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Highly targeted chemotherapeutic agents, which have emerged over the past decade, offer renewed hope to many patients diagnosed with cancers once considered difficult or impossible to treat. However, with the new hope many of these "super drugs" bring come new challenges in the management of side effects, some which can become debilitating enough to interfere with cancer treatment.
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â–º News from the International Symposium on Supportive Care in Oncology
Cancer Management in the Era of Targeted Agents
Highly targeted chemotherapeutic agents, which have emerged over the past decade, offer renewed hope to many patients diagnosed with cancers once considered difficult or impossible to treat. However, with the new hope many of these “super drugs” bring come new challenges in the management of side effects, some which can become debilitating enough to interfere with cancer treatment. These cross-discipline challenges were the focus of the Sixth International Symposium on Supportive Care in Oncology: Cancer Management in the Era of Targeted Agents held in New York City on February 22—23. Following are just some of the topics addressed; for a full list visit www.cancerconferences.com.
â–º Tamoxifin and Aromatase Inhibitors Affect Bone Health Differently in Patients With Breast Cancer
Diet and exercise become an even greater part of protecting bone health in patients with cancer
While aromatase inhibitors (AIs) are emerging as an additional treatment option for some women with early-stage breast cancer instead of tamoxifen, women taking tamoxifen generally have more bone mass and less bone fractures. This finding will be reflected in new treatment guidelines presented at the annual American Society of Clinical Oncology (ASCO) meeting in May 2008.
The new guidelines will consider when or if oncologists should intervene when a breast cancer patient on chemotherapy shows bone deterioration and how to treat it.
“Oncology specialists need to take an expanded role in routine and regular assessment of bone health in women receiving breast cancer treatment,” said Dr. Julie Gralow, director of the clinical research unit and Women’s Cancer Research program at Jonsson Comprehensive Cancer Center, UCLA School of Medicine.
The findings on the effect of AIs versus selective estrogen receptor modulators (SERMs) like tamoxifen on bone health emerged from the Anastrazole Prevents Relapse in Early Breast Cancer (ATAC) Trial, published in 2005. Anastrozole (Arimidex) was significantly better than tamoxifen (Nolvadex) (or the combination of tamoxifen and anastrozole) in terms of preventing a recurrence of breast cancer in postmenopausal women whose early-stage tumors were hormonesensitive, according to the National Cancer Institute. Patients taking anastrozole also experienced fewer serious side effects (endometrial cancer, blood clots, vaginal bleeding, hot flashes). Anastrozole is now considered a standard adjuvant treatment for this group of patients.
Yet bone fractures and joint pain were up to 50% more likely to occur among the anastrozole group, according to Dr. Gralow, who says this may be caused by in part the drug’s negative effect on the ability of estrogen to reach bone cells.
Preliminary results from some ongoing studies suggest ways oncologists can slow or prevent the loss of bone mass in women taking AIs. The Zometa-Femara Adjuvant Synergy Trial (Z-FAST) and the SABRE Trials showed the addition of bisphosphonates may prevent bone fractures, although Dr. Gralow said bone fractures began showing up 36 months into the Z-FAST trial. Other trials include an ongoing phase III trial examining the combination of a RANK ligand inhibitor (Amgen’s denosumab) with AIs to increase bone density of the spine. Another trial currently open for enrollment (S0307) is examining whether adding a bisphosphonate to hormonal therapy or chemotherapy will help prevent cancer from spreading to the bones or other parts of the body.
Before adding any osteoporosis drug to a breast cancer patient’s care plan, however, Dr. Gralow emphasized oncologists need to coordinate care with other doctors women with breast cancer may be seeing. “Oncologists need to make sure that other doctors are not giving patients osteoporosis drugs which may be adversely interacting with their chemotherapy regimens,” she said.
Steps oncologists can take now to protect the bone health of their breast cancer patients include the addition of calcium and vitamin D to their diets. Dr. Gralow said she regularly gives out information from the National Institutes of Health Office of Dietary Supplements (http://dietary-supplements. info.nih.gov) to her own patients. She also encourages them to exercise regularly and incorporate weight-bearing exercises into their daily lives.
“All of my patients have to exercise,” she said, “although they usually start two weeks before they have to see me.”
â–º Management of Peripheral Neuropathy, Thrombocytopenia With Proteasome Inhibitor Use
Multiple myeloma, mantle-cell Lymphoma patients require close monitoring and adjustments
Proteasome inhibitors like bortezomib (Velcade) have given new treatment options to oncologists and patients grappling with difficult-to-treat cancers like multiple myeloma (MM) and mantle cell lymphoma. But along with new hope, newer drugs have brought an increase in adverse events oncologists need to be aware of so that they can most effectively manage/optimize treatment and the benefits they confer.
Multiple myeloma, one of the conditions that can now be treated by proteasome inhibitors, affects almost 20,000 U.S. citizens annually, according to the Leukemia and Lymphoma Society. Most cases are diagnosed in people over 50, and black people are diagnosed with the disease twice as often as Latinos and whites.
Proteasome inhibitors block the action of proteasomes, large protein complexes that help destroy other cellular proteins when they are no longer needed. Nonclinical data have demonstrated that cancer cells are more susceptible to the effects of proteasome inhibition than normal cells. To date, over 85,000 people have been treated by the proteasome inhibitor, Velcade.
Thrombocytopenia and peripheral neuropathy appear to be the most serious adverse events associated with proteasome inhibitor therapy in MM and mantle cell lymphoma patients who have received at least one prior therapy, according to several studies cited by Michael P. Fanucchi, MD, medical director and chief of medical oncology at St. Vincent’s Comprehensive Cancer Center in New York City. Thirty-six percent of patients receiving bortezomib experienced thrombocytopenia according to one study of almost 1200 patients; close to one-quarter of those were grade 3 events. Thirty-nine percent of patients in the group experienced peripheral neuropathy. Other studies showed similar outcomes.
“Peripheral neuropathy associated with bortezomib is generally evident by the fifth cycle of treatment,” Dr. Fanucchi said. “It will usually level off by the sixth cycle.” If it does not, intervention may be indicated.
The frequency, characteristics and reversibility of peripheral neuropathy associated with bortezomib is the subject of an abstract extrapolated from The Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial (the trial that showed bortezomib delayed disease progression and increased overall survival in relapsed MM patients compared with steroidal treatments like dexamethasone.) Preliminary findings show dialing back the dosage of bortezomib in patients experiencing severe peripheral neuropathy allowed many patients to stay on regimen. Results of studies with Velcade in the relapsed setting show that clinical benefits increase the longer patients stay on therapy—with 8 cycles being the goal—therefore making the appropriate management and dose adjustments an important part of the overall approach to treatment.
Dr. Fanucchi suggested oncologists monitor their patients who are taking bortezomib for symptoms of neuropathy or pain at each clinical visit and to urge patients to contact them if they experience new or worsening symptoms. In some cases, where patients may be experiencing severe pain or trouble carrying out their daily living activities, withholding bortezomib until toxicity resolves and then reintroducing the drug at a lower dosage or frequency may help. “Early detection and appropriate dose/schedule modification,” Dr. Fanucchi says, “may result in the resolution or improvement in neuropathy.”
â–º Cardiologists Becoming Part of the Oncology-Care Team
ACE Inhibitors, beta blockers may cut the rate of cardiotoxicity that could appear following the use of some chemotherapy treatments
People receiving chemotherapy for breast, colon and certain blood cancers should also have their circulatory health diligently monitored, an objective some say can be achieved when oncologists and cardiologists work more closely together, from the onset of treatment and, in some instances, for long periods of surveillance following their anticancer treatment.
“Exciting new cancer therapies are being discovered,” Dr. Michael S. Ewer, Professor of Medicine at the University of Texas M. D. Anderson Cancer in Houston says. “However, in order to maximize their anticancer potential, cardiac toxicities need to be identified and addressed up front. Our goal should be to kill the cancer while at the same time doing all we can to protect the heart.” Working together, Dr. Ewer says, oncologists and cardiologists can find ways to safely use important drugs, not “make excuses to deny their use.”
Early Warning Signs of Cardiac Toxicity
Congestive heart failure (CHF) has occurred in patients receiving both traditional anthracycline therapies as well as some of the newer therapies like tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor [VEGF] receptor inhibitors, angiogenesis inhibitors (AIs), and other novel agents. Heart failure has been found to occur in patients taking TKI, VEGF or AI cancer therapies like sunitinib (Sutent), bevacizumab (Avastin) and trastuzumab (Herceptin); TKIs like imatinib (Gleevec) and dasatinib (Sprycel); and protease inhibitors such as bortezomib (Velcade). In some of these, the percentage of CHF has been shown to be about 1% (imatinib) but in the trastuzumab (Herceptin) pivotal trial, where it was used concomitantly with an anthracycline it was reported to be as high as 27%; subsequent trials where the agents were used sequentially yielded much lower rates.
Two forms of chemotherapy-related cardiac dysfunction (CRCD) are now appreciated. Type I is typically seen in patients taking anthracyclines and analogues (doxorubicin, epirubicin). Believed to be cumulative dose—related, Type I CRCD causes irreversible cellular damage to the heart and is associated with typical biopsy changes that may resolve with time. Type II CRCD, as is seen in some patients taking trastuzumab and some of the other newer agents, is generally not cumulative dose–related, results in heart cell dysfunction rather than cell death, and is generally reversible.
Signs of advanced CRCD include persistent tachycardia after exercise, shortness of breath, weight gain with water retention, and signs of CHF. “By that time clinically evident CHF appears,” Dr. Ewer said, “we’ve missed the boat.”
Hypertension is sometimes seen as a consequence of anticancer treatment, and in vulnerable patients may contribute to heart failure, said Dr. Ewer. (In one study cited by Dr. Ewer, 30% of metastatic renal cell carcinoma patients treated with sunitinib experienced hypertension.) Larger studies, which may place the concerns regarding sunitinib in clinical perspective, will hopefully be forthcoming.
Prevention, Early Detection, Damage Control or Reversal
Severe cardiac events can often be avoided with diligent monitoring of cardiac status and control of blood pressure, the addition of ACE inhibitors and/or beta blockers and, in some cases, consideration of altering the planned chemotherapeutic regimen; in the case of some of the agents associated with Type II CRCD reintroduction of the agent when the oncologic indications are sufficiently strong, re-introduction may be considered. With anthracyclines, where the cardiotoxicity is predictable, Dr. Ewer suggests using an equation such as — Y = X2 divided by 16, where Y = likelihood of developing CHF, X = number of cycles of chemotherapy, and 16 = the correction factor cycles of 50 mg/m2 cycles of doxorubicin; other correction factors for different anthrcyclines and schedules are being evaluated.
Cardiologists are formally stepping up their involvement in protecting the hearts of cancer patients. Late last year, The Heart Failure Society of America recommended regular blood pressure monitoring in cancer patients receiving AIs or VEGF inhibitors and more frequent blood pressure monitoring in patients with a history of hypertension receiving antiangiogenic therapy.
The renewed challenge of oncologists and cardiologists, Dr. Ewer said, is to “maintain cardiac function while effectively controlling the cancer.”
â–º Nausea and Vomiting Caused by Chemotherapy May be Lessened With New Drugs
Antiemetic agents are showing promise in helping to control some of the most debilitating side effects of chemotherapy
Chemotherapy induced nausea and vomiting (CINV) severely impacts the quality of life of patients already faced with battling cancer. Antiemetics help but can cause other side effects or interfere with cancer treatment. New antiemetic agents and novel combinations of older ones are showing promise in controlling both acute and delayed CINV without the trade-offs.
The current standard of antiemetic care is 5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron) and dexamethasone, a synthetic adrenal corticosteroid. However, 5-HT3 receptor antagonists have limitations; they control acute nausea and vomiting but not delayed nausea and vomiting (CINV within five days of receiving chemotherapy). Excessive, prolonged use of the cortecosteriod dexamethasone can become problematic in cancer patients with diabetes.
Newer antiemetic agents may offer patients additional options. Studies of neurokinin receptor antagonists (NK-1 agents) may give some patients better control of CINV when taken in conjunction with a 5-HT3 receptor antagonist. (While 5HT3 receptor antagonists block the vomiting and nausea response in the lining of the stomach, NK1 antagonists block the nausea and vomiting response in the brain.) In one small study, adding NK1 receptor antagonist aprepitant (Emend) to a 5-HT3 antagonist and dexamethasone reduced vomiting by 30% to 40% when given one hour before chemotherapy infusion; it will not stop vomiting once it begins. Aprepitant is also contraindicated in people taking cisapride (Propulsid), a drug used to treat acid reflux, or certain antihistamines, and can decrease the effectiveness of oral contraceptives. Other NK1 agents under review for control of CINV are casopitant and vestipitant (GSK), netupitant (Roche), and another experimental drug from Schering.
Combinations of older drugs meant to treat conditions entirely different from cancer may also offer more alternatives to patients with CINV. Olanzapine (Zyprexa), an oral antipsychotic drug traditionally used to treat schizophrenia, bipolar and other psychotic disorders, is in phase II trials as a possible treatment for acute and delayed nausea and vomiting associated with highly emetic chemotherapy.
For example, adriamycin/cyclophosphamide (A/C) combination therapy is the traditional firstline treatment in women with early-stage breast cancer, but it is highly emetic. Ondansetron, dexamethasone, and other antiemetics control nausea and vomiting in most A/C regimen patients, but can cause side effects like constipation, fatigue, and insomnia.
Phase II Hoosier Oncology Group trials of women with breast cancer on A/C therapy have been studying alternative drug combinations using olanzapine. In one trial (QL01-26) 30 A/C breast cancer patients with high-to-moderate emesis were treated with a three-drug combination of olanzapine, granisetron and dexamethasone for four days in the same time period they were receiving chemotherapy. All patients showed a marked reduction in CINV.
Another phase II Hoosier trial (Ql03-70) involved 40 patients on the A/C regimen who were given 10 mg of oral olanzapine combined with palonosetron (Aloxi) and dexamethasone. (Patients were given all three drugs on day 1 and olanzapine alone on days 2—4.) All experienced less emesis with no other severe side effects.
The Q103-70 study is particularly significant to doctors who want to dial back the amount of dexamethasone they give their CINV patients, according to Rudolph M. Navari, MD, PhD, of the University of Notre Dame in Indiana. “Oncologists don’t want to use too much dexamethasone in people with diabetes, so the olanzapine regimen can help them use less of it in their patients,” he says. Dr. Navari and colleagues like Steven D. Passik, PhD, of New York’s Memorial Sloan Kettering Cancer Center hope funding can be procured to proceed to phase III trials.
Given in high doses, olanzapine can have a sedative effect and, over a long period of time, runs the risk of causing hypoglycemia. Dr. Navari feels the risk of either is low because a small amount of drug is used over a short period of time.
“Antiemetics continue to be crucial in the treatment of patients with most malignancies,” said Richard Gralla, MD, vice president for cancer services and chief of hematology and oncology at the Monter Cancer Center in Lake Success, New York, because they preserve quality of life, permit safe “out-patient” treatment of cancer, and other contributions to cancer care. “Current agents given in newer ways…and newer antiemetics significantly improve control of both acute and delayed emesis.”
â–º Diarrhea During Chemotherapy May Have Multiple Causes
Chemotherapy is the usual culprit, but other factors may contribute as well
Chemotherapy-induced diarrhea (CTID) can become so severe in patients that they require prolonged hospitalization or even risk death, but new standards of care may greatly increase the quality of life for many of these patients.
Essentially all of the chemotherapies used for colorectal, breast, lung cancer and myelomas cause diarrhea. This includes both traditional therapies and the newer biological agents, according to data presented by Lowell B. Anthony, MD, professor of medicine at Louisiana State University Health Sciences Center in New Orleans. Dr. Anthony expressed particular concern over the findings of one small study of panitumumab (Vectibix), especially when used in combination with irinotecan (Camptosar) and other drugs for colorectal cancer.
“In a study of 19 patients receiving panitumumab in combination with irinotecan, bolus-5 fluorouracil and leucovorin as the IFL regimen, the incidence of grade 3/4 diarrhea was 58% and fatal in one patient,” he said. “This is unacceptable.” The incidence of severe diarrhea in another study of 24 patients receiving panitumumab in combination with FOLFIRI was significantly less at 25%, but still considered high.
Searching for the Cause
Oncologists find they have to sometimes become detectives when looking for the cause of diarrhea in patients; it may not always (or only) be related to their chemotherapy regimen. Irritable bowel syndrome, antibiotic-induced diarrhea (especially erythromycin) and even hyperthyroidism, though rare, can all be contributing factors.
“A critical question to ask your patients is whether the frequency remains after they have skipped a meal,” Dr. Anthony says. “On the other hand, patients can sometimes be ‘overzealous’ eaters when they start to feel better during treatment, eating large, fatty meals or too much fiber. So you need to ask them this, too.”
The first-line therapy typically used to address CTID is modification in the patient’s diet, careful review of other drugs the patient may be taking, and the addition of dose-appropriate loperamide. Another drug, octreotide, may also be promising. Preliminary results from small clinical trials and the STOP Trial showed fewer patients experience severe diarrhea, required IV fluid, or had diarrhea-related unscheduled health care visits in those taking long-acting release octreotide, with almost 60% of 74 patients observed reporting they were “satisfied to extremely satisfied” with the effect octreotide had on their diarrhea. Several other large clinical studies are currently underway.
CTID is a problem Dr. Anthony believes should not be under-addressed or dismissed as just a regular part of receiving chemotherapy. Left unattended, CTID can force oncologists to decrease or delay chemotherapy or, in itself, cause a severe, life-threatening situation. In addition, he says, it makes economic sense to treat it early. Loperamide is still the lowest-cost option of control, with octreotide being a moderate-to-high expensive choice. “But compared to ICU admission, which can end up costing between $10,000 to $30,000, the choice is clear,” said Dr. Anthony.
â–º Mucositis Can Make Life Miserable for Patients With Cancer
Severe infections can result from unsuccessful treatment of this painful chemotherapy side effect of the digestive tract
Mucositis (also called stomatitis), a common and painful side effect experienced by people receiving treatment for certain cancers, can cause painful inflammation and sores in the oral cavity and throughout the digestive tract. Oral mucositis is particularly troublesome in head and neck cancer patients because it can interfere with an already impaired ability to eat and speak and leave one susceptible to life-threatening infections. The Multinational Association for Supportive Care in Cancer (MASCC)/International Society for Oral Oncology are working together to establish new guidelines in the treatment of this side effect.
“Serious mucositis occurs in 30% to 80% of those patients receiving radiotherapy to the head and neck,” according to data cited by Deborah McGuire, PhD, a Registered Nurse and director of the oncology graduate program at the University of Maryland School of Nursing in Baltimore. “Hyperfractionated regimens are associated with Significantly increased risk.” In severe cases, radiation may Have to be reduced or interrupted to get mucositis under control.
Current MASCC guidelines, which can be accessed at www.mascc.org, currently suggest the “multidisciplinary development and evaluation of oral care protocols”, including the integration of basic oral care (such as regular replacement of a soft toothbrush) in the patients care plan. Dental professionals, patients, and patient families should all be included in the patient’s treatment, according to Dr. McGuire.
An FDA-approved medical device, Caphosol, is a topical oral agent indicated in the United States as an adjunct to standard oral care in treating oral mucositis caused by radiation or high-dose chemotherapy. Other would-be management agents, such as amifostine, antimicrobials, sucralfate, and “alternative therapies” such as aloe vera have thus far yielded inconclusive results and are even contraindicated in treating the troublesome side-effect.