metastatic-stage patients who received chemotherapy [6.07 months (95% CI, 4.75-7.39)] compared with those who received supportive therapy alone [2.50 months (95% CI, 2.16-2.84; P<.001)]. Metastatic-stage patients with partial or stable response to chemotherapy had higher OS [10.53 months (95% CI, 6.35-14.72)] in comparison with those with progression [6.33 months (95% CI, 5.79-6.88)] or an undocumented response [3.30 months (95% CI, 1.76-4.84; P<0.001)]. In patients who underwent surgical resection of localized disease, adjuvant therapy increased the adjusted OS and DFS as compared with surgical excision alone (P=0.013; 95% CI, 0.278-0.862). Positive margins reduced OS [hazard ratio (HR) 2.670; 95% CI, 1.467-4.860]. The present single-site study has demonstrated that OS may markedly differ on the basis of the disease status at the time of diagnosis. Metastatic-stage patients with stable or partial response to chemotherapy had an increased OS, as did surgical patients with localized disease who received adjuvant treatment, after adjusting for margin status.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non-Small-Cell Lung Cancer - Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non-small-cell lung cancer (OCOG-LUSTRE Trial). Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery. Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

Intracranial presentation of systemic Hodgkin's disease.

Intracranial involvement by Hodgkin's disease is rare. We report a patient with Hodgkin's disease who had intracranial disease at presentation. We also review the literature pertaining to intracranial Hodgkin's disease. Using the key words "Hodgkin's disease" and "central nervous system (CNS) disease", we searched the Pubmed and Cancerlit databases. References were systematically reviewed and data regarding the following variables was extracted: age, gender, signs and symptoms at presentation, histology of Hodgkin's disease, cerebrospinal fluid analysis, stage and treatment. Only 36 cases of intracranial Hodgkin's disease were identified in the literature. Intracranial Hodgkin's disease at presentation is even more uncommon with only 8 reported cases. Most cases of intracranial involvement by Hodgkin's disease occur at the time of relapse. The most common presenting feature of intracranial Hodgkin's disease is a cranial nerve palsy with brain parenchyma being the most common intracranial site of involvement. Mixed cellularity histology is the most frequent subtype of Hodgkin's disease among these patients and the median survival following intracranial presentation is 46 months. Treatment has varied extensively but includes whole brain radiation with or without combination chemotherapy. Our literature review suggests that the prognosis is not dismal with appropriate treatment.