First-in-Human Evaluation of Site-Specifically Labeled 89Zr-Pertuzumab in Patients with HER2-Positive Breast Cancer.

Radioimmunoconjugates targeting human epidermal growth factor receptor 2 (HER2) have shown potential to noninvasively visualize HER2-positive tumors. However, the stochastic approach that has been traditionally used to radiolabel these antibodies yields poorly defined and heterogeneous products with suboptimal in vivo performance. Here, we describe a first-in-human PET study on patients with HER2-positive breast cancer evaluating the safety, biodistribution, and dosimetry of 89Zr-site-specific (ss)-pertuzumab PET, a site-specifically labeled radioimmunoconjugate designed to circumvent the limitations of random stochastic lysine labeling. Methods: Six patients with HER2-positive metastatic breast cancer were enrolled in a prospective clinical trial. Pertuzumab was site-specifically modified with desferrioxamine (DFO) via a novel chemoenzymatic strategy and subsequently labeled with 89Zr. Patients were administered 74 MBq of 89Zr-ss-pertuzumab in 20 mg of total antibody intravenously and underwent PET/CT at 1 d, 3-4 d, and 5-8 d after injection. PET imaging, whole-body probe counts, and blood draws were performed to assess the pharmacokinetics, biodistribution, and dosimetry. Results: 89Zr-ss-pertuzumab PET/CT was used to assess HER2 status and heterogeneity to guide biopsy and decide the next line of treatment at progression. The radioimmunoconjugate was able to detect known sites of malignancy, suggesting that these tumor lesions were HER2-positive. The optimal imaging time point was 5-8 d after administration, and no toxicities were observed. Dosimetry estimates from OLINDA showed that the organs receiving the highest doses (mean ± SD) were kidney (1.8 ± 0.5 mGy/MBq), liver (1.7 ± 0.3 mGy/MBq), and heart wall (1.2 ± 0.1 mGy/MBq). The average effective dose for 89Zr-ss-pertuzumab was 0.54 ± 0.03 mSv/MBq, which was comparable to both stochastically lysine-labeled 89Zr-DFO-pertuzumab and 89Zr-DFO-trastuzumab. One patient underwent PET/CT with both 89Zr-ss-pertuzumab and 89Zr-DFO-pertuzumab 1 mo apart, with 89Zr-ss-pertuzumab demonstrating improved lesion detection and higher tracer avidity. Conclusion: This study demonstrated the safety, dosimetry, and potential clinical applications of 89Zr-ss-pertuzumab PET/CT. 89Zr-ss-pertuzumab may detect more lesions than 89Zr-DFO-pertuzumab. Potential clinical applications include real-time evaluation of HER2 status to guide biopsy and assist in treatment decisions.

Electro-acupuncture versus battle field auricular acupuncture in breast cancer survivors with chronic musculoskeletal pain: subgroup analysis of a randomized clinical trial.

PURPOSE: Chronic musculoskeletal pain is common and debilitating among breast cancer survivors. The PEACE trial demonstrated that electro-acupuncture (EA) and battle field auricular acupuncture (BFAA) both reduced pain more than usual care (UC) in cancer survivors. However, the comparative effectiveness between EA and BFAA among breast cancer survivors is unknown. METHODS: EA and BFAA received ten weekly treatments. UC was offered ten EA treatments after week 12. The primary endpoint was change in mean Brief Pain Inventory (BPI) pain severity from baseline to week 12. We analyzed the subset of 165 (46%) trial participants with a breast cancer primary diagnosis. We conducted constrained linear mixed model analyses, which constrained all arms to a common pre-randomization baseline mean. Model-based mean estimates at weeks 12 and 24 were compared between arms using model contrasts. RESULTS: Among 165 breast cancer survivors, common pre-randomization mean pain severity was 5.35 [95% Confidence Interval (CI) 5.04, 5.66]. At week 12, BPI pain severity score was 2.69 (2.26. 3.13) in EA, 3.60 (3.17, 4.02) in BFAA, and 5.06 (4.47, 5.65) in UC. EA reduced pain severity significantly more than BFAA at weeks 12 [- 0.90 (- 1.45, - 0.36), p = 0.001] and 24 [- 0.82, (- 1.38, - 0.27), p = 0.004]. EA and BFAA significantly improved both Patient-Reported Outcomes Measurement Information System (PROMIS) - Global Health physical health and mental health component scores at week 12 compared to UC. Mild toxicities were reported. CONCLUSION: EA was more effective than BFAA at reducing pain severity, but both similarly improved physical and mental health scores. Breast cancer survivors with chronic musculoskeletal pain may consider EA before BFAA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02979574. https://clinicaltrials.gov/ct2/show/NCT02979574.

Mechanistic and thermal characterization of acupuncture for chemotherapy-induced peripheral neuropathy as measured by quantitative sensory testing.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of chemotherapy. Acupuncture is a promising non-pharmacological intervention for CIPN. However, the physiological effects of acupuncture treatment remain poorly understood. We examined the effects of acupuncture on CIPN using semi-objective quantitative sensory testing (QST). METHODS: We conducted a randomized controlled trial of real acupuncture (RA) and sham acupuncture (SA) compared to usual care (UC) in cancer survivors with moderate-to-severe CIPN. Treatment response was assessed with QST measures of tactile and vibration detection thresholds in hands and feet, thermal detection, and pain thresholds at weeks 0, 8, and 12. Constrained linear mixed model (cLMM) regression was used for statistical analysis. RESULTS: 63 patients completed QST testing. At week 8, vibrational detection thresholds in feet were significantly lower in RA and SA (p = 0.019 and p = 0.046) than in UC, with no difference between RA and SA (p = 0.637). Both RA and SA also showed significantly higher cool thermal detection than UC (p = 0.008 and p = 0.013, respectively), with no difference between RA and SA (p = 0.790). No differences in tactile detection, vibrational detection in hands, warm thermal detection, and thermal pain thresholds were detected among the three arms at weeks 8 and 12. CONCLUSION: QST demonstrated different patterns in RA, SA, and UC. After eight weeks of RA, we observed significant improvements in the vibrational detection threshold in feet and cool thermal detection threshold in hands compared to UC. No significant differences were seen when compared to SA. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03183037); June 9, 2017.

Cancer-Related Fatigue Outcome Measures in Integrative Oncology: Evidence for Practice and Research Recommendations.

Cancer-related fatigue (CRF) is one of the most common symptoms across the cancer continuum and is often underreported and undertreated. Defined as a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or its treatment, CRF includes physical, emotional, cognitive, and spiritual dimensions. Patient-reported outcome (PRO) measures are the most widely used tool to screen for and assess fatigue and the associated negative impacts on quality of life. However, selecting subjective CRF measures can be complex. This has resulted in the availability of and inconsistent use of numerous PROs, limiting the ability to cross-compare outcomes clinically and within research. To address this, the PROs that are most widely reported in the literature are recommended to support the standardization of a core set of validated measures. The National Comprehensive Cancer Network single-item tool for clinical significance is recommended for quick use in clinical environments; the Brief Fatigue Inventory allows for fast, easy, helpful cutoffs on severity threshold for triage, and measures both severity and interference with daily functioning; while the MD Anderson Symptom Inventory allows for multisymptomatic assessment. In addition, a fundamental consideration for any PRO use is the administrative burden on the patient and clinician. In this review, we aim to summarize current, validated PROs specific to CRF to aid clinicians and researchers in patient care and in study design and implementation. We conclude with suggestions for future directions in CRF research that can increase the possibility for long-term impact on future guidelines of fatigue management.

Health-Related Quality of Life in Cancer Survivors with Chemotherapy-Induced Peripheral Neuropathy: A Randomized Clinical Trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating adverse effect of neurotoxic chemotherapy that significantly worsens the quality of life of cancer survivors. MATERIALS AND METHODS: Survivors of solid tumors with persistent moderate-to-severe CIPN defined as numbness, tingling, or pain rated ≥4 on an 11-point numeric rating scale (NRS) were randomized in a 1:1:1 ratio to 8 weeks of real acupuncture (RA) versus sham acupuncture (SA) versus usual care (UC). We previously reported the primary endpoint (NRS); here we report the following health-related quality of life endpoints: Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), and Brief Fatigue Inventory (BFI). For each endpoint, the mean changes from baseline and 95% confidence intervals were estimated within each arm and compared between arms using linear mixed models. RESULTS: We enrolled 75 survivors of solid tumors with moderate-to-severe CIPN into the study. Compared with baseline, at week 8, FACT/GOG-Ntx, HADS anxiety, and ISI scores significantly improved in RA and SA, but not in UC. Compared with UC, at week 8, FACT/GOG-Ntx scores significantly increased in RA and SA arms indicating improved CIPN-related symptoms and quality of life (p = .001 and p = .01). There was no statistically significant difference between RA and SA. There was no difference in HADS depression or BFI among RA, SA, and UC at weeks 8 and 12. CONCLUSION: Acupuncture may improve CIPN-related symptoms and quality of life in cancer survivors with persistent CIPN. Further large sample size studies are needed to delineate placebo effects. IMPLICATIONS FOR PRACTICE: The authors conducted a randomized sham acupuncture- and usual care-controlled clinical trial to evaluate the impact of acupuncture on health-related quality of life outcomes in patients with solid tumors with chemotherapy-induced peripheral neuropathy (CIPN). Statistically significant improvements in quality of life, anxiety, insomnia, and fatigue were achieved with 8 weeks of real acupuncture when compared with baseline, without statistically significant differences between real and sham acupuncture. These findings suggest that acupuncture may be effective for improving CIPN-related symptoms and quality of life and reducing anxiety and insomnia in cancer survivors with persistent CIPN, with further study needed to delineate placebo effects.

Yoga for cancer survivors with chemotherapy-induced peripheral neuropathy: Health-related quality of life outcomes.

BACKGROUND: Yoga is a meditative movement therapy focused on mind-body awareness. The impact of yoga on health-related quality of life (HRQOL) outcomes in patients with chemotherapy-induced peripheral neuropathy (CIPN) is unclear. METHODS: We conducted a pilot randomized wait-list controlled trial of 8 weeks of yoga (n = 21) versus wait-list control (n = 20) for CIPN in 41 breast and gynecological cancer survivors with persistent moderate to severe CIPN. HRQOL endpoints were Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). The Treatment Expectancy Scale (TES) was administered at baseline. We estimated mean changes and 95% confidence intervals (CIs) from baseline to weeks 8 and 12 and compared arms using constrained linear mixed models. RESULTS: At week 8, HADS anxiety scores decreased -1.61 (-2.75, -0.46) in the yoga arm and -0.32 (-1.38, 0.75) points in the wait-list control arm (p = 0.099). At week 12, HADS anxiety scores decreased -1.42 (-2.57, -0.28) in yoga compared to an increase of 0.46 (-0.60, 1.53) in wait-list control (p = 0.017). There were no significant differences in HADS depression, BFI, or ISI scores between yoga and wait-list control. Baseline TES was significantly higher in yoga than in wait-list control (14.9 vs. 12.7, p = 0.019). TES was not associated with HADS anxiety reduction and HADS anxiety reduction was not associated with CIPN pain reduction. CONCLUSIONS: Yoga may reduce anxiety in patients with CIPN. Future studies are needed to confirm these findings. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03292328.

Long-term disease control and survival observed after stereotactic ablative body radiotherapy for oligometastatic breast cancer.

PURPOSE: We examined the characteristics of breast cancer patients with oligometastases (OM) treated with stereotactic ablative body radiotherapy (SABR) to identify factors associated with local progression, distant metastasis progression, time to subsequent therapy, progression-free survival (PFS), and overall survival (OS). METHODS: We retrospectively reviewed a single-institution database of patients treated with radiotherapy between 2008 and 2018 and identified 79 patients who received SABR to OM. Twenty-seven patients had genetic testing of metastatic tumors using an institutional targeted sequencing platform. Kaplan-Meier analysis, Cox regression, and competing risk models were used to compare clinical and genetic correlates with outcomes. RESULTS: Median follow-up was 50 months (IQR: 29-66) with 67% of patients alive at the last follow-up. Of the 65% of patients who progressed, 82% progressed outside of the radiation field, 18% experienced local failure, and 80% had oligoprogression. Median OS was 86 months (IQR: 29-66), and PFS was 33 months (IQR: 10-38). Less than 5 years from diagnosis to SABR and triple-negative breast cancer (TNBC) were associated with worse OS. Advanced T stage, any prior chemotherapy, and TNBC were associated with worse PFS. Alterations in CEBPB, RB1, TBX3, PTEN, and CDK4 were associated with worse survival outcomes. CONCLUSION: Long-term systemic disease control and survival can be achieved with SABR for oligometastatic breast cancer. Hormone receptor-positive patients with a long disease interval from initial diagnosis and limited systemic progression history may be ideal for SABR to all sites of disease.

Characterization of chemotherapy-induced peripheral neuropathy using patient-reported outcomes and quantitative sensory testing.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect in cancer survivors. This study aimed to assess the characteristics of quantitative sensory testing (QST) and its correlation with patient-reported outcomes (PROs) in cancer patients with and without CIPN. METHODS: We conducted a cross-sectional analysis using baseline data from two clinical trials in solid tumor cancer survivors with no CIPN symptoms rated < 2 on a 0-10 Numerical Rating Scale (NRS) or moderate-to-severe CIPN rated ≥ 4 on the NRS. We collected PROs (NRS, Neuropathic Pain Scale, and Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity subscale at baseline. QST [Tactile Threshold (TT), Vibration Threshold (VT), Thermal Threshold (THT)] measurements were used to assess sensory fiber function; they were compared between patients with and without CIPN using Wilcoxon rank-sum tests. We used Spearman correlation coefficients to estimate associations between PROs and QST in all patients. RESULTS: Among 116 participants with CIPN (median NRS 5.00) and 10 participants without CIPN (median NRS 0.00), the median (interquartile range) TT was 3.84 (3.47, 4.12) and 3.53 (3.00, 3.84) in feet, respectively (p = 0.043). The median VT was 17.90 (9.42, 26.95) and 7.73 (5.94, 11.11) in feet, respectively (p = 0.001). Thermal cool threshold was 30.00 °C (28.90, 30.57) and 30.67 °C (30.57, 30.93), respectively (p = 0.007). Correlation coefficients between PROs and QST measures ranged between 0.02 and 0.50 in absolute magnitude. CONCLUSION: Patients with moderate-to-severe CIPN had significantly impaired tactile, vibratory, and thermal thresholds compared to patients without CIPN. QST correlates with PROs, suggesting CIPN symptom severity may correspond to sensory fiber functionality. QST may be incorporated into future CIPN research.

Patient-Reported Outcomes of Pain and Related Symptoms in Integrative Oncology Practice and Clinical Research: Evidence and Recommendations.

Pain is a primary concern among patients with cancer and cancer survivors. Integrative interventions such as acupuncture, massage, and music therapy are effective nonpharmacologic approaches for cancer pain with low cost and minimal adverse events. Patient-reported outcomes (PROs) that have been validated in many clinical and research settings can be used to evaluate pain intensity, associated symptom burden, and quality of life. Clearly defined, reliable PROs can improve patient satisfaction and symptom control. As integrative oncology continues to evolve and expand, cancer-related pain PROs must be standardized to accurately guide clinicians and researchers. Well-validated pain PROs, such as the Brief Pain Inventory, are among the most commonly used for pain intensity assessment. Multiple symptom assessment tools such as the MD Anderson Symptom Inventory, the Memorial Symptom Assessment Scale, the Edmonton Symptom Assessment System, and the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events measurement system can also capture pain-associated symptom burden. Electronic PROs provide flexibility in collecting and analyzing PRO data. Clinical trials using carefully selected PROs and rigorous statistical analysis plans are fundamental to conducting high-quality integrative oncology research and promoting utilization of effective integrative interventions to improve patient outcomes. In this review, we aim to summarize current, validated PROs specific to cancer-related pain to aid integrative oncology clinicians and researchers in patient care and in study design and implementation.

A Technology-Assisted, Brief Mind-Body Intervention to Improve the Waiting Room Experience for Chemotherapy Patients: Randomized Quality Improvement Study.

BACKGROUND: Patients waiting for chemotherapy can experience stress, anxiety, nausea, and pain. Acupressure and meditation have been shown to control such symptoms. OBJECTIVE: This study aimed to evaluate the feasibility and effectiveness of an integrative medicine app to educate patients about these self-care tools in chemotherapy waiting rooms. METHODS: We screened and enrolled cancer patients in chemotherapy waiting rooms at two Memorial Sloan Kettering Cancer Center locations. Patients were randomly assigned into an intervention arm in which subjects watched acupressure and meditation instructional videos or a control arm in which they watched a time- and attention-matched integrative oncology lecture video. Before and after watching the videos, we asked the patients to rate four key symptoms: stress, anxiety, nausea, and pain. We performed the analysis of covariance to detect differences between the two arms postintervention while controlling for baseline symptoms. RESULTS: A total of 223 patients were enrolled in the study: 113 patients were enrolled in the intervention arm and 110 patients were enrolled in the control arm. In both groups, patients showed significant reductions in stress and anxiety from baseline (all P<.05), with the treatment arm reporting greater stress and anxiety reduction than the control arm (1.64 vs 1.15 in stress reduction; P=.01 and 1.39 vs 0.78 in anxiety reduction; P=.002). The majority of patients reported that the videos helped them pass time and that they would watch the videos again. CONCLUSIONS: An integrative medicine self-care app in the waiting room improved patients' experiences and reduced anxiety and stress. Future research could focus on expanding this platform to other settings to improve patients' overall treatment experiences.

Chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer survivors: a comparison of patient-reported outcomes and quantitative sensory testing.

PURPOSE: CIPN is a common, debilitating, and dose-limiting side effect of chemotherapy. Here, we describe characteristics of patients with CIPN using both patient-reported outcomes (PRO) and quantitative sensory testing (QST). METHODS: Breast cancer survivors with persistent moderate to severe CIPN defined by a rating of 4 or greater on a 0-10 Numeric Rating Scale (NRS) from two ongoing clinical trials were included. PROs included the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity (FACT/GOG-Ntx). QST included tactile and vibration detection threshold measurements. Data were analyzed using descriptive statistics and Spearman correlation coefficients. RESULTS: 49 female patients with a mean age of 61 years were assessed; 63% were Caucasian. Mean NRS scores were 4.2, 5.7, and 4.3 on 0-10 scale for pain, numbness, and tingling, respectively. Mean NPS score was 41.0 on a 0-100 scale, and the mean FACT/GOG-Ntx score was 25.8 on a 0-44 scale. QST showed mild to moderate impairments in tactile and vibration perception. The FACT/GOG-Ntx subscale for numbness was negatively correlated with tactile and vibration thresholds in both hands and feet (both p < 0.05). NPS was positively correlated with tactile thresholds in the hands and feet (p < 0.05). CONCLUSION: Patients with moderate to severe CIPN report moderate pain, numbness, and tingling, and exhibit reduced tactile and vibration perception on QST. Weak to moderate correlations were observed between PRO and QST. These data suggest that QST outcomes are associated with CIPN symptoms and may be useful in helping monitor and manage CIPN treatment.

Acupuncture for Bortezomib-Induced Peripheral Neuropathy: Not Just for Pain.

BACKGROUND: Bortezomib-induced peripheral neuropathy (BIPN) is a common and debilitating side effect. Our pilot study demonstrated that acupuncture is safe and can decrease total neuropathic symptoms. However, there is lack of knowledge in which individual BIPN symptoms benefited from acupuncture. PURPOSE: To characterize individual symptoms reduced by acupuncture in patients with BIPN. METHODS: Patients with multiple myeloma treated with bortezomib who developed BIPN grade 2 or above, based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), were enrolled and received 10 acupuncture treatments over 10 weeks. Self-reported BIPN-associated symptoms assessments were collected weekly at baseline, during, and after acupuncture treatment using the Neuropathy Pain Scale (NPS) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaires. Changes in individual symptoms were analyzed based on FACT/GOG-Ntx and NPS scores. RESULTS: There were statistically significant reductions in individual symptoms in both NPS and FACT/GOG-Ntx. The FACT/GOG-Ntx reductions were most pronounced in hand/feet numbness/tingling, discomfort, and trouble walking. The sensory symptoms, such as tingling and numbness, especially in the feet, reduced the most ( P < .0001), and motor dysfunction also reduced significantly ( P = .0001). Both hearing and dysfunction scores were also statistically significantly increased, indicating improved symptoms. The NPS scores showed significant symptom relief in all 10 items from the NPS assessment, particularly in cold sensitivity and an unpleasant feeling. CONCLUSIONS: Acupuncture can improve multiple symptoms associated with BIPN, particularly numbness and tingling in hands and feet, cold sensitivity, and an unpleasant feeling. Further randomized control trials are warranted to confirm our findings.