Barton, Debra L.

PURPOSE The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other health care providers on integrative approaches to managing pain in patients with cancer. METHODS The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included pain intensity, symptom relief, and adverse events. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 227 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Among adult patients, acupuncture should be recommended for aromatase inhibitor–related joint pain. Acupuncture or reflexology or acupressure may be recommended for general cancer pain or musculoskeletal pain. Hypnosis may be recommended to patients who experience procedural pain. Massage may be recommended to patients experiencing pain during palliative or hospice care. These recommendations are based on an intermediate level of evidence, benefit outweighing risk, and with moderate strength of recommendation. The quality of evidence for other mind-body interventions or natural products for pain is either low or inconclusive. There is insufficient or inconclusive evidence to make recommendations for pediatric patients. More research is needed to better characterize the role of integrative medicine interventions in the care of patients with cancer. Additional information is available at https://integrativeonc.org/practice-guidelines/guidelines and www.asco.org/survivorship-guidelines .

9628 Background: As multiple treatments have been studied for the management of hot flashes in randomized, controlled trials, hot flash placebo responses have been quite variable across trials. Based on observations of trial reports, it was hypothesized that the magnitude of placebo effect might correlate with the number of baseline hot flashes in different studies. The current project examines the effect of the baseline hot flash frequency required for study participation and also the actual number of baseline hot flashes observed as these individually relate to the eventual reductions of hot flash frequency observed in patients receiving placebos. Methods: Data were collected from placebo-controlled, double-blinded, randomized trials, identified by a PubMed search, which reported hot flash frequency at baseline, 4–6 weeks and 12 weeks. Trials were excluded if they had less than 20 participants completing the placebo arm. Data gathered, in each study, included the number of hot flashes required to enroll in the study, the average hot flash number during the baseline period, and the hot flash changes in the placebo arms of each study (percent reduction from the baseline period). A simple statistical analysis was conducted in a descriptive fashion since standard deviation was not available in many trials. Scatter plots and Pearson's correlation coefficients demonstrated the relationships between the placebo hot flash percent reduction from baseline and both the minimum required number of hot flashes at baseline, and the mean number of hot flashes at baseline. Results: 45 trials with 49 placebo arms were included in this analysis. A significant positive correlation was seen between the number of hot flashes required to enroll in a study and the percent reduction of hot flashes from baseline at 4–6 weeks (Rho = 0.481, p = 0.003). There was also a significant positive correlation between the number of hot flashes at baseline and the percent reduction of hot flashes from baseline at 4–6 weeks (Rho = 0.481, p= 0.002) and at 12 weeks (Rho = 0.573, p= 0.003). Conclusions: These data support that higher baseline hot flash enrollment requirements and also higher baseline hot flash frequencies are associated with an increased placebo response. No significant financial relationships to disclose.

9587 Background: CIPN is characterized by adjectives not covered directly by most common measures of pain and functional limitations. Possible descriptors include numbness, tingling and shooting/burning pain. A prospective neuropathy treatment trial provided data to explore the relationship between self-reported aspects of this symptom. Methods: Baseline EORTC QLQ CIPN20 data and NCI CTCAE V3.0 (CTC)neuropathy grade (I-IV) were provided for all patients on trial. Spearman correlation coefficients and Kappa's coefficients of agreement were calculated between individual items and subscales of the CIPN20 as well as the CTC neuropathy scale. Simple regression models were applied to examine the association between the sensory symptoms and motor function in the fingers/hands (F/H). 200 patients provided 80% power to detect a correlation coefficient of 0.20 with a 5% Type I error. Results: A majority of patients reported “quite a bit” to “very much” numbness (57%) or tingling (62%) in F/H compared to “a little” or “not at all” (numbness (43%), tingling (38%)) by the CIPN20. In contrast, only 13% of the participants had grade III/IV neuropathy determined by the CTC scale. Fewer patients reported the higher two levels of CIPN20-measured shooting/burning pain in F/H (20% “quite a bit” to “very much”). Numbness and tingling were highly correlated (kappa=0.56), while neither were in high agreement with shooting/burning pain (kappa= 0.05 (tingling) and 0.14 (numbness)). The CIPN20 sensory and motor subscales were significantly associated with each other (p<.0001) but were not or only weakly associated with the CTC. Specifically, tingling, numbness, and shooting/burning pain were not associated with the CTC (R=0.16, 0.18 and 0 .11, respectively). Using the CIPN20, all three sensations; numbness, tingling and shooting or burning pain were strongly associated with motor function. Conclusions: The most common moderate to severe CIPN symptoms were numbness and tingling with shooting/burning pain being less common. Shooting/ burning pain appears to be a separate symptom experience from numbness and tingling. The CTC neuropathy grading scale appears to be less sensitive than the CIPN20 in picking up sensory symptoms. No significant financial relationships to disclose.

9531 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a prevalent dose limiting toxicity for several important cancer treatment agents. CIPN can impair function and cause distress. There are no proven pharmacologic treatments for established CIPN currently. This double blind randomized placebo controlled trial evaluated a compounded topical gel for this problem. The novelty of this treatment is that it might incorporate several agents with different mechanisms of action to provide relief locally without negative systemic effects. Methods: Patients with CIPN (rated ≥4 out of 10) for at least one month, related to previous and/or concurrent exposure to neurotoxic agents, were randomized to baclofen 10 mg, amitriptyline HCL 40 mg and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) vs placebo (PLO) to determine its effect on numbness, tingling, pain, and motor function. Exclusion criteria included other causes and/or current treatment for peripheral neuropathy. The primary endpoint was the baseline adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results: Between February and May 2008, 208 patients were enrolled onto this trial. Four week data are shown in the table below, higher numbers being better. The percentage of patients that had improvements of at least 10, on a 100 point scale, in the motor subscale was statistically significantly higher in the BAK-PLO arm, p=.04. There were no unwanted toxicities associated with the BAK-PLO that were significantly different from placebo and no evidence of CNS or systemic toxicity. Conclusions: Topical treatment with BAK-PLO appears to moderately improve symptoms of CIPN. This topical gel was well tolerated without systemic side effects. [Table: see text] No significant financial relationships to disclose.

e24115 Background: Paclitaxel, a widely used chemotherapeutic agent, is associated with an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is no standard of care for P-APS. Commonly used analgesics, including NSAIDs and narcotics, have considerable toxicity profiles. Omega-3 fatty acids, a common dietary supplement, have well established anti-inflammatory and neuroprotective properties. The primary aim of the study was to assess if omega 3 fatty acids could prevent P-APS. Methods: Patients scheduled to receive weekly paclitaxel (70-90mg/m2) were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior to starting paclitaxel and continued until paclitaxel was discontinued. Patients completed acute pain questionnaires at baseline, Days 2-7, prior to each subsequent treatment and one month after completion of therapy. The EORTC- QLQ CIPN 20 questionnaire was completed prior to each dose of paclitaxel and 1 month after completion. The primary objective was to compare the effect of omega 3 fatty acids, versus placebo, on the maximum pain score for the week following the 1st treatment and each subsequent paclitaxel treatment, and to compare pain medication use between the 2 arms. The secondary objective was to compare the effect of the intervention on the severity of CIPN. Results: 49 patients were randomized to treatment versus placebo. Linear mixed effects models were applied with the addition of a bootstrap approach to overcome limitations in the distributional assumptions to compare outcomes between treatment groups. Placebo results were similar to the reported natural history of P-APS. There was no significant difference in trends over time between the 2 groups in the maximum pain score at week 1 (p = .14) and over 12 weeks (p = .21). There was also no difference noted in the rates of use of over the counter analgesics (p = .39) and narcotics (p = .46). CIPN results did not differ between the 2 groups (p = .08). Conclusions: The results of this pilot study do not support the use of omega-3 fatty acids for the prevention of paclitaxel-associated pain syndrome. Clinical trial information: NCT01821833 .

8507 Background: Problems with sexual functioning are an issue negatively affecting the quality of life of female cancer survivors. Testosterone has been implicated as an important hormone in sexual functioning such as libido. Studies of transdermal testosterone have shown benefit in enhancing libido in women who have been diagnosed with hypoactive sexual desire disorder after bilateral oophorectomy. This phase III placebo-controlled clinical trial evaluated whether transdermal testosterone would increase libido in female cancer survivors. Methods: Women with a history of cancer, currently without evidence of disease, were eligible if they reported a decrease in sexual desire and had a sexual partner. Women must have been postmenopausal. Eligible women were randomized to receive 2% testosterone in Vanicream (10 mg daily) versus placebo Vanicream for four weeks, then crossed over to the opposite treatment. The primary endpoint, libido, was measured via the desire subscales of the Changes in Sexual Functioning Questionnaire (CSFQ), which were completed at baseline and at the end of 4 and 8 weeks of treatment. The primary endpoint was the average intra-patient change from baseline to four weeks in the CSFQ subscales between the two arms. A total of 64 patients per group were needed to provide 80% power to detect a difference of 8 units between the treatment means. Two-sided alternative hypothesis testing and a 5% Type I error rate were used. Results: One hundred fifty women were enrolled onto this study. Complete data were available for 132 women. For those on active testosterone cream, serum bioavailable testosterone levels increased significantly over placebo, with a mean change from baseline of 12 and 10 ng/dl for the first and second period, respectively (p<.0001). The average intra-patient change from baseline to week 4 in libido was 5.5 on testosterone and 4.4 on placebo (p=0.58). No carryover effect was detected. The difference in average intra-patient changes from baseline for the entire crossover design between the two arms was only 1.1 points (95% confidence interval of -1.2 to 3.4, p=0.35). Conclusion: Testosterone is not a panacea for libido troubles in women with a history of cancer. Further studies are needed to determine whether there is a role for transdermal testosterone in this population. No significant financial relationships to disclose.

9075 Background: Chemotherapy-induced peripheral neuropathy (CIPN), a common dose-limiting side effect of chemotherapy, remains without known effective interventions. Preliminary data support that Scrambler therapy, a device which treats pain via non-invasive cutaneous electrostimulation, is beneficial for the treatment of CIPN. This pilot trial was performed to investigate the effect of Scrambler therapy for the treatment of CIPN. Methods: Eligible patients included those age ≥18 years, ECOG PS ≤2, life expectancy ≥3 months, with pain or CIPN symptoms of ≥1 month duration and tingling or pain ≥4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area for up to 10 daily 30 minute sessions. Symptoms were monitored daily during therapy using a questionnaire to measure symptoms of neuropathy with a numerical analogue scale. Results: We report on the first 11 CIPN patients, enrolled between 7/18/2011 and 12/12/2011, 3 men and 8 women; mean age 57 years. Patients had history of exposure to various chemotherapeutic agents and the majority had symptoms >2 years. The table portrays data at baseline, at the end of the 10 planned days of therapy, and the percent changes from baseline to the end of treatment, regarding patient reported pain, tingling, and numbness over the preceding 24 hours. There were no adverse events. Persistent benefit out to 5 weeks was seen in some patients; maturing data will be available by May 2012. Descriptive summary statistics formed the basis of data analysis. Further patients are being entered on this trial. Conclusions: Scrambler therapy appears to be beneficial in the treatment of CIPN. A prospective placebo-controlled clinical trial should be performed to confirm these preliminary findings. [Table: see text]

9001 Background: Ginseng is popularly used as a treatment for fatigue, one of the most common and disabling symptoms in people diagnosed with cancer. It is termed an “adaptogen”, thought to help the body combat negative effects of stress. This trial was to evaluate 2,000 mg American Ginseng versus placebo for cancer-related fatigue (CRF). Methods: Patients with cancer undergoing or having completed curative intent treatment and experiencing fatigue, rated at least 4 on a numeric analogue fatigue scale (1-10) for ≥1 month, were eligible. Exclusion criteria included CNS lymphoma, brain malignancies, or prior use of ginseng or chronic systemic steroids. Other etiologies for fatigue, such as pain and sleep, were also excluded. Patients were randomized to receive, in a double blind manner, 2,000 mg/d of American Ginseng or placebo in BID dosing for 8 weeks. The primary endpoint was change from baseline in the general subscale of the Multidimensional Fatigue Symptom Inventory (MFSI) at 4 weeks. Other MFSI subscales and the fatigue-inertia subscale of the Profile of Mood States (POMS) were also analyzed. Data were transformed to a 0-100 scale. Results: 364 patients were enrolled from 10/2008 to 07/2011. Data at 4 and 8 weeks are provided for several fatigue endpoints in the table below; higher numbers are better. Mental, emotional and vigor subscales of the MFSI were not significantly different between arms. There were no statistically significant differences in any grade of toxicity or self reported side effects between ginseng and placebo. Conclusions: This trial provides data to support that American Ginseng reduces general and physical CRF over 8 weeks without side effects. The treatment did not provide significant reductions in fatigue at 4 weeks and did not impact mental, emotional, and vigor dimensions of fatigue. [Table: see text]

1557 Background: Peripheral neuropathy (PN), a common and intrusive side effect of chemotherapy in clinical trials, has been assessed via the clinician-rated common terminology criteria for adverse events (CTCAE) and/or patient-reported outcome (PRO) measures (Morton, ASCO, 2005). We assessed the relative sensitivity of CTCAE and PRO measures for evaluating interventions for preventing and ameliorating CIPN. Methods: Data from285 patients in two prevention trials (N05C3, N04C7) and 432 patients from three intervention trials (N00C3, N01C3, N06CA) were analyzed separately. CTCAE version 3.0 item for neuropathy was compared to 2 NCCTG numerical analogue CIPN items, 6 EORTC CIPN20 individual items, 2 McGill Pain Questionnaire items, and one Brief Pain Inventory item. The sample size provided over 80% power to detect a true Spearman rank correlation of 0.15 assessed the relationship between CTCAE and PRO measures. Results: Results from both the prevention and treatment trials were similar in terms of the relationship between the CTCAE and PRO measures. No correlation coefficients between the CTCAE and any of the PRO items at baseline were above 0.35, with the majority around 0.2. Higher scores for the numbness items were observed than for the CTCAE in 47% of the patients at baseline and 39% during treatment in the treatment trials. Many patients had severe numbness PRO scores but mild CTCAE scores (12%) at baseline and (8%) during treatment in the treatment trials. Results for the numbness and tingling PRO measures were redundant. The correlations of the CTCAE with pain were weak, all below 0.35 at baseline with differences as much as 29 points on average on a 0-100 transformed scale. Conclusions: The CTCAE and PRO measures of PN measure different constructs. The CTCAE includes both functional and ADL/motor aspects which may or may not be related to the singular constructs of pain, numbness, tingling, or adjectival characteristics of pain assessed by the PRO measures. The two measures cannot be used in place of each other.

9513 Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p=.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 = the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10= totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.