Acupuncture vs Massage for Pain in Patients Living With Advanced Cancer: The IMPACT Randomized Clinical Trial.

Importance: Pain is challenging for patients with advanced cancer. While recent guidelines recommend acupuncture and massage for cancer pain, their comparative effectiveness is unknown. Objective: To compare the effects of acupuncture and massage on musculoskeletal pain among patients with advanced cancer. Design, Setting, and Participants: A multicenter pragmatic randomized clinical trial was conducted at US cancer care centers consisting of a northeastern comprehensive cancer center and a southeastern cancer institute from September 19, 2019, through February 23, 2022. The principal investigator and study statisticians were blinded to treatment assignments. The duration of follow-up was 26 weeks. Intention-to-treat analyses were performed (linear mixed models). Participants included patients with advanced cancer with moderate to severe pain and clinician-estimated life expectancy of 6 months or more. Patient recruitment strategy was multipronged (eg, patient database queries, mailings, referrals, community outreach). Eligible patients had English or Spanish as their first language, were older than 18 years, and had a Karnofsky score greater than or equal to 60 (range, 0-100; higher scores indicating less functional impairment). Interventions: Weekly acupuncture or massage for 10 weeks with monthly booster sessions up to 26 weeks. Main Outcomes and Measures: The primary end point was the change in worst pain intensity score from baseline to 26 weeks. The secondary outcomes included fatigue, insomnia, and quality of life. The Brief Pain Inventory (range, 0-10; higher numbers indicate worse pain intensity or interference) was used to measure the primary outcome. The secondary outcomes included fatigue, insomnia, and quality of life. Results: A total of 298 participants were enrolled (mean [SD] age, 58.7 [14.1] years, 200 [67.1%] were women, 33 [11.1%] Black, 220 [74.1%] White, 46 [15.4%] Hispanic, and 78.5% with solid tumors). The mean (SD) baseline worst pain score was 6.9 (1.5). During 26 weeks, acupuncture reduced the worst pain score, with a mean change of -2.53 (95% CI, -2.92 to -2.15) points, and massage reduced the Brief Pain Inventory worst pain score, with a mean change of -3.01 (95% CI, -3.38 to -2.63) points; the between-group difference was not significant (-0.48; 95% CI, -0.98 to 0.03; P = .07). Both treatments also improved fatigue, insomnia, and quality of life without significant between-group differences. Adverse events were mild and included bruising (6.5% of patients receiving acupuncture) and transient soreness (15.1% patients receiving massage). Conclusions and Relevance: In this randomized clinical trial among patients with advanced cancer, both acupuncture and massage were associated with pain reduction and improved fatigue, insomnia, and quality of life over 26 weeks; however, there was no significant different between the treatments. More research is needed to evaluate how best to integrate these approaches into pain treatment to optimize symptom management for the growing population of people living with advanced cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04095234.

COMT Val158Met Affects the Analgesic Response to Acupuncture Among Cancer Survivors With Chronic Pain.

Catechol-O-methyltransferase (COMT) is the major enzyme involved in the catabolism of dopamine, a neurotransmitter in the brain's reward system. The common COMT polymorphism Val158Met (rs4680 G>A) modulates pain response to opioids through a reward-motivated mechanism; however, its role in nonpharmacological pain medicine has not been clinically characterized. We genotyped 325 participants from a randomized controlled trial of cancer survivors with chronic musculoskeletal pain. We found that carrying methionine at position 158 (158Met) of COMT, encoded by the A allele, significantly increased the analgesic response to electroacupuncture (74% vs 50%; odds ratio [OR]: 2.79; 95% confidence interval [CI]: 1.31, 6.05; P < .01), but not to auricular acupuncture (68% vs 60%; OR: 1.43; 95% CI: .65, 3.12; P = .37) or usual care (24% vs 18%; OR: 1.46; 95% CI: .38, 7.24; P = .61) compared to Val/Val. These findings raise the possibility that COMT Val158Met might be an important predictor of analgesic response to electroacupuncture, providing novel insights into precision nonpharmacologic pain management tailored to individual genetic backgrounds. PERSPECTIVE: This work suggests the modulating effects of the polymorphism in COMT Val158Met on the response to acupuncture. Further research needs to validate these findings, increase the mechanistic understanding of acupuncture, and guide further development of acupuncture as a precision pain management strategy.

Telehealth-Based Music Therapy Versus Cognitive Behavioral Therapy for Anxiety in Cancer Survivors: Rationale and Protocol for a Comparative Effectiveness Trial.

BACKGROUND: Cancer survivors represent one of the fastest growing populations in the United States. Unfortunately, nearly 1 in 3 survivors experience anxiety symptoms as a long-term consequence of cancer and its treatment. Characterized by restlessness, muscle tension, and worry, anxiety worsens the quality of life; impairs daily functioning; and is associated with poor sleep, depressed mood, and fatigue. Although pharmacological treatment options are available, polypharmacy has become a growing concern for cancer survivors. Music therapy (MT) and cognitive behavioral therapy (CBT) are evidence-based, nonpharmacological treatments that have demonstrated effectiveness in treating anxiety symptoms in cancer populations and can be adapted for remote delivery to increase access to mental health treatments. However, the comparative effectiveness of these 2 interventions delivered via telehealth is unknown. OBJECTIVE: The aims of the Music Therapy Versus Cognitive Behavioral Therapy for Cancer-related Anxiety (MELODY) study are to determine the comparative effectiveness of telehealth-based MT versus telehealth-based CBT for anxiety and comorbid symptoms in cancer survivors and to identify patient-level factors associated with greater anxiety symptom reduction for MT and CBT. METHODS: The MELODY study is a 2-arm, parallel-group randomized clinical trial that aims to compare the effectiveness of MT versus CBT for anxiety and comorbid symptoms. The trial will enroll 300 English- or Spanish-speaking survivors of any cancer type or stage who have experienced anxiety symptoms for at least 1 month. Participants will receive 7 weekly sessions of MT or CBT delivered remotely via Zoom (Zoom Video Communications, Inc) over 7 weeks. Validated instruments to assess anxiety (primary outcome), comorbid symptoms (fatigue, depression, insomnia, pain, and cognitive dysfunction), and health-related quality of life will be administered at baseline and at weeks 4, 8 (end of treatment), 16, and 26. Semistructured interviews will be conducted at week 8 with a subsample of 60 participants (30 per treatment arm) to understand individual experiences with the treatment sessions and their impact. RESULTS: The first study participant was enrolled in February 2022. As of January 2023, 151 participants have been enrolled. The trial is expected to be completed by September 2024. CONCLUSIONS: This study is the first and largest randomized clinical trial to compare the short- and long-term effectiveness of remotely delivered MT and CBT for anxiety in cancer survivors. Limitations include the lack of usual care or placebo control groups and the lack of formal diagnostic assessments for psychiatric disorders among trial participants. The study findings will help guide treatment decisions for 2 evidence-based, scalable, and accessible interventions to promote mental well-being during cancer survivorship. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46281.

Effect of acupuncture versus usual care on sleep quality in cancer survivors with chronic pain: Secondary analysis of a randomized clinical trial.

BACKGROUND: Chronic pain negatively affects sleep; it is unclear whether pain relief from acupuncture contributes to sleep quality improvements in cancer survivors. This study aimed to evaluate the effect of acupuncture versus usual care on sleep quality among cancer survivors with comorbid sleep disturbance and chronic musculoskeletal pain. METHODS: Sleep outcome data from the Personalized Electroacupuncture Versus Auricular Acupuncture Comparative Effectiveness (PEACE) randomized clinical trial were analyzed. Electroacupuncture or auricular acupuncture was compared with usual care for sleep quality improvement over 10 weeks of treatment among cancer survivors with clinically significant sleep disturbance and chronic musculoskeletal pain at baseline. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) global score. RESULTS: Among 268 participants (mean [standard deviation (SD)] age, 61.4 [12.6] years; 191 women [71.3%]; mean [SD] baseline PSQI global score, 10.3 [3.3] points), electroacupuncture and auricular acupuncture resulted in greater reductions in the PSQI global score from baseline to 10 weeks in comparison with usual care: 1.42 points (95% confidence interval [CI], 0.45-2.38; p = .004) and 1.59 points (95% CI, 0.62-2.55; p = .001), respectively. The improvement in sleep quality for the acupuncture groups was sustained for 24 weeks from randomization. Furthermore, a greater proportion of patients in the electroacupuncture and auricular acupuncture groups had clinically meaningful improvement in sleep quality compared to the usual care group (41.0% and 42.9% vs. 21.4%; p = .044). CONCLUSIONS: Among cancer survivors with comorbid sleep disturbance and chronic pain, electroacupuncture and auricular acupuncture produced a clinically relevant and persistent improvement in sleep quality. These findings suggest that acupuncture may be an evidence-based nonpharmacologic intervention to improve sleep health for cancer survivors with pain. PLAIN LANGUAGE SUMMARY: This study analyzed the sleep quality data from a published randomized clinical trial that evaluated the effect of electroacupuncture or auricular acupuncture versus usual care on pain relief among people who survived cancer. This analysis included a prespecified subgroup of 268 participants with co-occurring sleep disturbance and chronic musculoskeletal pain at baseline and found that patients who used acupuncture for pain relief demonstrated greater improvements in sleep quality compared with patients who received usual care. Sleep quality improvement by acupuncture was sustained after the treatment ended.

Acupuncture versus massage for pain in patients living with advanced cancer: a protocol for the IMPACT randomised clinical trial.

INTRODUCTION: Pain, comorbid fatigue and sleep disturbances are common and distressing symptoms for patients with advanced cancer, negatively impacting their quality of life. Clinical guidelines recommend non-pharmacological interventions, including acupuncture and massage, for pain management in adult patients with cancer in adjunct to conventional care. However, high-quality evidence about the comparative effectiveness and long-term durability of these therapies for symptom management is limited. METHODS AND ANALYSIS: We describe the design of a two-arm, parallel group, multicentre randomised controlled trial that investigates the use of acupuncture versus massage for musculoskeletal pain among 300 patients with diverse types of advanced cancer. The primary aim is to evaluate the long-term effectiveness (26 weeks from randomisation) of acupuncture vs massage for pain (primary outcome) and comorbid symptoms (fatigue, sleep disturbance and quality of life). The secondary aim is to identify patient-level demographic characteristics (eg, sex, race, age), clinical factors (eg, insomnia, pain severity) and psychological attributes that are associated with a greater reduction in pain for either acupuncture or massage. Patients will receive weekly acupuncture or massage treatments for 10 weeks, followed by monthly booster sessions up to 26 weeks. The primary endpoint will be the change in worst pain intensity score from baseline to 26 weeks. We will collect validated patient-reported outcomes at multiple time points over 26 weeks. ETHICS AND DISSEMINATION: The Institutional Review Board at Memorial Sloan Kettering Cancer Center in New York approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. Our findings will help patients and healthcare providers make informed decisions about incorporating non-pharmacological treatments to manage pain for patients with advanced cancer. TRIAL REGISTRATION NUMBER: NCT04095234.

Cerebrospinal fluid diversion for leptomeningeal metastasis: palliative, procedural and oncologic outcomes.

BACKGROUND: Leptomeningeal metastasis (LM) occurs in 3-5% of patients with solid metastatic tumors and often portends a severe prognosis including symptomatic hydrocephalus and intracranial hypertension. Cerebrospinal fluid (CSF) shunting can provide symptomatic relief in this patient subset; however, few studies have examined the role of shunting in the palliation, prognosis and overall oncologic care of these patients. OBJECTIVE: To identify and evaluate risk factors associated with prognosis after CSF diversion and assess surgical, symptomatic and oncologic outcomes in this population. METHODS: A retrospective study was conducted on patients with solid-malignancy LM treated with a shunt at a NCI-designated Comprehensive Cancer Center between 2010 and 2019. RESULTS: One hundred and ninety patients with metastatic LM underwent CSF diversion. Overall survival was 4.14 months from LM diagnosis (95% CI: 3.29-4.70) and 2.43 months (95% CI: 2.01-3.09) from shunting. Karnofsky performance status (KPS) at time of shunting and brain metastases (BrM) number at LM diagnosis demonstrated significant associations with survival (HR = 0.66; 95% CI [0.51-0.86], p = 0.002; HR = 1.40; 95% CI [1.01-1.93] per 10 BrM, p = 0.04, respectively). Eighty-three percent of patients experienced symptomatic relief, and 79% were discharged home or to rehabilitation facilities post-shunting. Post-shunt, 56% of patients received additional systemic therapy or started or completed WBRT. Complications included infection (5%), symptomatic subdural hygroma/hematoma (6.3%), and shunt externalization/removal/repair (8%). Abdominal seeding was not identified. CONCLUSIONS: CSF diversion for LM with hydrocephalus and intracranial hypertension secondary to metastasis can achieve symptomatic relief, hospital discharge, and return to further oncologic therapy, with a complication profile unique to this pathophysiology. However, decision-making in this population must incorporate end-of-life goals of care given limited prognosis.

The effect of surgery on radiation necrosis in irradiated brain metastases: extent of resection and long-term clinical and radiographic outcomes.

OBJECTIVE: Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes. METHODS: A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003 to 2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups. RESULTS: Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (N = 42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p < 0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p < 0.05). Among surviving patients, a significant proportion were able to decrease their steroid use: steroid-dependency decreased from 54% preoperatively to 15% at 12 months postoperatively (p = 0.001). CONCLUSIONS: RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR; and reduced steroid dependency.

Effectiveness of Electroacupuncture or Auricular Acupuncture vs Usual Care for Chronic Musculoskeletal Pain Among Cancer Survivors: The PEACE Randomized Clinical Trial.

IMPORTANCE: The opioid crisis creates challenges for cancer pain management. Acupuncture confers clinical benefits for chronic nonmalignant pain, but its effectiveness in cancer survivors remains uncertain. OBJECTIVE: To determine the effectiveness of electroacupuncture or auricular acupuncture for chronic musculoskeletal pain in cancer survivors. DESIGN, SETTING, AND PARTICIPANTS: The Personalized Electroacupuncture vs Auricular Acupuncture Comparative Effectiveness (PEACE) trial is a randomized clinical trial that was conducted from March 2017 to October 2019 (follow-up completed April 2020) across an urban academic cancer center and 5 suburban sites in New York and New Jersey. Study statisticians were blinded to treatment assignments. The 360 adults included in the study had a prior cancer diagnosis but no current evidence of disease, reported musculoskeletal pain for at least 3 months, and self-reported pain intensity on the Brief Pain Inventory (BPI) ranging from 0 (no pain) to 10 (worst pain imaginable). INTERVENTIONS: Patients were randomized 2:2:1 to electroacupuncture (n = 145), auricular acupuncture (n = 143), or usual care (n = 72). Intervention groups received 10 weekly sessions of electroacupuncture or auricular acupuncture. Ten acupuncture sessions were offered to the usual care group from weeks 12 through 24. MAIN OUTCOMES AND MEASURES: The primary outcome was change in average pain severity score on the BPI from baseline to week 12. Using a gatekeeping multiple-comparison procedure, electroacupuncture and auricular acupuncture were compared with usual care using a linear mixed model. Noninferiority of auricular acupuncture to electroacupuncture was tested if both interventions were superior to usual care. RESULTS: Among 360 cancer survivors (mean [SD] age, 62.1 [12.7] years; mean [SD] baseline BPI score, 5.2 [1.7] points; 251 [69.7%] women; and 88 [24.4%] non-White), 340 (94.4%) completed the primary end point. Compared with usual care, electroacupuncture reduced pain severity by 1.9 points (97.5% CI, 1.4-2.4 points; P < .001) and auricular acupuncture reduced by 1.6 points (97.5% CI, 1.0-2.1 points; P < .001) from baseline to week 12. Noninferiority of auricular acupuncture to electroacupuncture was not demonstrated. Adverse events were mild; 15 of 143 (10.5%) patients receiving auricular acupuncture and 1 of 145 (0.7%) patients receiving electroacupuncture discontinued treatments due to adverse events (P < .001). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial among cancer survivors with chronic musculoskeletal pain, electroacupuncture and auricular acupuncture produced greater pain reduction than usual care. However, auricular acupuncture did not demonstrate noninferiority to electroacupuncture, and patients receiving it had more adverse events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02979574.

Yoga for Chemotherapy-Induced Peripheral Neuropathy and Fall Risk: A Randomized Controlled Trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect that worsens quality of life and increases the risk of falls in cancer survivors. Evidence of yoga's safety and efficacy in treating CIPN is lacking. METHODS: In a randomized controlled study, we assigned breast and gynecological cancer survivors with persistent moderate-to-severe CIPN pain, numbness, or tingling with a score of 4 or greater (0-10 numeric rating scale [NRS]) for at least 3 months after chemotherapy to 8 weeks of usual care or yoga focused on breathwork and musculoskeletal conditioning. Primary endpoint was treatment arm differences for NRS, and secondary endpoints were Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale (FACT/GOG-Ntx), and Functional Reach Test after week 8. We tested treatment arm differences for each outcome measure using linear mixed models with treatment-by-time interactions. All statistical tests were two-sided. RESULTS: We randomly assigned 41 participants into yoga (n = 21) or usual care (n = 20). At week 8, mean NRS pain decreased by 1.95 points (95% confidence interval [CI] = -3.20 to -0.70) in yoga vs 0.65 (95% CI = -1.81 to 0.51) in usual care (P = .14). FACT/GOG-Ntx improved by 4.25 (95% CI = 2.29 to 6.20) in yoga vs 1.36 (95% CI = -0.47 to 3.19) in usual care (P = .035). Functional reach, an objective functional measure predicting the risk of falls, improved by 7.14 cm (95% CI = 3.68 to 10.59) in yoga and decreased by 1.65 cm (95% CI = -5.00 to 1.72) in usual care (P = .001). Four grade 1 adverse events were observed in the yoga arm. CONCLUSION: Among breast and gynecological cancer survivors with moderate-to-severe CIPN, yoga was safe and showed promising efficacy in improving CIPN symptoms.

Personalized electro-acupuncture versus auricular-acupuncture comparative effectiveness (PEACE): A protocol of a randomized controlled trial for chronic musculoskeletal pain in cancer survivors.

INTRODUCTION: Chronic pain is a leading cause of disability and remains under-treated in nearly half of patients with cancer. The opioid crisis has highlighted an urgent public health need for effective nonpharmacological pain management. Electroacupuncture (EA) and Battlefield Acupuncture (BFA) represent nonpharmacological modalities used in clinical practice to manage pain; however, their effectiveness has not been rigorously evaluated in oncology settings. METHODS: We describe the design of a 3-arm, parallel, single-center, multisite randomized controlled trial that investigates EA and BFA versus usual-care wait-list control (WLC) for chronic musculoskeletal pain among 360 patients with diverse cancer types across various stages. The primary aim is to compare effects of EA and BFA versus WLC on pain, physical function, and co-morbid symptoms. The secondary aim is to examine the interaction between patient outcome expectancy and acupuncture modality (EA vs BFA) on pain reduction. The tertiary aim is to evaluate the association between genetic polymorphisms and responses to acupuncture. Patients will be randomized in a 2:2:1 ratio to EA:BFA:WLC. Acupuncture groups will receive weekly treatments over 10 weeks. WLC will receive usual care over the same evaluation period as the acupuncture groups. The primary endpoint will be the change in average pain intensity score from baseline to week 12. We will collect validated patient-reported outcomes and blood/saliva samples at multiple timepoints over 24 weeks. DISCUSSION: Our findings will advance nonpharmacological pain management in oncology and inform personalized treatment approaches that integrate individuals' expectations and genetic biomarkers to deliver "precision" acupuncture to cancer patients with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02979574.

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Radiotherapy and temozolomide for anaplastic astrocytic gliomas.

We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m(2)), and six adjuvant 28-day cycles of either dose-dense (150 mg/m(2), days 1-7, 15-21) or metronomic (50 mg/m(2), days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m(2), days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35%, subtotal 23%, and biopsy 42%. Histology was AA in 90%, and AOA in 10%. MGMT promoter methylation was methylated in 20%, unmethylated in 50%, and uninformative in 30% of 30 tested. Median progression-free survival was 2.1 years (95% CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials.

(124)I-huA33 antibody PET of colorectal cancer.

UNLABELLED: Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI). METHODS: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. RESULTS: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. CONCLUSION: Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma.

PURPOSE: Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. PATIENTS AND METHODS: Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m(2) days 1 to 7 and 15 to 21) or metronomic (50 mg/m(2) continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS: Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). CONCLUSION: Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Effect of creatinine clearance on patterns of toxicity in older patients receiving adjuvant chemotherapy for breast cancer.

OBJECTIVE: A number of age-related physiological changes contribute to an increased risk of toxicity of cancer chemotherapy in the elderly. One of the most important of these changes is the progressive decline in renal function with aging. We sought to determine the association between calculated creatinine clearance (CL(CR)) and grade 3 or 4 toxicities during adjuvant chemotherapy in women > or =65 years of age with breast cancer. DESIGN AND METHODS: We identified 1405 patients > or =65 years of age who had been treated for primary invasive breast cancer at Memorial Sloan-Kettering Cancer Center between January 1998 and December 2000. Patients were included in this analysis if they had stage I-III breast cancer and had received adjuvant chemotherapy. Patients were excluded if they had a prior history of breast cancer or chemotherapy, or had no baseline creatinine value available for review. RESULTS: The 126 patients who met our criteria had received either cyclophosphamide, methotrexate and fluorouracil (CMF) [n = 65, mean age 71, range 65-78] or an anthracycline-based regimen (n = 61, mean age 69, range 65-79). The majority of patients (97%) had a normal creatinine. CL(CR), as calculated by the Cockcroft-Gault and Jeliffe formulas, decreased with increasing age (increased age associated with decreased Cockcroft-Gault [p = 0.02]; increased age associated with decreased Jeliffe [p < 0.01]). In multivariate analysis, after controlling for age and co-morbidity, a CL(CR) <50 mL/min by the Cockcroft-Gault formula was associated with an increased risk of fever and neutropenia (odds ratio [OR] 3.60; 95% CI 1.00, 12.94; p = 0.05) and a CL(CR) <50 mL/min by the Jeliffe formula was associated with a trend towards an increased risk of fever and neutropenia (OR 3.30; 95% CI 0.91, 12.33; p = 0.07), grade 3 or 4 haematological toxicity (OR 2.43; 95% CI 0.90, 6.55; p = 0.08), and need for erythropoietin (OR 4.15; 95% CI 0.81, 2.99; p = 0.09). An increase in creatinine (as a continuous variable) was associated with a trend towards an increased risk of grade 3 or 4 haematological toxicity (OR 5.81; 95% CI 0.96, 35.33; p = 0.06). CONCLUSIONS: In this cohort of older breast cancer patients, a decreased CL(CR) and increased creatinine was associated with an increased risk of fever and neutropenia or haematological toxicity. CL(CR) should be considered when determining chemotherapy dosage in the elderly.

Patterns of toxicity in older patients with breast cancer receiving adjuvant chemotherapy.

OBJECTIVE: To retrospectively determine the relationship of age to toxicity from adjuvant chemotherapy for breast cancer. DESIGN AND METHODS: We identified 1,405 consecutive patients age 65 or older with primary invasive breast cancer who were seen at Memorial Sloan-Kettering Cancer Center from January 1998 to December 2000. Patients selected from this cohort for analysis were aged 65 or older at diagnosis; received their follow-up care at Memorial Sloan-Kettering Cancer Center; had stage I, II, or III breast cancer; and received adjuvant chemotherapy consisting of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), an anthracycline-based regimen (AC [doxorubicin and cyclophosphamide], or AC-T [AC and paclitaxel or docetaxel]). Exclusion criteria included prior chemotherapy or previous breast cancer. RESULTS: One hundred thirty-two patients were included in this study, with a mean age of 70 (range 65--79). Comorbidity measured by the Charlson comorbidity index was low: score 0 (83%), 1 (12%), 2 (5%); with stages: I(18%), IIA (41%), IIB (27%), IIIA (8%), IIIB (6%), T1Nx (1%). Patients receiving an anthracycline-based regimen were more likely to experience grade 3 or 4 toxicity (p=0. 01), require hospitalization (p<0.001), and/or develop febrile neutropenia (p<0.001). Treatment delays due to myelosuppression occurred more frequently in patients receiving CMF (p<0.001). The type of chemotherapy regimen (anthracycline compared to CMF) was a better predictor for toxicity than increased age or comorbidity score. CONCLUSIONS: In this cohort of older patients with breast cancer, the risk for toxicity from adjuvant chemotherapy depended more on the type of regimen (anthracycline vs. CMF) than the patient's chronological age.

Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer.

PURPOSE: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. EXPERIMENTAL DESIGN: Patients with >/=4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m(2), respectively, x6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m(2)) alternating with docetaxel (35 mg/m(2)) x18. RESULTS: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26-63 years), median number of positive nodes was 9 (range, 4-32), and median tumor size was 2.5 cm (range, 0.6-11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. CONCLUSION: FEC x6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.