Lisa A. Rybicki

Symptom prevalence in advanced cancer: age, gender, and performance status interactions.

Age, gender, and performance status (PS) are important patient characteristics which might influence to cancer symptom profile. We conducted a secondary analysis of a symptom database to examine any interaction of these factors on symptom prevalence. 38 symptoms were assessed in 1000 consecutive patients with advanced cancer. The association of the three demographic factors with each symptom was examined using logistic regression analysis. Eight symptoms were associated with more than one of the three factors. Model-based estimates of symptom prevalence were calculated for 30 groups based on combinations of age, gender, and ECOG PS (0-4). Prevalence differences between various groups >10% were empirically classified as clinically relevant. The frequency of all eight symptoms (pain, constipation, sleep problems, nausea, anxiety, vomiting, sedation, and blackouts) was associated with more than one of the demographic characteristics of age, gender, and PS level. The prevalence of all eight decreased with older age. Females had more nausea, anxiety, and vomiting than males; males greater sleep problems. The prevalence of constipation, sedation, and blackouts was higher with worse PS, whereas pain and anxiety became less common with worse PS. Age, gender, and PS appeared to be associated with variations in the prevalence of eight gastrointestinal and neuropsychological symptoms in cancer patients. They should be included as important variables in clinical practice symptom research data.

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced‐intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA‐identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2–4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3–4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non‐relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3–4 acute GVHD (HR 2.92, 95% CI 1.2–7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed. Am. J. Hematol. 90:144–148, 2015.

Nonmyeloablative Second Transplants are Associated with Lower Nonrelapse Mortality and Superior Survival Than Myeloablative Second Transplants

Allogeneic hematopoietic stem cell transplantation (SCT) for patients who have previously undergone allogeneic or autologous SCT is potentially curative, but dangerous. To identify patient, disease, and treatment characteristics associated with outcome, we analyzed prognostic factors in 98 consecutive patients who underwent second transplants using allogeneic donors at the Cleveland Clinic between May 1987 and October 2008. Inclusion criteria included age ≥18 years, first SCT either autologous or allogeneic, and second SCT allogeneic. Patients whose second transplant was myeloablative (MA) had shorter survival (median 3.2 versus 14.7 months, P < .001) than patients whose second transplant was nonmyeloablative (NMA). In multivariable analysis, MA second transplant was associated with a higher risk of NRM (hazard ratio [HR] 2.01, P = 0.022) and death (HR 2.13, P = 0.002). Improved survival after NMA second transplant occurred primarily in patients without acute leukemia and when the first transplant was allogeneic. Among 17 patients transplanted within 3 months of first transplant, mortality was 100% and median survival was 2.3 months. MA transplantation within 3 months of prior SCT carries an unacceptably high rate of NRM. NMA second transplants were associated with substantially less NRM and despite a higher incidence of relapse, significantly improved survival compared to MA second transplants.

Perceptions of family members of palliative medicine and hospice patients who experienced music therapy

PurposeEvidence shows that music therapy aids in symptom management and improves quality of life for palliative medicine and hospice patients. The majority of previous studies have addressed patient needs, while only a few addressed the needs of family members. The primary purpose of this study was to understand family members’ perceptions of music therapy experienced by a relative in palliative medicine or hospice. Patient self-reported scales and music therapist assessment of change were also investigated.MethodsPatients scored their symptoms (pain, anxiety, depression, shortness of breath, and mood) before and after music therapy sessions. One family member present during the session assessed perceived effect on the patient’s pain, anxiety, depression, shortness of breath, stress level, restlessness, comfort level, mood, and quality of life. The effect on family member’s stress level, quality of life, and mood and helpfulness of the music therapy session for the patient and self were studied. Recommendations about future patient participation in music therapy and qualitative comments were also solicited.ResultsFifty family member/patient dyads participated in the study. Family member perceptions were positive, with 82% of responders indicating improvement for self and patient in stress, mood, and quality of life; 80% rating the session as extremely helpful; and 100% of 49 recommending further music therapy sessions for the patient. Patients reported statistically significant improvement in pain, depression, distress, and mood scores.ConclusionsFamily members of patients in palliative medicine and hospice settings reported an immediate positive impact of music therapy on the patient and on themselves. More research needs to be conducted to better understand the benefits of music therapy for family members.

Should we cluster patients or symptoms? The myth of symptom clusters based on ‘depression, insomnia, pain’ and ‘depression, fatigue, pain’

Context ‘Depression, fatigue, pain’ (DFP) and ‘depression, insomnia, pain’ (DIP) symptom clusters (SCs) have been proposed in cancer. These symptoms are common and co-occur, that is, they constitute clusters of patients rather than symptoms. Objectives The following research questions were addressed: (1) What is the frequency of co-occurrence of two symptom groups (DFP and DIP) in advanced cancer? (2) What is the degree of symptom item association within each symptom group? (3) Were either of these symptom trios associated with prognosis? Methods We reanalysed a symptom data set of 1000 patients with advanced cancer. We identified the frequency of co-occurrence of two symptom groups: DFP and DIP, using both prevalence and severity data. The symptom associations were tested by χ2 and Spearman correlations. We also determined whether either of these symptom trios were associated with a major biological outcome, that is, survival by time-to-event analyses. Results (1) Although DFP and DIP co-occured in about a quarter of the population, they were not SCs, but rather patient clusters. (2) Many persons had only one symptom from any symptom pair, and correlation coefficients were low for all symptom pairs. (3) Neither DFP nor DIP were associated with survival. Conclusions Neither DFP nor DIP symptom item combinations constituted a specific cancer SC contrary to prior reports. DFP co-occurred in 27% and DIP in only 20%. Additionally, these symptom combinations were not associated with a biological outcome, that is, poor prognosis. Patient subgroups identified by shared symptom experiences alone do not identify SCs.

Long-term survival after high-dose chemotherapy with autologous hematopoietic cell transplantation in metastatic breast cancer

OBJECTIVE/BACKGROUND The most common indication for high-dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (AHCT) in the 1990s was breast cancer. Several randomized trials and a more recent meta-analysis failed to show a survival benefit for AHCT in metastatic breast cancer (MBC); however, they demonstrated a better-than-expected 10-year to 15-year survival in 5-15% of patients. We thus evaluated the long-term results of treatment with HDC and AHCT in MBC at our institution. METHODS From 1984 to 2000, 285 patients underwent AHCT for MBC. The patient characteristics were collected through the Cleveland Clinic, United Transplant Database. A retrospective review of the medical records of the long-term surviving breast-cancer patients treated with HDC and AHCT was conducted. RESULTS With a median follow-up of 169 months, 34 (12%) remain alive. Of the 251 patients who died, 218 (87%) died of metastatic disease. A comparison by age (<50 years and >50 years) and hormonal status did not demonstrate any differences in relapse (p=.33 and p=.32, respectively) or survival (p=.13 and p=.42). Of the 34 long-term survivors, sufficient data were available on 28 patients, and further evaluation revealed that the majority had a primary or locally recurrent oligometastatic disease. CONCLUSION This retrospective evaluation of patients who underwent AHCT for MBC demonstrates long-term survival in a small subset of patients, primarily those with primary or recurrent oligometastatic disease. Oligometastatic breast cancer is a distinct entity within MBC, which may be curable with multimodality therapy. We thus conclude there remains no overall-survival benefit to HDC in MBC.

Efficacy of Standard Dose R-CHOP Alternating With R-HDAC Followed by Autologous Hematopoietic Cell Transplantation as Initial Therapy of Mantle Cell Lymphoma, a Single-Institution Experience

Background Young fit patients with mantle cell lymphoma (MCL) are commonly treated with induction chemotherapy followed by high‐dose chemotherapy and autologous hematopoietic cell transplantation (AHCT). Induction regimens with modifications of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and/or incorporation of high‐dose cytarabine (HDAC) appear more effective than R‐CHOP alone. Patients and Methods We adopted a modification of the Nordic protocol using standard, rather than higher dose R‐CHOP, alternating with HDAC (rituximab plus HDAC), for 3 cycles each or, for patients already treated with R‐CHOP alone before referral for AHCT, an additional 2 cycles of rituximab plus HDAC. We herein report our experience with 28 patients treated with this regimen who proceeded to AHCT, and compare their outcomes with patients treated with either standard‐dose R‐CHOP (n = 38) or R‐HCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate, and cytarabine; n = 21), before AHCT. Results With a median follow‐up duration of 26 months, our data show that this modification of the Nordic regimen is a highly effective pre‐AHCT first‐line therapy for MCL (3‐year progression‐free and overall survival rates of 69% and 75%, respectively). Conclusion By using a less intense induction, this regimen can serve as a platform for combined use of novel agents, with less risk of additive toxicity. Micro‐Abstract In a retrospective study of 87 patients with mantle cell lymphoma treated with 3 different induction regimens, we show that a modification of the Nordic regimen in which a standard, rather than dose‐intense, R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) alternating with high‐dose cytarabine is a highly effective preautologous hematopoietic cell transplantation therapy.

Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era

Micro‐Abstract Whether to clinically approach follicular lymphoma (FL) Grade 3 as an indolent or aggressive lymphoma, especially since the introduction of rituximab, is unclear. Our experience with FL Grade 3A, compared with FL Grade 3B or with concomitant diffuse large B cell lymphoma, primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone suggests possible long‐term remissions. This must be confirmed with longer follow‐up and additional studies. Background: Follicular lymphoma (FL) is heterogeneous. Although FL Grade 3B (FL3B) is treated as aggressive FL (aggFL), an optimal approach to FL Grade 3A (FL3A) remains unclear because few data exist on clinical outcomes on the basis of subclassification of FL Grade 3 (FL3) since the introduction of rituximab. We report outcomes of FL3 in the rituximab era. Patients and Methods: We identified and analyzed a retrospective cohort of 53 patients with FL3A, 3B, and FL Grade 3 with areas of diffuse large B‐cell lymphoma (DLBCL). They were divided into 2 groups: aggFL (n = 21) included patients with FL3B (n = 10) and FL3 (A or B) with concomitant DLBCL (n = 11); indolent lymphoma (n = 32) included only FL3A. Results: Baseline characteristics did not differ between the groups. rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R‐CHOP) was initial treatment in 15 (79%) of patients with aggFL and 21 (72%) of those with FL3A; rituximab was included in initial therapy in 18 (95%) and 24 (83%), respectively. Comparing aggFL and FL3A, 5‐year overall survival was 90% versus 79% (P = .97) and 5‐year progression‐free survival (PFS) 44% versus 34% (P = .75), respectively. Conclusion: We conclude that outcomes for FL3, primarily treated with R‐CHOP, do not differ between FL3A and aggFL (FL3B and FL3/DLBCL). The aggFL group showed a plateau in PFS confirming these should be treated with curative intent. FL3A patients, mainly managed with R‐CHOP, also show an apparent plateau in PFS. Although longer follow‐up and confirmation in other data sets is required, this indicates potential undertreatment of FL3A with less aggressive regimens often used for indolent lymphoma.

Comparative Effectiveness of Busulfan and Fludarabine versus Fludarabine and 400 cGy Total Body Irradiation Conditioning Regimens for Acute Myeloid Leukemia/Myelodysplastic Syndrome

Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A comparative effectiveness analysis was performed to assess outcomes of busulfan and fludarabine (BuFlu) versus those of fludarabine and 400 cGy total body irradiation (FluTBI) conditioning. Thirty-three subjects received BuFlu and 38 received FluTBI. The BuFlu group received more red blood cell transfusions (P = .02) and had a longer time to platelet recovery (P = .004). There were no differences between the regimens regarding incidence of acute or chronic graft-versus-host disease (GVHD), quality of life, or 2-year outcome estimates for relapse (48; 95% confidence interval [CI], 30 to 64 and 50; 95% CI, 33 to 65), nonrelapse mortality (29; 95% CI, 14 to 45 and 29; 95% CI, 15 to 44), relapse-free survival (27; 95% CI, 13 to 43 and 29; 95% CI, 16 to 44), and overall survival (35; 95% CI, 19 to 51; and 37; 95% CI, 22 to 52), respectively. These comparable outcomes have implications for health care resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and additional strategies to prevent relapse and limit toxicities as well as cost-effectiveness analyses are warranted.

Minimal Mortality from Veno-Occlusive Disease Following Busulfan-Based Preparative Regimens: A Large Single Institution Experience

Hepatic veno-occlusive disease (VOD) is a frequently cited life threatening limitation of busulfan containing regimens. Reported incidence ranges from 5% to .50% and mortality rates can be substantial. Using a prospectively maintained database, a retrospective analysis was conducted to identify patients undergoing autologous or myeloablative allogeneic stem cell transplant with busulfan/cyclophosphamide or busulfan/cyclophosphamide/etoposide as the preparative regimen at a single institution from 1993– 2007. The objective was to estimate the mortality from VOD. 1508 transplant patients (1037 autologous and 471 allogeneic) were identified with 1 to 15 years of follow up. The autologous group had VOD as the primary cause of death in only 3 patients (0.7% of deaths, 0.3% total population). In this group the most common cause of death was relapse (32% of total population, 74.9% of total deaths). The cumulative incidence of non relapse mortality (NRM) was 10.6% with respiratory failure (6.8%) being most common. The allogeneic group had VOD as the primary cause of death in only 8 patients (1.7% of total population, 2.4% of total deaths). In this group the most common cause of death was relapse (22% of total population, 31.1% of deaths). The cumulative incidence of NRM was 47.8% with graft versus host disease (30.6%) being most common. Liver related mortality was not a significant factor in either subset of patients. This is the largest single institution analysis on the mortality risk of VOD following busulfan-based preparation. Unlike some smaller previous reports, lethal VOD was infrequent following busulfan-based preparation and not a significant cause of mortality. When both autologous and allogeneic transplant groups were combined, VOD was the primary cause of death in \1% of patients. In conclusion, in a large single institution with significant experience administering busulfan-based preparative regimens for stem cell transplant VOD as a primary cause of death is extremely low.