Irradiated Bone Marrow Volume is Associated with Hematologic Toxicity in Patients with Multiple Myeloma.

PURPOSE/OBJECTIVE(S): Palliative radiotherapy (RT) is effective for multiple myeloma (MM) but may cause cytopenia. Bone marrow volume receiving 10Gy (BMV10Gy) has been associated with hematologic toxicity (HT) in cervical cancer, but no studies have investigated this in MM. We hypothesized that absolute BMV10Gy is associated with acute HT in MM patients receiving palliative RT. MATERIALS/METHODS: This single-institution retrospective analysis evaluated 125 MM patients who received palliative RT between 2007-2023 and had ≥ 2 weeks of follow up laboratory data. Lab values were recorded pre-RT, post-RT, and at nadir within 90 days of completing RT. Clinical HT was defined as new transfusion/growth factor, admission for hematologic toxicity, and/or systemic therapy pause/discontinuation. BM was defined as bone volume within RT field. BMV5-40Gy (cc) was recorded for each treatment. Logistic regressions were performed with clinical HT as the primary endpoint. RESULTS: 105 (84%) patients received concurrent systemic therapy. Median BMV10Gy was 266cc (IQR 157-501cc). Median RT EqD2 was 26Gy (IQR 23-33Gy). On univariable analysis, BMV5Gy, BMV10Gy, and BMV15Gy were significantly associated with clinical HT (p=0.014, p=0.018, p=0.050, respectively) while RT EqD2 dose was not (p=0.997). On multivariable analysis, BMV10Gy was significantly associated with clinical HT (p=0.049) after adjusting for dose, number of lesions treated, lesion location (spine, pelvis, limb, soft tissue), and systemic therapy class. Disease course (number of prior systemic therapies) was significantly associated with clinical HT on univariable and multivariable analysis, with late relapsed/refractory patients (≥3 prior systemic therapies) having 9.6 higher odds of clinical HT compared to newly diagnosed patients (p<0.001). CONCLUSION: To our knowledge, this is the first study to associate volume of irradiated BM with acute HT in MM. In addition to BM V5-15Gy, number of prior relapses and systemic therapy lines were significantly associated with HT. Disease history should be evaluated, and RT field volumes minimized for patients with poor bone marrow reserve (e.g., late relapsed/refractory disease).

Feasibility of Left Anterior Descending Coronary Artery Sparing Radiation Therapy for Locally Advanced Lung Cancer.

Efforts to mitigate radiation therapy (RT)-associated cardiotoxicity have focused on constraining mean heart dose. However, recent studies have shown greater predictive power with cardiac substructure dose metrics, such as the left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) ≥10%. Herein, we investigated the feasibility of LAD radiation sparing in contemporary intensity modulated RT (IMRT)/volumetric modulated arc therapy (VMAT) lung cancer plans. Single institution retrospective analysis of 54 patients with locally advanced lung cancer treated with thoracic RT was conducted between February 2018 and August 2021. After excluding 33 (5 = non-IMRT/VMAT or intentionally LAD-optimized; 28 = LAD V15Gy <10%), 21 plans with LAD V15Gy ≥10% were identified for LAD reoptimization with intent to meet LAD V15Gy <10% while maintaining meeting organ at risk (OAR) metrics and target coverage with original plan parameters. Dosimetric variables were compared using paired t tests. Most patients (57.1%, 12/21) were treated with definitive RT, 8 of 21 patients (38.1%) with postoperative RT, and 1 with neoadjuvant RT. The median prescribed RT dose was 60 Gy (range, 50.4-66 Gy) in 30 fractions (range, 28-33 fractions). LAD reoptimized plans (vs original) led to significant reductions in mean LAD V15Gy (39.4% ± 13.9% vs 9.4% ± 13.0%; P < .001) and mean LAD dose (12.9 Gy ± 4.6 Gy vs 7.6 Gy ± 2.8 Gy; P < .001). Most (85.7%; 18/21) LAD reoptimized plans achieved LAD V15Gy <10%. There were no statistically significant differences in overall lung, esophageal, or spinal cord dose metrics. Only 1 reoptimization (1/21) exceeded an OAR constraint that was initially met in the original plan. To our knowledge, this is the first report describing the feasibility of LAD-optimized lung cancer RT planning using the newly identified LAD V15Gy constraint. We observed that LAD V15Gy <10% is achievable in more than 85% of plans initially exceeding this constraint, with minimal dosimetric tradeoffs. Our results support the feasibility of routine incorporation of the LAD as an OAR in modern thoracic IMRT/VMAT planning.

Left Anterior Descending Coronary Artery Radiation Dose Association With All-Cause Mortality in NRG Oncology Trial RTOG 0617.

PURPOSE: A left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15 Gy) ≥10% has been recently observed to be an independent risk factor of major adverse cardiac events and all-cause mortality in patients with locally advanced non-small cell lung cancer treated with radiation therapy. However, this dose constraint has not been validated in independent or prospective data sets. METHODS AND MATERIALS: The NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0617 data set from the National Clinical Trials Network was used. The LAD coronary artery was manually contoured. Multivariable Cox regression was performed, adjusting for known prognostic factors. Kaplan-Meier estimates of overall survival (OS) were calculated. For assessment of baseline cardiovascular risk, only age, sex, and smoking history were available. RESULTS: There were 449 patients with LAD dose-volume data and clinical outcomes available after 10 patients were excluded owing to unreliable LAD dose statistics. The median age was 64 years. The median LAD V15 Gy was 38% (interquartile range, 15%-62%), including 94 patients (21%) with LAD V15 Gy <10% and 355 (79%) with LAD V15 Gy ≥10%. Adjusting for prognostic factors, LAD V15 Gy ≥10% versus <10% was associated with an increased risk of all-cause mortality (hazard ratio [HR], 1.43; 95% confidence interval, 1.02-1.99; P = .037), whereas a mean heart dose ≥10 Gy versus <10 Gy was not (adjusted HR, 1.12; 95% confidence interval, 0.88-1.43; P = .36). The median OS for patients with LAD V15 Gy ≥10% versus <10% was 20.2 versus 25.1 months, respectively, with 2-year OS estimates of 47% versus 67% (P = .004), respectively. CONCLUSIONS: In a reanalysis of RTOG 0617, LAD V15 Gy ≥10% was associated with an increased risk of all-cause mortality. These findings underscore the need for improved cardiac risk stratification and aggressive risk mitigation strategies, including implementation of cardiac substructure dose constraints in national guidelines and clinical trials.

Intracranial Activity of Cabozantinib in MET Exon 14-Positive NSCLC with Brain Metastases.

INTRODUCTION: A significant portion of NSCLCs with MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping alterations are sensitive to small-molecule mesenchymal-epithelial transition tyrosine kinase inhibitors. However, the incidence and management of brain metastases in this molecular subset is unknown and represents an unmet clinical need. METHODS: Hybrid capture-based comprehensive genomic profiling identified a patient with a MET exon 14 skipping alteration, and serial magnetic resonance imaging was utilized to follow intracranial disease during crizotinib and subsequent cabozantinib therapy. RESULTS: Intracranial progression developed in the context of ongoing extracranial disease control during crizotinib therapy. Rapid intracranial response was observed after change to cabozantinib. CONCLUSIONS: This report provides the first detailed description of brain metastases in MET exon 14-positive NSCLC and provides preliminary support for the intracranial activity of cabozantinib. Prospective study is warranted and needed to refine the management of intracranial disease in MET exon 14-positive NSCLC.

Clinical experience using a video-guided spirometry system for deep inhalation breath-hold radiotherapy of left-sided breast cancer.

The purpose was to report clinical experience of a video-guided spirometry system in applying deep inhalation breath-hold (DIBH) radiotherapy for left-sided breast cancer, and to study the systematic and random uncertainties, intra- and interfraction motion and impact on cardiac dose associated with DIBH. The data from 28 left-sided breast cancer patients treated with spirometer-guided DIBH radiation were studied. Dosimetric comparisons between free-breathing (FB) and DIBH plans were performed. The distance between the heart and chest wall measured on the digitally reconstructed radiographs (DRR) and MV portal images, dDRR(DIBH) and dport(DIBH), respectively, was compared as a measure of DIBH setup uncertainty. The difference (Δd) between dDRR(DIBH) and dport(DIBH) was defined as the systematic uncertainty. The standard deviation of Δd for each patient was defined as the random uncertainty. MV cine images during radiation were acquired. Affine registrations of the cine images acquired during one fraction and multiple fractions were performed to study the intra- and interfraction motion of the chest wall. The median chest wall motion was used as the metric for intra- and interfraction analysis. Breast motions in superior-inferior (SI) direction and "AP" (defined on the DRR or MV portal image as the direction perpendicular to the SI direction) are reported. Systematic and random uncertainties of 3.8 mm and 2mm, respectively, were found for this spirometer-guided DIBH treatment. MV cine analysis showed that intrafraction chest wall motions during DIBH were 0.3mm in "AP" and 0.6 mm in SI. The interfraction chest wall motions were 3.6 mm in "AP" and 3.4 mm in SI. Utilization of DIBH with this spirometry system led to a statistically significant reduction of cardiac dose relative to FB treatment. The DIBH using video-guided spirometry provided reproducible cardiac sparing with minimal intra- and interfraction chest wall motion, and thus is a valuable adjunct to modern breast treatment techniques.

The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors.

Cancer and its treatment can compromise bone health, leading to fracture, pain, loss of mobility, and hypercalcemia of malignancy. Bone metastasis occurs frequently in advanced prostate and breast cancers, and bony manifestations are commonplace in multiple myeloma. Osteoporosis and osteopenia may be consequences of androgen-deprivation therapy for prostate cancer, aromatase inhibition for breast cancer, or chemotherapy-induced ovarian failure. Osteoporotic bone loss and bone metastasis ultimately share a pathophysiologic pathway that stimulates bone resorption by increasing the formation and activity of osteoclasts. Important mediators of pathologic bone metabolism include substances produced by osteoblasts, such as RANKL, the receptor activator of nuclear factor kappa B ligand, which spurs osteoclast differentiation from myeloid cells. Available therapies are targeted to various steps in cascade of bone metastasis.

Wedge resection and brachytherapy for lung cancer in patients with poor pulmonary function.

BACKGROUND: Although lobectomy is the standard for lung cancer because a wedge resection has a 3 to 5 times greater incidence of local recurrence, poor pulmonary function may preclude lobectomy. For these patients, low-dose-rate brachytherapy has recently been used to decrease local recurrence after sublobar resection. Current techniques expose operating room personnel and patient contacts to unnecessary radioactivity risks. We present our technique of sublobar resection combined with afterload catheters for high-dose-rate brachytherapy for patient benefit with minimal risk to others. METHODS: Forty-eight patients (25 women, 23 men) underwent wedge resection, node dissection, and brachytherapy. A remote-afterloading high-dose-rate unit for radiation produced a median dose of 2450 cGy (350 cGy per fraction over 7 fractions twice daily for 4 days). The dose was prescribed to 1 cm deep to the stapled line. Biologically, this dose is approximately 5000 cGy and above (180 cGy/d equivalent) at the depth of 5 mm in reference to the resection margin. RESULTS: Two patients died. The length of mean stay was 5.5 days (median, 5 days). Complications included prolonged air leak in 5 patients, atrial fibrillation in 5, pneumonia in 3, trapped lung in 2, and 1 each with empyema, bleeding, and recurrent laryngeal nerve injury. Three patients required a blood transfusion. Within the follow-up of 1 to 27 months, there were four recurrences. CONCLUSIONS: Wedge resection and brachytherapy appears to be a reasonable treatment for patients with lung cancer and pulmonary function that prohibits a lobectomy.