Loretta Loftus

A Pilot Study Evaluating the Effect of Mindfulness-Based Stress Reduction on Psychological Status, Physical Status, Salivary Cortisol, and Interleukin-6 Among Advanced-Stage Cancer Patients and Their Caregivers:

Purpose: To investigate whether a mindfulness-based stress reduction program for cancer (MBSR-C) improved psychological and physical symptoms, quality of life (QOL), and stress markers among advanced-stage cancer patients and caregivers. Design: A pilot within-subject design was used. Method: Patients previously diagnosed with advanced-stage breast, colon, lung, or prostate cancer and on treatment were recruited from the Moffitt Cancer Center and Research Institute. Twenty-six patient–caregiver dyads completed a modified 6-week, self-study MBSR-C program based on the Kabat–Zinn model. Psychological and physical symptoms and QOL were compared pre– and post–MBSR-C sessions. Salivary cortisol and interleukin-6 were assessed pre– and post–MBSR-C session at 1, 3, and 6 weeks. Findings: Following the 6-week MBSR program, patients showed improvements in stress and anxiety (p < .05); caregivers’ psychological and QOL also improved but were not statistically significant. Both patients and caregivers had decreases in cortisol at Weeks 1 and 3 (p < .05) but not at Week 6. Similar to cortisol levels at Week 6, salivary interleukin-6 levels were lower overall (before/after an MBSR-C session), compared with Week 1 for patients and caregivers. Conclusions: MBSR-C may be a beneficial intervention for reducing stress, anxiety, cortisol levels, and symptoms in advanced-stage cancer patients and may also benefit caregivers.

Time to Adjuvant Chemotherapy for Breast Cancer in National Comprehensive Cancer Network Institutions

BACKGROUND High-quality care must be not only appropriate but also timely. We assessed time to initiation of adjuvant chemotherapy for breast cancer as well as factors associated with delay to help identify targets for future efforts to reduce unnecessary delays. METHODS Using data from the National Comprehensive Cancer Network (NCCN) Outcomes Database, we assessed the time from pathological diagnosis to initiation of chemotherapy (TTC) among 6622 women with stage I to stage III breast cancer diagnosed from 2003 through 2009 and treated with adjuvant chemotherapy in nine NCCN centers. Multivariable models were constructed to examine factors associated with TTC. All statistical tests were two-sided. RESULTS Mean TTC was 12.0 weeks overall and increased over the study period. A number of factors were associated with a longer TTC. The largest effects were associated with therapeutic factors, including immediate postmastectomy reconstruction (2.7 weeks; P < .001), re-excision (2.1 weeks; P < .001), and use of the 21-gene reverse-transcription polymerase chain reaction assay (2.2 weeks; P < .001). In comparison with white women, a longer TTC was observed among black (1.5 weeks; P < .001) and Hispanic (0.8 weeks; P < .001) women. For black women, the observed disparity was greater among women who transferred their care to the NCCN center after diagnosis (P (interaction) = .008) and among women with Medicare vs commercial insurance (P (interaction) < .001). CONCLUSIONS Most observed variation in TTC was related to use of appropriate therapeutic interventions. This suggests the importance of targeted efforts to minimize potentially preventable causes of delay, including inefficient transfers in care or prolonged appointment wait times.

The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists

PURPOSE The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor-positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS. METHODS One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested. RESULTS Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants. CONCLUSIONS Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas.

Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score <18 (low risk) were compared with those with Recurrence Score ≥18 (intermediate/high risk). Carcinomas associated with Recurrence Score ≥18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score ≥18. A Ki-67-positive stromal/tumor cells ratio of >1 predicted Recurrence Score ≥18 with an area under the curve of 0.8967 on receiver operator curve analysis (P<0.0001). Our results suggest that the presence of increased stromal cellularity and/or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

Relationship of stress management skill to psychological distress and quality of life in adults with cancer

Background: Distress is common among cancer patients, especially those undergoing chemotherapy. Although skill in stress management is often the target of intervention efforts, its relationship to distress and quality of life in patients about to begin cancer treatment has not been examined.

Effects of self-directed stress management training and home-based exercise on quality of life in cancer patients receiving chemotherapy: a randomized controlled trial.

Research has shown that self‐directed stress management training improves mental well‐being in patients undergoing chemotherapy. The present study extends this work by evaluating separate and combined effects of stress management training and home‐based exercise.

Lymphocyte Recovery After Breast Cancer Treatment and Mindfulness-Based Stress Reduction (MBSR) Therapy

Objectives: This randomized controlled trial was conducted to examine immune recovery following breast cancer (BC) therapy and evaluate the effect of mindfulness-based stress reduction therapy (MBSR) on immune recovery with emphasis on lymphocyte subsets, T cell activation, and production of T-helper 1 (Th1; interferon [IFN]-γ) and T-helper 2 (Th2; interleukin-4 [IL-4]) cytokines. Method: Participants who completed the study consisted of 82 patients diagnosed with Stage 0–III BC, who received lumpectomy and adjuvant radiation ± chemotherapy. Patients were randomized into an MBSR(BC) intervention program or a control (usual care) group. Immune cell measures were assessed at baseline and within 2 weeks after the 6-week intervention. The numbers and percentages of lymphocyte subsets, activated T cells, and Th1 and Th2 cells in peripheral blood samples were determined by immunostaining and flow cytometry. Results: Immune subset recovery after cancer treatment showed positive associations with time since treatment completion. The B and natural killer (NK) cells were more susceptible than T cells in being suppressed by cancer treatment. Women who received MBSR(BC) had T cells more readily activated by the mitogen phytohemagglutinin (PHA) and an increase in the Th1/Th2 ratio. Activation was also higher for the MBSR(BC) group if <12 weeks from the end of treatment and women in MBSR(BC) <12 weeks had higher T cell count for CD4+. Conclusion: MBSR(BC) promotes a more rapid recovery of functional T cells capable of being activated by a mitogen with the Th1 phenotype, whereas substantial recovery of B and NK cells after completion of cancer treatment appears to occur independent of stress-reducing interventions.

Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas

Several molecular tests have been developed to estimate risk of distant recurrence and help clinical decision-making regarding adjuvant chemotherapy in patients with early stage breast carcinoma. Both Oncotype DX, a 21-gene expression profile, and Mammostrat, an immunohistochemistry-based assay, are validated to stratify patients into groups with low, intermediate and high risk of distant recurrence. However, they have not been compared head-to-head and little data are available regarding their correlation with clinicopathologic tumor features. In this study, we compared the clinicopathologic tumor features with risk estimations by Oncotype DX and Mammostrat in 106 low-grade estrogen receptor (ER)-positive breast carcinomas. Double immunohistochemical stain for pancytokeratin and Ki-67 was performed to assess cell proliferation in cancer vs stromal/inflammatory cells. Tumors showing intermediate/high risk by Oncotype DX, but not by Mammostrat, showed increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells. Discrepant cases showing intermediate/high risk by Oncotype DX but low risk by Mammostrat were associated with increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells, compared with concordant cases showing low risk by both assays. Our results suggest that low-grade ER-positive breast carcinomas with increased stromal/inflammatory cell proliferation may show an apparent increased risk of distant recurrence as assessed by Oncotype DX, which uses RNA extracted from a mixture of tumor and stromal/inflammatory cells in the assay. Mammostrat, which examines cancer cells only, may provide a better estimation of likely tumor behavior in a subgroup of low-grade breast carcinomas.

Evaluating patients with chronic pain after breast cancer surgery: the search for relief.

CHRONIC PAIN AFTER BREAST CANCER SURGERY OCcurs in approximately 50% of patients. The severity is variable, but sensory disturbances including paresthesias and phantom breast phenomena occur in approximately 47%. Potentially, this problem may increase with higher incidence of detected breast cancer and improved survival. Reasons for chronic discomfort after surgery are varied and complex, but nerve damage associated with axillary lymph node dissection is the most commonly reported cause and is associated with a doubling in prevalence compared with cases without this procedure. Interactions among treatment modalities such as type of breast surgery, axillary procedures, adjuvant chemotherapy, and radiation therapy add to the difficulty involved in the overall evaluation. In this issue of JAMA, Gartner and colleagues report findings from a cross-sectional study from Denmark that evaluated women undergoing an operation for unilateral primary breast cancer and documented the prevalence, location, severity, and frequency of persistent pain and sensory disturbances in 12 well-defined treatment groups. More than 3000 women completed questionnaires that addressed issues of specific regions of symptoms, severity of pain, frequency of symptoms, physician visits due to pain in the operated region, use of analgesics or other treatment for pain in the operated region, and pain in other locations. The responses were also analyzed with regard to age of the patient and treatment modalities for the breast cancer. The results are compelling. Almost half (47%) of the respondents reported pain in one or more areas, and 52% of those patients rated the discomfort as severe or moderate. As many as 76% of patients with severe pain experienced discomfort on a daily basis. The breast area was the most frequently reported site of pain, followed by the axilla, the arm, and the side of the body, and 40% experienced pain in other nonsurgical areas. The use of analgesics was relatively prevalent; other modalities for relief of pain such as physiotherapy and massage were also used. Predictive factors most significantly associated with chronic pain included young age (18-39 years), especially if the patient was treated with breast-conserving surgery. Treatment with adjuvant radiation therapy, but not chemotherapy, increased the risk for development of pain. Mastectomy carried a higher risk for moderate and severe distress compared with breast-conserving surgery. Axillary node dissection was more often associated with frequency of pain as well as severity of pain than sentinel node biopsy, regardless of the type of surgery to the breast. Patients with complaints of pain in other areas of the body were more likely to develop increased pain in the surgical site (65%) compared with women without pain in nonsurgical sites (37%). Sensory disturbance was more frequently reported by younger patients. The likelihood for development of any sensory discomfort was highest for patients treated with breastconserving surgery, axillary lymph node dissection, and chemotherapy with breast radiation therapy or breast and localregional radiation therapy. Of patients who reported sensory disturbances, 65% also experienced a type of pain suggesting that sensory abnormalities and nerve injury may lead to increased pain risk. Comparisons with other studies examining this issue may be difficult due to inconsistencies in definitions of chronic pain, different measurements of pain, studies from single institutions, changes in mix of surgical techniques and adjuvant treatment over time, and variable intervals in assessment of pain after surgery. Insufficient numbers of patients may also limit conclusions. An advantage of the study by Gartner et al is the large number of patients, 3253 nationwide, compared with other studies with 85 to 1600 patients. The larger population provides better risk estimates for all treatment modalities. Also, treatment principles are standardized at all breast cancer treatment facilities in Denmark according to European guidelines and national

Systemic Therapy for Bone Metastases

BACKGROUND Accelerated bone loss in patients with cancer is a frequent problem that may result from invasion of the cancer to bone, paraneoplastic tumor proteins, and/or hormonal therapies utilized for cancer treatment. Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both osteolytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy. METHODS This article reviews the results of trials that investigated the safety and efficacy of pharmacologic agents, including bisphosphonates and denosumab, for treatment of bone metastases. This analysis is derived from an assessment of the medical literature. RESULTS Beneficial systemic therapies for bone metastases have been developed to decrease SREs. Possible antitumor effects of the bisphosphonates are explored. In addition, the utility of markers of bone turnover in relation to response to therapy and survival, the safety and toxicity of bone-targeted therapies, treatment guidelines, and economic considerations are also discussed. CONCLUSIONS Effective systemic therapies for metastatic bone disease are available. Ongoing and future research projects in this field are also presented.