Frequency,Outcome, and Predictors of Success Within 6 Weeks of an Opioid Rotation Among Outpatients with Cancer Receiving Strong Opioids

Background.

Opioid rotation is used to treat uncontrolled pain and/or opioid-related adverse effects. Our aim was to determine the frequency, indications, outcomes, and predictors of successful opioid rotation in outpatients with cancer.

Methods.

Medical records of consecutive outpatients with cancer who received strong opioids and returned for follow-up visit within ≤6 weeks to our supportive care center from January to December 2008 were reviewed. Data on patient characteristics, symptoms, opioid use, indications for opioid rotation, outcomes, and morphine equivalent daily dose were collected. Successful opioid rotation was defined as a two-point or 30% reduction in the symptom score or the resolution of opioid-induced neurotoxicity and continuation of the new opioid at follow-up.

Results.

Opioid rotation was performed in 120 of 385 patients (31%). The median patient age was 55 years. There were 6/120 patients with missing data. Of the 114 evaluable patients, 68 (60%) were men, 81 (71%) were white, 27 (24%) had gastrointestinal cancer, and 90 (80%) had advanced-stage disease. The median Eastern Cooperative Oncology Group score was 1 (interquartile range: 1–2) and the median time between opioid rotation and follow-up was 14 days (interquartile range: 7–21 days). The most common indications for opioid rotation were uncontrolled pain (95/114; 83%) and opioid-induced neurotoxicity (13/114; 12%). A total of 35 patients (31%) had partial opioid rotation. The median improvements in pain and symptom distress score were −2 (interquartile range: −4 to 0; p < .001) and −5 (interquartile range: −14 to 7; p = .004), respectively. The morphine equivalent daily dose did not change significantly after opioid rotation (p = .156). A total of 65% of patients (74/114) had successful opioid rotation. There were no clinically significant independent predictors for successful opioid rotation.

Conclusion.

Opioid rotation was conducted in 31% of outpatients with cancer, with a 65% success rate. The most frequent reason for opioid rotation was uncontrolled pain. There were no independent predictors for successful opioid rotation.     

Patterns of Storage,Use, and Disposal of Opioids Among Cancer Outpatients

Purpose.

Improper storage, use, and disposal of prescribed opioids can lead to diversion or accidental poisoning. Our objective was to determine the patterns of storage, utilization, and disposal of opioids among cancer outpatients.

Patients and Methods.

We surveyed 300 adult cancer outpatients receiving opioids in our supportive care center and collected information regarding opioid use, storage, and disposal, along with scores on the CAGE (cut down, annoyed, guilty, eye-opener) alcoholism screening questionnaire. Unsafe use was defined as sharing or losing opioids; unsafe storage was defined as storing opioids in plain sight.

Results.

The median age was 57 years. CAGE was positive in 58 of 300 patients (19%), and 26 (9%) had a history of illicit drug use. Fifty-six (19%) stored opioids in plain sight, 208 (69%) kept opioids hidden but unlocked, and only 28 (9%) locked their opioids. CAGE-positive patients (p = .007) and those with a history of illicit drug use (p = .0002) or smoking (p = .03) were more likely to lock their opioids. Seventy-eight (26%) reported unsafe use by sharing (9%) or losing (17%) their opioids. Patients who were never married or single (odds ratio: 2.92; 95% confidence interval: 1.48–5.77; p = .006), were CAGE positive (40% vs. 21%; p = .003), or had a history of illicit drug use (42% vs. 23%; p = .031) were more likely to use opioids unsafely. Overall, 223 of 300 patients (74%) were unaware of proper opioid disposal methods, and 138 (46%) had unused opioids at home.

Conclusion.

A large proportion of cancer patients improperly and unsafely use, store, and dispose of opioids, highlighting the need for establishment of easily accessed patient education and drug take-back programs.     

An Ethnographic Study of Barriers to Cancer Pain Management and Opioid Availability in India

Background.

The world’s global cancer burden disproportionally affects lower income countries, where 80% of patients present with late-stage disease and have limited access to palliative care and effective pain-relieving medications, such as morphine. Consequently, millions die each year with unrelieved pain.

Objective.

The objective of this study was to examine barriers to opioid availability and cancer pain management in India, with an emphasis on the experiences of nurses, who are often the front-line providers of palliative care.

Methods.

Fifty-nine participants were recruited using a purposive, snowball sampling strategy. Ethnographic data collection included in-depth, semistructured interviews (n = 54), 400+ hours of participant observation, and review of documents over 9 months at a government cancer hospital in South India. Systematic qualitative analysis led to identification of key barriers that are exemplified by representative quotes.

Results.

Morphine is more available at this study site than in most of India, but access is limited to patients seen by the palliative care service, and significant gaps in supply still occur. Systems to measure and improve pain outcomes are largely absent. Key barriers related to pain management include the role of nursing, opioid misperceptions, bureaucratic hurdles, and sociocultural/infrastructure challenges.

Implications.

Interventions must streamline process details of morphine procurement, work within the existing sociocultural infrastructure to ensure opioids reach patients most in need, target unexpected audiences for symptom management education, and account for role expectations of health care providers.

Conclusion.

Macro- and micro-level policy and practice changes are needed to improve opioid availability and cancer pain management in India.     

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases �C the UK experience

Background:

The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab.

Methods:

Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented.

Results:

Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6–24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15–27%) and median TTP was 22 weeks (95% CI: 17–27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9–39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15–28).

Conclusions:

Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.     

Clinical and Genetic Factors Related to Cancer‐Induced Bone Pain and Bone Pain Relief

Objective.

The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response.

Materials and Methods.

A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP).

Results.

A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in “walking ability in the past 24 hours” (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes.

Conclusion.

Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP.     

Frequency,Predictors, and Medical Record Documentation of Chemical Coping Among Advanced Cancer Patients

Background.

In this prospective study, we determined the frequency of opioid-related chemical coping among advanced cancer patients, as diagnosed by palliative medicine specialists. We also determined predictors for chemical coping and the concordance between the physician’s diagnosis and documentation in the medical records.

Patients and Methods.

Palliative medicine specialists evaluated and diagnosed consecutive patients seen for chemical coping. The proportion of patients identified as chemically coping was compared with the proportion documented in the medical records. Demographic data; cancer diagnosis; history of smoking; substance abuse; psychiatric disease; morphine equivalent daily dosage; Cut-down, Annoyed, Guilty, and Eye-opener (CAGE) questionnaire scores; and Edmonton Symptom Assessment System scores were also collected.

Results.

A total of 432 patients were evaluated. Overall, 76 patients (18%; 95% confidence interval [CI]: 14%–21%) were diagnosed as chemically coping. Documentation of chemical coping in the medical records was reported for only 15 patients (4%; 95% CI: 2%–6%). CAGE positivity (odds ratio [OR]: 2.89), younger age (OR: 0.97 per year), better performance status (OR: 0.68 per point), pain (OR: 1.20 per point), and well-being (OR: 1.28 per point) were found to be significant predictors of chemical coping by protocol definition. After recursive partitioning, 21 of 50 patients (42%) who were CAGE positive and had an Eastern Cooperative Oncology Group performance status ≤2 were diagnosed as chemically coping.

Conclusion.

Approximately 18% of palliative care patients seen were diagnosed as chemically coping by palliative medicine specialists. The frequency of documentation in the medical records was significantly lower. Better and safer ways for physicians to assess and report chemical coping are needed.

Implications for Practice:

Cancer pain is a multidimensional symptom for which opioids are the mainstay of treatment. However, opioids can have a double effect resulting in drug-seeking behaviors. Chemical coping occurs when a patient uses opioids in a nonprescribed way to cope with various stressful events. This can lead to misuse of opioids and complications including neurotoxicities, respiratory depression, and death. Proper diagnosis and documentation is needed to ensure proper management of pain and to avoid unnecessary harm. The findings of this study suggest that ∼18% of advanced cancer patients seen by a palliative care service were diagnosed as chemical coping, but only 4% were documented in the medical records.     

Factors associated with response to methylphenidate in advanced cancer patients

Background.

There has been increasing interest in the use of methylphenidate for cancer-related fatigue (CRF) in patients with advanced cancer. However, there is limited literature on the specific patient characteristics associated with response to methylphenidate. Our objective of this study was to identify the specific patient characteristics associated with response to methylphenidate and to compare day 1 response with day 8 response.

Methods.

We retrospectively reviewed the records of patients in two prospective controlled clinical trials that we had conducted who had received methylphenidate for cancer-related fatigue. Baseline patient characteristics, symptoms (as assessed by the Edmonton Symptom Assessment System [ESAS] and Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and response (change in fatigue) at the end of day 1 treatment were analyzed to determine their association with response to methylphenidate on day 8.

Results.

A total of 82 patients with advanced cancer who received methylphenidate for CRF were included in our review. The median age was 55 years, 66% were female, 74% were white, and the most common cancer type was breast (37%). Fifty out of 82 patients (61%) responded to methylphenidate (≥7 points in FACIT-F). The intensity of baseline fatigue positively correlated with the response to methylphenidate (p < .001). Change in fatigue in response to methylphenidate was not associated with intensity of baseline depression, anxiety, drowsiness, or daily opioid dose. Better improvement of fatigue after treatment on day 1 was associated with more improvement with fatigue on day 8 as assessed by FACIT-F (p = .0004) and ESAS (p = .0001). Day 1 response as a predictor of day 8 response had a sensitivity of 0.84, a positive predictive value of 0.67, and specificity of 0.6.

Conclusions.

Response to methylphenidate is associated with higher baseline fatigue but not with higher baseline depression or sedation. Additionally, day 1 improvement is highly sensitive as a predictor of long-term improvement.     

Pain in underserved community-dwelling Chinese American cancer patients: demographic and medical correlates

Background.

Little is known about cancer pain in Chinese Americans. The objective of this study was to describe the epidemiology of pain in this population. This information is needed to identify and address unmet clinical needs for culturally relevant interventions targeting pain and its consequences.

Methods.

A consecutive sample of underserved ethnic Chinese patients in a large community-based oncology practice was screened for persistent or frequent pain. Those patients with pain completed translated instruments assessing demographics, linguistic acculturation, disease-related characteristics, and pain-related characteristics.

Results.

Of 312 patients screened, 178 (57.1%) reported frequent or persistent pain, 175 were eligible, and 170 participated. Most participants (85.9%) were born in China and 84.7% overall spoke Cantonese only. The most common cancers were gastrointestinal (28.2%), lung (21.8%), breast (20.6%), head and neck (12.9%), and genitourinary (4.7%); 43.5% had metastatic disease. The mean worst pain severity on a 0–10 numeric scale was 4.7 (standard deviation, 2.4), with 28.2% of patients rating their worst pain at ≥7 of 10. Although 37.6% used opioids and 47.1% used nonopioids, 45.8% reported “little” or “no” pain relief from medications. Complementary or alternative medicine therapies for cancer pain were used by 35.8%. In multiple regression analyses, worst pain was positively associated with acculturation to the English language and opioid therapy, and pain-related distress was positively associated with opioid therapy.

Conclusion.

Pain is prevalent among community-dwelling, ethnic Chinese American cancer patients. Additional studies are needed to confirm these results and investigate the finding that higher linguistic acculturation is associated with reports of more intense pain.     

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

Background:

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome.

Methods:

Eighty-seven chemotherapy-naïve mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m^-2) and CPT-11 (150 mg m^-2), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m^-2 bid on days 1–7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS.

Results:

The capecitabine RD was 1000 mg m⁻² bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6–13.4) and 27 months (95% CI; 17.2–36.8), respectively.The GSTP1-G genotype, the Köhne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004).

Conclusion:

First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.     

Predictors of Long‐Term Opioid Treatment Among Patients Who Receive Chemoradiation for Head and Neck Cancer

Introduction.

The factors associated with successful opioid discontinuation after cancer treatment are not well-known. We determined the proportion of patients with advanced head and neck cancer who continued using opioids 3 months after the completion of radiation therapy with or without chemotherapy.

Methods.

We included 70 patients with head and neck cancer referred to our institution''s supportive care center between January 1, 2008, and December 31, 2010. Patients who no longer used opioids 3 months after the completion of radiation therapy were classified as stoppers; patients who continued using opioids were considered nonstoppers. We compared demographics, cancer-related characteristics, alcoholism, substance abuse history, use of psychoactive drugs, and opioid-related factors between stoppers and nonstoppers.

Results.

In all, 44 of 70 patients (63%) and 23 of 70 patients (33%) continued opioids 3 months and 6 months after the completion of radiation therapy, respectively. A total of 18 of 44 nonstoppers (41%) and 3 of 26 stoppers (12%) were positive for alcoholism based on the CAGE questionnaire (i.e., Cut down, Annoying, Guilty, Eye opener; odds ratio: 5.3). Demographic and clinical characteristics did not differ between stoppers and nonstoppers. The median duration of any type of opioid use of CAGE-positive patients was significantly longer than that of CAGE-negative patients (median: 261 days vs. 93 days; hazard ratio: 2.5).

Conclusion.

CAGE positivity is a risk factor for opioid use beyond 3 months after the completion of radiation therapy and for duration of opioid treatment. Routine CAGE screening and meticulous follow-up are needed for these patients.     

Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review

Background:

The immune system has a central role in controlling cancer, and factors that influence protective antitumour immunity could therefore have a significant impact on the course of malignant disease. Opioids are essential for the management of cancer pain, and preclinical studies indicate that opioids have the potential to influence these tumour immune surveillance mechanisms. The aim of this systematic literature review is to evaluate the clinical effects of opioids on the immune system of patients with cancer.

Methods:

A systematic search of Ovid MEDLINE (PubMed) and Embase, Cochrane database and Web of Knowledge for clinical studies, which evaluated the effects of opioids on the immune system in patients with cancer, was performed.

Results:

Five human studies, which have assessed the effects of opioids on the immune system in patients with cancer, were identified. Although all of these evaluated the effect of morphine on immunologic end points in patients with cancer, none measured the clinical effects.

Conclusions:

Evidence from preclinical, healthy volunteer and surgical models suggests that different opioids variably influence protective anti-tumour immunity; however, actual data derived from cancer populations are inconclusive and definitive recommendations cannot be made. Appropriately designed and powered studies assessing clinical outcomes of opioid use in people with cancer are therefore required to inform oncologists and others involved in cancer care about the rational use of opioids in this patient group.     

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

Background:

Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer.

Methods:

Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m⁻² plus irinotecan 250 mg m⁻² (Day 1)) or 3-weekly DF (docetaxel 85 mg m⁻² (Day 1) followed by 5-fluorouracil 750 mg m⁻² per day as a continuous infusion (Days 1–5)).

Results:

A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively).

Conclusion:

Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.     

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer

Background:

In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS).

Methods:

In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment.

Results:

From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1% complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001).

Conclusions:

FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.     

A preliminary report on adjuvant analgesic efficacy of HANS in opioid tolerant patients with cancer pain

Objective： To observe the adjuvant analgesic efficacy of Han＇s Acupoint Nerve Stimulator （HANS） in opioid tolerant patients with cancer pain. Methods： A prospective non-controlled study was conducted. Opioid tolerant patients with cancer pain were enrolled and treated with both routinely analgesics and adjuvant HANS （2/100 Hz for 30 min/d, 5 d on and 2 d off for two weeks）. Cancer pain, quality of life （QOL）, anxiety and depression were assessed before enrollment and on d 8 and d 15 with the BPI-C, EORTC QLQ-C30, and self-rating anxiety scale （SAS）/ self-rating depression scale （SDS）, respectively; the therapeutic frequency of breakthrough pain （BP） and daily opioid dose were also recorded. Results： Totally 47 patients meeting the inclusion criteria participated in this study; 43 patients completed the two-week treatment and assessment. The mean scores of patient＇s ＂worst＂ and ＂least＂ pain intensity assessed with BPI-C decreased significantly on d 8 and d 15; the therapeutic frequency of BP also significantly decreased; but the average daily dose of opioids did not change significantly. For the nine symptoms in EORTC QLQ-C30 assessment, the mean scores of pain, fatigue, constipation and insomnia were significantly lower on d 8 and d 15 compared with baseline; the mean scores of the overall health status, nausea/vomiting and the incidence rates of both anxiety and depression also decreased significantly on d 15. Conclusions： To opioid tolerant patients with cancer pain, adjuvant treatment with HANS could improve pain release and patients＇ QOL by decreasing the severity of pain, fatigue, constipation, insomnia and other concomitant symptoms; it could also decrease the incidence rates of anxiety and depression.     

Prospective randomised evaluation of traditional Chinese medicine combined with chemotherapy: a randomised phase II study of wild toad extract plus gemcitabine in patients with advanced pancreatic adenocarcinomas

Background:

An intravenous formulated extract of the venom of the wild toad Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, huachansu, is currently used in China for the treatment of lung, liver, pancreatic, and colorectal cancers. We performed a randomised, single-blinded, phase II clinical study of huachansu plus gemcitabine versus placebo plus gemcitabine in patients with locally advanced and/or metastatic pancreatic adenocarcinomas.

Methods:

Patients with tissue-proven locally advanced and/or metastatic pancreatic adenocarinoma were randomly assigned to receive either gemcitabine 1000 mg m⁻² on days 1, 8, and 15 with huachansu 20 ml m⁻² daily for 21 days (arm A) or placebo (arm B); treatment cycles were 28 days in length. Primary end point was 4-month progression-free overall survival (PFS); secondary end points were objective radiographical response rate (ORR), time to progression (TTP), and toxicity.

Results:

A total of 80 subjects were enrolled; 76 patients were evaluable (received at least 1 week therapy). Median overall survival was 160 days for arm A and 156 days for arm B (P=0.339); ORR was 9 and 3% in arms A and B, respectively (P=0.332), median TTP was 98 and 115 days, respectively (P=0.825); the median 4-month PFS was 99 and 98 days, respectively (P=0.679).

Conclusion:

Huachansu when combined with gemcitabine did not improve the outcome of patients with locally advanced and/or metastatic pancreatic cancer.     

Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

Purpose.

Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients.

Methods.

Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m² as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50–59 years, 60–69 years, ≥70 years).

Results.

Overall, 827 patients were included in the analysis (<50 years, n = 253; 50–59 years, n = 289; 60–69 years, n = 206; ≥70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia).

Conclusion.

Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.     

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network

Background:

BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas.

Methods:

The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1–3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ⩾2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ⩾12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR).

Results:

By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91–307) and 46 days (95% CI, 44–56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%).

Conclusion:

Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.     

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer （NSCLC）

Purpose： A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） in advanced non-small-cell lung cancer （NSCLC）. This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. Patients and methods： EGFR gene typing in 33 advanced NSCLC patients received gefitinib （250 mg/day） were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. Results： The overall objective response rate （ORR） and median progression-flee survival （PFS） in the 33 patients treated by gefitinib were 45.5% and 3.0 （2.0-4.0） months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients （P〈0.01）. Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients （P〈0.05, P〈0.01, respectively）. However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR （P〈0.01）. Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS （P〈0.05）. Conclusions： EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.     

Meat consumption and the risk of incident distal colon and rectal adenoma

Background:

Most studies of meat and colorectal adenoma have investigated prevalent events from a single screening, thus limiting our understanding of the role of meat and meat-related exposures in early colorectal carcinogenesis.

Methods:

Among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who underwent baseline and follow-up sigmoidoscopy (n=17 072), we identified 1008 individuals with incident distal colorectal adenoma. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between meat and meat-related components and incident distal colorectal adenoma using multivariate logistic regression.

Results:

We observed suggestive positive associations for red meat, processed meat, haeme iron, and nitrate/nitrite with distal colorectal adenoma. Grilled meat (OR=1.56, 95% CI=1.04–2.36), well or very well-done meat (OR=1.59, 95% CI=1.05–2.43), 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) (OR=1.75, 95% CI=1.17–2.64), benzo[a]pyrene (OR=1.53, 95% CI=1.06–2.20), and total mutagenic activity (OR=1.57, 95% CI=1.03–2.40) were positively associated with rectal adenoma. Total iron (diet and supplements) (OR=0.69, 95% CI=0.56–0.86) and iron from supplements (OR=0.65, 95% CI=0.44–0.97) were inversely associated with any distal colorectal adenoma.

Conclusion:

Our findings indicate that several meat-related components may be most relevant to early neoplasia in the rectum. In contrast, total iron and iron from supplements were inversely associated with any distal colorectal adenoma.     

Clinical Activity of Ipilimumab in Acral Melanoma: A Retrospective Review

Background.

Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma.

Methods.

We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS.

Results.

A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3–2.7 months); median OS was 16.7 months (95% CI: 10.9–22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%).

Conclusion.

Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma.

Implications for Practice:

Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.