Oral Medications in Oncology: Patient Education and Improved Outcomes

At a symposium held in conjunction with the Twenty-Seventh Annual Congress of the Oncology Nursing Society, three specialists in cancer care presented the latest data on the use of oral medications. Topics included the use of oral fluoropyrimidines for breast and colon cancers, oral antiemetics for patients receiving chemotherapy, and the role of the oncology nurse in patients receiving oral chemotherapy agents.

This program was supported by an unrestricted educational grant from Roche Pharmaceuticals.

Speakers

Case Studies of Breast & Colon Cancer: Using Oral Fluoropyrimidines  

Most patients prefer oral medications because of convenience and problems with intravenous (IV) lines/needles, and would prefer an oral agent if response and duration of response are at least equal to that of IV treatment (Lui 1997, survey). Sujata Rao, MD, Clinical Associate Professor, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, presented case studies to demonstrate the potential use of oral fluoropyrimidines in patients with breast or colon cancer.

Case Report: Metastatic Colorectal Cancer
JK is a 61-year-old professor diagnosed with metastatic colorectal cancer. He wishes for the treatment with the least impact on his job/lifestyle, although ultimately he wishes to receive aggressive therapy, with the greatest response possible. According to Dr. Rao, the efficacy of oral capecitabine should be considered in comparison with IV 5-fluorouracil (5-FU)/leucovorin.

Capecitabine is a novel oral fluoropyrimidine that mimics the action of continuous infusion 5-FU. Capecitabine is currently approved as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred, but is also being investigated for use in other indications. Indeed, the pooled data from phase III trials showed a superior tumor response rate with capecitabine than with Mayo Clinic Regimen IV 5-FU/leucovorin (26% vs 17%). Even correcting for performance status and analyzing different metastatic sites, capecitabine demonstrated superior response rates. Survival data were equivalent in the two treatment arms. The only adverse effect more common with capecitabine than with 5-FU/leucovorin was hand-foot syndrome. “However, capecitabine should be used with caution in patients having renal impairment or taking warfarin, and is contraindicated in those with severe renal insufficiency,” said Dr. Rao.

Other oral agents that might be considered for JK include UFT, a combination of uracil and tegafur. However, studies of UFT have yielded decreased response rates and median survival time, and increased grade 3/4 diarrhea compared with IV 5-FU/leucovorin. Another agent, irinotecan, has been combined with 5-FU and compared with 5-FU alone. Approximately 40% of patients showed no survival benefit and increased toxicity with the combination treatment. However, the irinotecan combination did show a survival benefit in a subset of patients who were younger, had good performance status, no previous adjuvant therapy, and only one site of metastasis.

Case Report: Metastatic Breast Cancer
LR is a 54-year-old attorney with a 4-year history of T2 N0 M0, estrogen receptor-negative, her2-negative breast cancer. LR was treated with IV cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvantly, and 1 year ago, had metastasis to the liver. She was treated with a doxorubicin-based regimen, but was started on paclitaxel after new hepatic lesions developed. After 2 months, LR’s computerized tomography scan showed two new pleural nodules. “For LR, the potential response, survival time, and toxicity with oral capecitabine should be considered,” Dr. Rao said.

Oral capecitabine is approved as a monotherapy for patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, and as combination therapy with docetaxel for patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. In phase II trials (Blum 2001), patients having metastatic breast cancer and previous therapy with either paclitaxel or docetaxel (96%) were treated with oral capecitabine. The overall response rate was 26%, median survival time 12.2 months, median duration of response 8.3 months, and time to progression 3.2 months. The most common toxicities were hand-foot syndrome (22%), diarrhea (16%), and stomatitis (12%). In another phase II trial (O’Shaughnessy 1998), patients with metastatic breast cancer received first-line treatment with oral capecitabine or IV CMF. Most patients had received previous hormonal therapy. Response rates (30% vs 16%), time to progression (4.1 vs 3.0 months), and median survival (19.6 vs 17.2 months) were superior with capecitabine. Hand-foot syndrome and grade 3 events were more common with capecitabine; however, neutropenia was more common with CMF.

In another scenario, a woman with metastatic breast cancer treated with an anthracycline (no taxane) had new hepatic metastasis and pleural nodules. According to Dr. Rao, options for this patient might include paclitaxel, capecitabine, docetaxel, or docetaxel plus capecitabine. O’Reilly and colleagues (1998) treated patients with anthracycline-resistant breast cancer with second-line paclitaxel or capecitabine. Three patients in the capecitabine arm and none in the paclitaxel arm had a complete response. Mean time to progression was 7.6 months with capecitabine, 9.4 months with paclitaxel. Common toxicities included vomiting, diarrhea, and hand-foot syndrome with capecitabine, and alopecia, paresthesia, and neutropenia with paclitaxel.

In phase III trials of anthracycline-resistant metastatic breast cancer, patients received either capecitabine plus docetaxel or docetaxel alone. Results showed median time to progression of 4.2 months with docetaxel and 6.1 months with the combination, and an overall survival time of 11.5 months with docetaxel and 14.5 months with the combination. With the single agent more fatigue and neutropenic fever, and with the capecitabine plus docetaxel more diarrhea and hand-foot syndrome, were observed.

In closing, Dr. Rao noted that current studies are underway to investigate the use of capecitabine in combination with various agents for patients with colorectal or breast cancers. “It is hoped that capecitabine combinations may ultimately offer improved outcomes for patients with these and other cancers,” the speaker concluded.

Mechanism of Action and Efficacy of Oral Antiemetics

Over the last two decades, nausea and vomiting have consistently been listed in the top 10 symptom management concerns of patients undergoing cancer therapy (Coates 1983, Griffin 1996), said Richard Gralla, MD, Professor of Medicine; Chief, Solid Tumor Service, Division of Medical Oncology; Associate Director and Director of Clinical Research, Herbert Irving Comprehensive Cancer Center; Columbia University, New York City. According to Dr. Gralla, “In providing antiemetic therapy, the strategy is to prevent rather than treat acute and delayed nausea and vomiting; therefore, antiemetic regimens should be planned up front, and given directly following chemotherapy administration.”

The first step to providing effective antiemetic treatment is achieving an awareness of the risk for emesis with the various chemotherapy agents as well as of the antiemetic treatment guidelines recommended for each risk category. In chemotherapy agents at high risk, emesis occurs in nearly all, in moderate risk in > 30%, low risk > 10%, and minimal risk < 10% (Table 1). Current efficacy data indicate that antiemetic therapy may yield complete control in 70% of patients receiving cisplatin and 85% of those receiving a moderate-risk agent. “However, does efficacy translate into clinical effectiveness? To provide optimal antiemetic management, current antiemetic treatment guidelines must be followed,” Dr. Gralla said. The consensus among guidelines dictates that treatment of moderate-risk acute emesis requires a 5-hydroxy tryptamine receptor antagonist (5HT3 RA) agent plus a corticosteroid, and delayed emesis a corticosteroid plus metoclopramide or 5HT3 RA agent. Unfortunately, Roila and colleagues (2000) found that the guidelines for acute emesis are followed only 57% and delayed emesis only 61% of the time. In 40% of cases, a 5HT3 RA was used alone for acute emesis, and in 35% of cases, no antiemetic therapy was offered for delayed emesis.

The goals of antiemetic therapy with chemotherapy include complete control in all settings, avoidance of side effects, maximum convenience and ease of use to patients and families, and cost-effectiveness. According to Dr. Gralla, use of newer oral antiemetic agents is an important component in translating efficacy into effectiveness and achieving these goals.

How 5HT3 Receptor Antagonists Work
Emesis occurs through several mechanisms including stimulation of enterochromaffin cells in the duodenum, leading to release of serotonin. This serotonin binds and stimulates the vagus nerve, which in turn stimulates the spinal cord, medulla oblongata (including the chemoreceptor trigger zone), and then the brain’s vomiting center. Once the vomiting center is stimulated, nausea may ensue. “To block the receptors at any location along this pathway may potentially block emesis,” Dr. Gralla explained. One approach used with the 5HT3 RA agents, is to block the 5HT3 (serotonin) receptors that line the gut. “The presence of 5HT3 receptors in the gut makes them a prime target for antiemesis therapy. Especially with the use of novel new oral agents, bioavailability becomes less important, absorption at the receptor site paramount,” said Dr. Gralla.

Addressing Acute and Delayed Emesis
In addressing acute emesis, Perez and colleagues (1998) showed that, in patients receiving moderate-risk chemotherapy agents, complete acute emesis control results were equivalent between oral granisetron and intravenous (IV) ondansetron. In another study, Gralla and colleagues (1998) treated patients receiving cisplatin with either oral granisetron plus a corticosteroid or IV ondansetron plus a corticosteroid. Complete control of acute emesis was equivalent in the two groups (59% vs 61%). More recently, Hesketh and colleagues (2000) treated patients receiving high-risk chemotherapy agents with oral granisetron given at either 1 mg or 2 mg before chemotherapy, in a randomized trial including nearly 100 patients. This trial showed complete control of acute emesis to be similar between the two doses (65% vs 61%). “Studies also show that to improve these results, we need to add a single dose of dexamethasone. Adding dexamethasone to granisetron, for example, can raise the complete acute emesis control rates from 70% to greater than 90%, in patients receiving moderately emetic chemotherapy [Igar et al 1995],” Dr. Gralla stressed. In addition, the speaker pointed out that the patient populations helped most with addition of dexamethasone are those at highest risk for emesis: women, younger patients, and those who have a lower chronic alcohol intake history.

The onset of delayed emesis may occur as early as 17 to 24 hours after administration of chemotherapy. In general, the risk of acute emesis predicts the likelihood of delayed emesis. While the pathogenesis of delayed emesis is not well understood, use of corticosteroids is considered key. In addition, studies have shown significant improvement in complete control by adding an antiemetic agent to dexamethasone (Kris et al 1989). In addition, metoclopramide plus dexamethasone appears equivalent with ondansetron plus dexamethasone in achieving complete control of emesis. “The recommendations for control of delayed emesis are similar to those for acute emesis, with an emphasis on combination therapy for moderate- and high-risk groups and on preventive dosing,” said Dr. Gralla (Table 2). Dr. Gralla added that oral agents are more convenient for many patients to use at home, and thus may play a key role in delayed emesis prevention.

In closing, Dr. Gralla emphasized that, especially for high- and moderate-risk groups, antiemesis therapy must be preventive. “Oncology professionals need to follow current antiemetic guidelines, use currently available agents properly, and establish and implement a clear proactive plan to address both acute and delayed emesis in patients undergoing chemotherapy,” he concluded.

Table 1. Emetic Risk Groups with Representative Agents

High
  • Cisplatin
  • Dacarbazine
  • Nitrogen mustard

Moderate
   • Anthracyclines
  • Carboplatin
  • Cyclophosphamide

Low
  • Taxanes
  • Topoisomerase I inhibitors
  • Mitoxantrone

Minimal
  • Fluoropyrimidines
  • Vincas
  • Bleomycin

Patient Management and Education in the Administration of Oral Fluoropyrimidine Therapy

For many individuals with cancer, the occurrence of metastatic disease is not an unexpected event in their cancer journey. Developing a plan of care that strives to achieve survival benefit and ensuring quality of life within the patient’s own world view are paramount in providing quality cancer care. Therefore, nurses need to be aware of where new potential treatment options may fit into the metastatic phase of the disease trajectory, said Jody Pelusi, PhD, FNP, AOCN®, Program Chair, Nurse Practitioner from the Northern Arizona Hematology & Oncology Associates and Banner Health Care System in Arizona. The use of oral agents, such as capecitabine, may provide not only a clinical benefit, but also more personal control and treatment convenience for patients with metastatic colorectal or breast cancer, by reducing the frequency and amount of time spent in the oncology office, and potentially increasing the time individuals have to enjoy their lives.

Initial Assessment
Capecitabine is a prodrug, a chemical precursor of 5-fluorouracil (5-FU). Capecitabine undergoes three enzymatic changes in the body prior to becoming 5-FU within the body tissues. It is believed that if higher levels of 5-FU can be obtained at the tumor site, there should be a higher therapeutic index and minimization of systemic exposure of healthy body tissues. In assessing patients for potential treatment with oral capecitabine, oncology nurses need to review patients’ previous treatments, and evaluate the potential impact of any previously occurring side effects and any comorbidities. Capecitabine is contraindicated in patients who have severe renal impairment, DPD deficiency, or who are pregnant or breastfeeding. Special consideration and/or monitoring should be provided to patients taking warfarin, phenytoin, or high doses of folic acid supplements or those prone to diarrhea. In patients who are candidates for capecitabine therapy, nurses must ensure that patients’ baseline assessment includes special attention to oral cavity and hygiene practices, nutrition and hydration routines, skin condition and care (especially feet and hands), bowel patterns, gastrointestional status, all medications and health practices, pain and fatigue levels, and patient ability to take medication correctly and track side effects.

Administration and Dosing
Capecitabine dosing is twice daily for 14 days, followed by a 7-day rest period, making it an every 21-day cycle. The U.S. Food and Drug Administration has approved a total daily dose of capecitabine of 2500 mg/m2 (in two divided doses). However, according to Dr. Pelusi, community oncologists commonly utilize a total daily dose of 2000 mg/m2 (divided into two doses). If patients miss a capecitabine dose, they should not make it up, but wait and take the next prescribed dose when it is due (no doubling up). If patients have emesis, they are not to repeat the dose, but are to notify their provider. The treatment is always stopped if the patient experiences a grade 2 or higher toxicity (Table 1). If the dose has been held due to the occurrence of side effects, it is not restarted until the side effects have cleared or been reduced to a grade 1 toxicity level. Depending on the frequency of the toxicity occurrence, dose reduction may be needed (Table 2). Because many patients experience a clinical benefit while on this medication, they need to understand the necessity of stopping the medication if a grade 2 or higher toxicity occurs. Many patients will continue to experience a clinical benefit even if the medication has to be stopped for a short period of time. Overall treatment with capecitabine continues until there is progression of the disease or the development of unmanageable side effects.

Management of Side Effects
Potential adverse effects of capecitabine can include: stomatitis, diarrhea, nausea, vomiting, palmar-plantar erythrodysesthesia (hand-foot syndrome), and alterations in warfarin and phenytoin levels. Less than 4% of patients in clinical trials experienced alopecia, hematologic changes, or hyperbilirubinemia. The key to preventing and minimizing the side effects begins before the treatment. Having patients keep a wellness log that includes nutritional intake, hygiene practices, lifestyle behaviors, sleep and bowel patterns, and pain and fatigue levels can help nurses to design a plan of care for symptom prevention. Ensuring that oral and skin care regimens, along with good nutrition and hydration, are initiated prior to therapy is extremely valuable for the prevention and minimization of common side effects.

In closing, Dr. Pelusi noted that proper education for patients and their caregivers is essential to ensuring correct administration, monitoring, and management with this oral agent. “Whether chemotherapy administration is intravenous or oral, oncology nurses remain the key to ensuring quality cancer care is provided at every phase in the disease trajectory,” she concluded.