Supportive Care Research Runs the Gamut from Genetic Markers of Treatment Side Effects to Neuropathic Pain Therapies


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Several new well-designed studies published since the last update allowed panel members to develop evidence-based informed guidelines, which will hopefully improve clinical practice.

— Rachel Gibson, PhD

Attendees from around the world gathered for the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held June 28–30 in New York. Below are highlights from the meeting, representing progress in some areas and the need for further advances in others.

Genomics in Predicting Treatment Side Effects

Using a Bayesian method to analyze the millions of single nucleotide polymorphisms (SNPs) from an individual patient with cancer can reliably identify a cluster or network of such variations that predict treatment-related side effects, according to a presentation by Stephen Sonis, MD, Brigham and Women’s Hospital, Boston. Citing data from two unpublished studies using this method, Dr. Sonis showed that the accuracy of this approach was greater than 95%.

“We believe this [method] will be a game changer and will let us prospectively evaluate and understand who is at risk for side effects from cancer therapy. This can have a major impact on how we address side effects and how we optimize outcomes for our patients,” he stated. Dr. Sonis commented that the ability to preselect which patients are at risk for specific side effects can save money by optimizing resources and also will enable smaller, faster clinical trials.

Single nucleotide polymorphisms are the most common variation in the genome, he explained. There are about 25,000 genes, but over 10 million single nucleotide polymorphisms. “Unlike genes, [single nucleotide polymorphisms] may or may not be associated with function. This means we are not restricted to looking at genes only involved in coding,” he said.

Old vs New Paradigm

“The old paradigm [ie, using a single gene to find an association] was a bit arrogant in that it presumed that we already knew what we were looking for. Findings using the new paradigm are more robust and much more likely to be valid,” Dr. Sonis stated. The Bayesian method analyzes 1 to 2 million individual single nucleotide polymorphisms and their interactions to pick “team players.” This type of analysis does not predetermine the number of “players,” he explained.

A retrospective study at Dana-Farber Cancer Institute used Bayesian networks to identify 82 single nucleotide polymorphisms that could predict which patients would develop mucositis with an accuracy of 99.3%. The investigators examined charts of myeloma and lymphoma patients slated for transplant from 2006 to 2001, identified 153 subjects, and classified them as oral mucositis (OM)–negative (102 patients) or OM–positive (51 patients), with positivity defined as 2 consecutive days of WHO grade > 2 OM. After extracting DNA from patient saliva specimens, the researchers were able to identify 82 SNPs that predicted the OM-positive patients with a high degree of accuracy.

Ongoing Study

The Oncology Preferences and Risk of Toxicity (OnPART™) development study, currently being conducted at the West Clinic in Memphis, seeks to determine whether this method is applicable in a broader range of sold tumors and patients receiving other treatments. The tumors being studied include breast cancer, colorectal cancer, ovarian cancer, and non–small cell lung cancer (NSCLC, in patients treated with at least three cycles of chemotherapy. The chemotherapy-related side effects that are being analyzed include nausea/vomiting, mucositis, fatigue, diarrhea, peripheral neuropathy, and cognitive dysfunction. These were classified as none or mild vs moderate to severe.

At the MASCC/ISOO meeting, Dr. Sonis shared preliminary data from the OnPART development study—data that were generated the day before his presentation. In a subset of patients with breast cancer (N = 30) treated with dose-dense doxorubicin/cyclophosphamide plus paclitaxel (Taxol), the side effects were as follows: nausea/vomiting, 42%; oral mucositis, 38%; diarrhea, 23%; fatigue, 58%; cognitive dysfunction, 23%; and peripheral neuropathy, 16%. In this preliminary analysis, the Bayesian network predicted which patients would develop chemotherapy-induced diarrhea with an accuracy of 96.7%.

“These findings are remarkably consistent with the first study at Dana-Farber in transplant patients with myeloma,” Dr. Sonis stated.

Updated Guidelines for GI Mucositis

MASCC’s updated guidelines for management of gastrointestinal (GI) mucositis incorporated new evidence that led to few changes from the version issued in 2007.

“Regimen-related mucosal injury is a clinical and economic challenge to oncology practice. It is important to continue to update the clinical guidelines for the prevention and treatment of GI mucositis. Several new well designed studies published since the last update allowed panel members to develop evidence-based informed guidelines, which will hopefully improve clinical practice,” explained Rachel Gibson, PhD, University of Adelaide, Australia.

A team of experts from Australia, The Netherlands, and the United States reviewed 1,536 relevant papers published on or before December 20, 2010. A total of 146 papers were included in the final analysis.

For prevention of chemotherapy- and radiation-induced diarrhea in patients with pelvic malignancies, use of Lactobacilllus spp–containing probiotics was deemed a “suggested guideline” based on overwhelmingly positive evidence. Amifostine was suggested to reduce chemotherapy- and radiation-induced esophagitis in patients with NSCLC.

For patients undergoing standard-dose radiation therapy, the panel recommended against using mesalamine or olsalazine (Dipentum) for prevention of GI mucositis.

Because of conflicting data, the panel was not able to strongly recommend or suggest that circadian rhythm (ie, giving radiation in the morning vs evening) could protect patients from radiation-induced GI mucositis or grade 3/4 diarrhea. The evidence to date suggested that giving radiation in the evening could reduce mucositis and grade 3 or 4 diarrhea, but this was based on only one trial.

Recommendations

The panel recommended that intravenous amifostine be given prior to radiotherapy to prevent radiation-induced proctitis and recommended against use of misoprostol suppositories and oral sucralfate for prevention of radiation-induced side effects. However, sucralfate enemas were suggested for management of chronic radiation-induced proctitis in patients with rectal bleeding.

Oral sulfasalazine at 500 mg three times daily was suggested for reducing the incidence and severity of radiation-induced enteropathy in patients receiving external-beam radiation to the pelvis.

Hyperbaric oxygen was suggested as a potentially effective treatment for proctitis and GI mucositis in patients undergoing radiation, but the cost may be prohibitive, Dr. Gibson commented.

Octreotide was recommended at a subcutaneous dose of at least 100 mg three times daily for treatment of diarrhea uncontrolled by loperamide in patients on standard- and high-dose chemotherapy for stem cell transplant.

Cardiotoxicity of Molecularly Targeted Agents vs Anthracyclines

Molecularly targeted agents are associated with less risk of cardiotoxocity than anthracyclines. Cardiac damage occurring with molecularly targeted agents is caused by cellular dysfunction and is usually reversible, whereas anthracycline-induced cardiac damage is caused by cell death and is irreversible, explained Michael S. Ewer, MD, of The University of Texas MD Anderson Cancer Center in Houston.

The risk of cardiac dysfunction with either molecularly targeted agents or anthracyclines is related to prior damage. Risk factors for cardiac injury include prior chemotherapy and prior radiation, and include “anything that has previously damaged the heart, makes it more susceptible to ongoing damage, or leads to vascular or ischemic injury,” he stated.

Patients on molecularly targeted therapy need cardiac monitoring, but extensive monitoring and aggressive treatment of left-ventricular ejection fraction may not be necessary as it is in the case of anthracyclines, Dr. Ewer continued. “Many patients [who develop decreased left-ventricular ejection fraction and incipient heart failure] can be treated with standard heart failure drugs, given a rest from targeted therapy, and then have the targeted agent restarted safely,” he stated. Other targeted therapies such as bevacizumab (Avastin), sunitinib (Sutent), and imatinib (Gleevec) can cause hypertension, fluid retention, and thromboembolic phenomenon.

In the case of trastuzumab (Herceptin), studies involving more than 10,000 patients with breast cancer treated with adjuvant trastuzumab therapy found that the risk of heart failure and decline in left-ventricular ejection fraction was increased, but only two cardiac deaths were reported, Dr. Ewer said.

The risk of cardiac toxicity is increased when anthracyclines are given together with trastuzumab. Timing is important, and separating the administration of these agents reduces the cardiac effects, he advised.

Sunitinib increases the risk of hypertension in clinical trials, yet hypertension is associated with longer survival. Both symptomatic and asymptomatic changes in left-ventricular ejection fraction are seen more frequently on sunitinib and then plateau over time. “This suggests that sunitinib does not destroy myocytes,” Dr. Ewer stated.

Many patients who develop hypertension on sunitinib can continue to receive the drug if they are treated with blood pressure–lowering medications. The incidence of cardiovascular death is low on sunitinib, he noted.

Bevacizumab also causes hypertension, which should be managed aggressively. If malignant hypertension develops, bevacizumab should be withdrawn.

Lapatinib (Tykerb) may cause a decrease in left-ventricular ejection fraction as well, but from the cardiac standpoint the drug is generally safe, and long-term use and use in combinations is feasible, Dr. Ewer said.

Few Effective Interventions for Cachexia

The presence of cachexia is strongly prognostic, but there are currently no good treatments for the syndrome. Many studies have shown that feeding patients is of no benefit, and appetite stimulants are only minimally helpful. It is important to educate patients and their families about this cancer-associated disorder.

“Cachexia is not starvation. It is weight loss and anorexia in the setting of incurable cancer,” said Aminah Jatoi, MD, Mayo Clinic, Rochester, Minnesota.

It is well known that patients with good appetites live longer, and that patients who lose greater than 5% from premorbid weight have a worse prognosis. The predominant loss in patients with cancer is of muscle mass, she continued. Weight loss and cachexia can occur with standard chemotherapy and with targeted agents.

Neither parenteral nor enteral nutrition are helpful for cachexia in patients with refractory cancers. “These forms of nutrition should be used only in patients where there is a potential for cure. They are not helpful in patients with refractory cancers,” noted Dr. Jatoi. “The general consensus is that routine use of total parenteral nutrition should be discouraged in patients undergoing chemotherapy, and a recent meta-analysis found that enteral nutrition had no advantage,” she said.

“Feeding is not the way to manage patients with incurable refractory cancers,” she continued. “Education is the most important thing we can do for our patients. Cancer is the driving process, and an evolving literature shows that this syndrome can cause family strife and grief. Having a long discussion about the syndrome and its causes with the patient and family is very important.”

Appetite stimulants such as megesterol acetate or corticosteroids may improve appetite, but have no survival benefit and do not improve quality of life. “Only about 20% to 30% of patients will have some improvement in appetite with megesterol acetate independent of a placebo effect,” Dr. Jatoi explained.

“The bottom line is that we need better interventions to help patients with this syndrome,” she stated. Agents being studied in clinical trials for treatment of cancer-associated weight loss include selective androgen receptor modulators, antimyostatin agents, and JAK inhibitors.

She cautioned that when interpreting clinical trials, one should consider dropouts and the placebo effect. “Beware of basing clinical practice on preliminary phase I or II studies,” she said.

Treatment of Neuropathic Pain: Work in Progress

“Virtually all the treatments we use to treat neuropathic pain are off-label,” said Charles Loprinzi, MD, Mayo Clinic. “There is a glimmer of hope that new treatments, such as Scrambler Therapy and menthol, may prove helpful.”

The antidepressants duloxetine (Cymbalta) and venlafaxine—both serotonin norepinpehrine reuptake inhibitors—are sometimes used to treat chemotherapy-induced peripheral neuropathy. At this year’s ASCO Annual Meeting, a randomized trial showed that about one-third of patients with chemotherapy-induced peripheral neuropathy due to oxaliplatin or taxanes had clinically meaningful pain relief with duloxetine.6 While not universally effective, this is an important finding, Dr. Loprinzi noted.

Fewer side effects were seen with duloxetine than previously reported, and Dr. Loprinzi attributed this to starting at a lower dose than on the package insert. He noted that venlafaxine should also be started at a lower dose.

Reports and anecdotal experience suggest that venlafaxine decreases neuropathic pain. “Small studies suggest that there is some effect with venlafaxine given prior to chemotherapy,” he noted.

“Both duloxetine and venlafaxine appear to have some effect on [chemotherapy-induced peripheral neuropathy], but nearly as great an effect as we would like,” he stated. More work is needed to further substantiate this apparent benefit.

A small placebo-controlled study by Debra Barton, PhD, AOCN, FAAN, RN, and others supported the use of topical baclofen/amitriptyline/ketamine to improve some aspects of chemotherapy-induced peripheral neuropathy, but not others.7 That study used a lower dose of this topical treatment than the investigators wanted to use, and Dr. Loprinzi said that the topical preparation should be studied at a higher dose.

Another small study from China reported, in abstract format at the 2012 ASCO Annual Meeting, that acetyl-L-carnitine may improve peripheral neuropathy symptoms, but another abstract at the same meeting reported that this same agent increased taxane neuropathy. “The bottom line is that the jury is still out on acetyl-L-carnitine,” he said.

Scrambler Therapy—a proprietary technique developed by Competitive Technologies, Inc—is an innovative form of percutaneous electrical stimulation applied to painful areas of the body that was developed for neuropathic pain.8 The technique is different from traditional transcutaneous electrical nerve stimulation (TENS), which works primarily with musculoskeletal pain, Dr. Loprinzi said.

“At first I was skeptical, but we have obtained a machine, and our early experience at Mayo is positive,” he stated.

Although gabapentin and pregabalin are commonly used to treat chemotherapy-induced peripheral neuropathy, there has been no published evidence of any benefit.

A small phase II trial found that topical menthol may be helpful in patients with severe chemotherapy-induced peripheral neuropathy. “This is an exciting new area, and there may be something effective here,” he said. Future studies are planned. ■

Disclosure: Dr. Sonis is a founder of InformGenomics, the study’s sponsor. Drs. Gibson and Ewer reported no potential conflicts of interest. Dr. Loprinzi disclosed that Competitive Technologies provided a Scrambler machine to the Mayo Clinic for clinical studies.

References

1. Sonis S: Molecular predictors in supportive care. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 30, 2012.

2. Gibson R: Updated clinical practice guidelines for GI mucositis. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 29, 2012.

3. Ewer M: Cardiac issues and targeted agents. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 29, 2012.

4. Jatoi A: Cachexia. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 30, 2012.

5. Loprinzi C: Treatment of established chemotherapy neuropathy: Completed and ongoing studies. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 30, 2012.

6. Smith EM, Pang H, Cirrincione C, et al: CALGB 170601: A phase III double-blind trial of duloxetine to treat chemotherapy-induced peripheral neuropathy. 2012 ASCO Annual Meeting. Abstract CRA9013. Presented June 5, 2012.

7. Barton D: A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 19:833-841, 2011.

8. Pachman DR, Linquist BM, Barton DL, et al: Pilot study of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy. 2012 ASCO Annual Meeting. Abstract 9075. Presented June 2, 2012.



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