Early Intervention: Rethinking Platelet Growth Factors

At a symposium held in conjunction with the Twenty-Seventh Annual Congress of the Oncology Nursing Society, three specialists in oncology nursing, pharmacy, and psychology, respectively, addressed the need for new strategies in preventing and managing treatment-related thrombocytopenia in patients with cancer. Topics included the importance of delivering planned doses of chemotherapy on time and of using growth factors effectively in the prevention and management of hematologic toxicities.

This program was supported by an educational grant from Wyeth Pharmaceuticals.

Speakers

Early Intervention: Using Growth Factors Effectively  

Myelosuppression is the number one dose-limiting toxicity associated with chemotherapy, but it doesn’t have to be, according to Jeannine M. Brant, RN, MS, AOCN®, Program Chair, Oncology Clinical Nurse Specialist, Pain Consultant, St. Vincent Healthcare, Billings, Montana. “The recent development of growth factors translates into the potential to help minimize hematologic toxicity, including thrombocytopenia, and keep planned doses of chemotherapy on schedule,” she said. Ms. Brant provided information supporting the need for early intervention, rather than rescue, in using growth factors in patients who are at high risk for thrombocytopenia.

Delivering Planned Doses on Time
For patients with cancer, deliverance of an effective chemotherapy regimen requires maintaining the dose intensity (DI), defined as the amount of drug delivered per unit of time and the relative dose intensity (RDI), defined as the amount of drug administered per unit of time expressed as the fraction of that used in the standard regimen (Hryniuk et al 1986). In 1995, Bonadonna and colleagues clearly showed a correlation between DI and survival. These researchers followed 386 women who underwent radical mastectomy for stage II node-positive breast cancer from 1973 to 1993. Patients then received either 12 cycles of cyclophosphamide, methotrexate, fluorouracil (CMF) or no further therapy. The results showed significantly poorer relapse-free and overall 20-year survival rates in the observation-only group; however, the most startling finding was in those who received substandard doses of chemotherapy. In those who received > 85% of the planned dose, relapse-free and overall survival was 52%. In those who received only 65% to 84% or < 65% of the planned dose, relapse-free survival was 33% and 30% and overall survival was 32% and 25%, respectively. In another study, Kwak and colleagues (1990) conducted a retrospective analysis of 115 patients treated for diffuse large-cell lymphoma between 1975 and 1986. Patients received either CHOP or MBACOD or MACOP-b therapy. These results showed significantly better survival rates in those receiving > 75% of the planned chemotherapy dose, with the main predictive factor being how much doxorubicin was administered. “These and other data clearly indicate the importance of maintaining DI and schedule on therapeutic outcomes in patients with breast, ovarian, colon, and small-cell lung cancers, as well as lymphoma and adult myelogenous leukemia. In terms of survival outcomes, giving reduced chemotherapy doses can often be the equivalent of giving no chemotherapy at all,” Ms. Brant explained.

Focusing on Early Intervention
Thrombocytopenia is one hematologic toxicity that often occurs in patients receiving chemotherapy. While a platelet lifespan in circulation is about 7 to 9 days, chemotherapy cycles given over time may result in a cumulative decrease in platelet count. Thrombocytopenia is thus a main dose-limiting toxicity of chemotherapy, and may be characterized by petechiae; ecchymosis; bleeding of the gums, nose, and orifices; gastrointestinal bleeding and melena; and life-threatening hemorrhage or cerebral hemorrhage. “However, reducing the dosage or delaying the administration of a potentially curative chemotherapy regimen is also a life-threatening prospect,” said Ms. Brant. One of the keys to preventing patients from experiencing low platelet levels and thus ensuring maintenance of planned chemotherapy doses on time is applying early intervention in patients who are at high risk (Table 1). Among the most toxic thrombocytopenia-producing regimens are CHOP, gemcitabine/carboplatin, ifosfamide/carboplatin/etoposide, and gemcitabine/cisplatin, followed by carboplatin/docetaxel/gemcitabine and topotecan (Shipp et al 1995; Langer et al 1999; Krigel 1994; Pectasides et al 1999; Von Pawel et al 1999).

Early intervention with growth factors, such as oprelvekin, is one strategy to maintaining full chemotherapy doses on time for patients who are at high risk for thrombocytopenia. Oprelvekin, a recombinant interleukin-11 product, works by stimulating progenitor cells and then the production of megakaryocytes and normal platelets (Dale 2001). This agent is approved by the U.S. Food and Drug Administration for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in patients with nonmyeloid malignancies who are at high risk for severe thrombocytopenia. Consistent with the platelet life cycle, oprelvekin, administered 6 to 24 hours after completion of chemotherapy, will begin to show a rise in platelet count approximately 9 days later. Dosing is continued until the post-nadir platelet count is > 50,000 cells/uL, but the agent must be discontinued at least 2 days before the next chemotherapy cycle. The most common side effects with oprelvekin include peripheral edema (59%), dyspnea (48%), and tachycardia (20%). According to Ms. Brant, oncology nurses play a key role in managing such side effects, using diuretics (with close monitoring) to control fluid retention, edema, and dyspnea.

Ms. Brant emphasized that patient assessment is the most valid indicator for whether platelet growth factors should be used. “For example, if the platelet counts are low, the clinician must evaluate for edema, cardiac function, renal status, and functional status. If all are positive, growth factors would be appropriate. If one of these factors is out of line, platelet growth factors may not be recommended,” she said.

In summary, the development of oprelvekin (and perhaps other investigational growth factors) offers new promise for patients suffering from the myelosuppressive effects of chemotherapy. “Using growth factors as a prevention rather than rescue strategy for thrombocytopenia may afford more patients not only with the ability to undergo full-dose on-time chemotherapy cycles, but also with an increased chance for survival,” Ms. Brant concluded.

Table 1. Risk Factors for Thrombocytopenia

•l Prior myelosuppressive chemotherapy
  -Some treatment regimens (eg, CHOP) are more likely than others to cause profound thrombocytopenia
  -Progressively lower platelet counts after each course
  -Significant drop in platelets after initial chemotherapy cycle
• Initial platelet count < 150,000 cells/uL
• Prior radiation therapy to hips, pelvis, or long bones

Dose Reductions and Delays of Chemotherapy in the Clinical Setting

The delivery of curative-intent chemotherapy for early-stage breast cancer and non-Hodgkin’s lymphoma (NHL) may be suboptimal throughout much of the United States. In many of these patients, hematologic toxicity is the main reason that full chemotherapy doses are not delivered on time, according to Shane D. Scott, PharmD, BCPS, BCOP, Associate Professor (Clinical), Department of Internal Medicine and Co-Director, Clinical Trials Support, Holden Comprehensive Cancer Center, University of Iowa, Iowa City. “An increased awareness of the role of primary and secondary prophylaxis of myelosuppression with growth factors is essential to improve adherence to curative-intent regimens in U.S. clinical practice,” Dr. Scott said.

Chemotherapy Regimen Modification in Breast Cancer
Several studies have emphasized the importance of maintaining dose intensity (DI) in patients receiving adjuvant chemotherapy for early-stage breast cancer. Bonadonna and colleagues (1995) found that patients with stage II, node-positive breast cancer receiving > 85% of the planned chemotherapy dose had 20% better survival rates than those receiving < 65% to 85% of the planned dose. Wood (1994) and Budman (1998) found similar results. Budman and colleagues, for example, treated patients with stage II, node-postive breast cancer with either high- , moderate- , or low-dose adjuvant fluorouracil/doxorubicin/cyclophosphamide regimens. The findings indicated significant differences in survival rates by dose, with the low dose achieving disease-free and overall survival rates of 56% and 72%, and the high dose showing disease-free and overall survival rates of 66% and 78%, respectively. However, the chemotherapy DI also had a cumulative effect on platelet counts.

In addition, an Oncology Practice Pattern Study (OPPS) was recently conducted to examine Iowa and national data for patients undergoing non-research protocol adjuvant treatment for stage I to III breast cancer. National data were drawn from 100 consecutive patients (1992-1999) from each of 13 treatment facilities (managed care, academic, community practices). Iowa data were randomly selected from their SEER database, and were stratified across the state (1993-1996) by tertiary centers treating > 12 and < 12 patients per year. Trained abstractors then collected data on the chemotherapy regimens as planned, patient characteristics, laboratory values, all points of care during treatment, chemotherapy regimens as delivered, and administration of antibiotics and growth factors. Results showed that most women had early-stage disease with no comorbidities, and received either cyclophosphamide/methotrexate/fluorouracil- or doxorubicin-based adjuvant chemotherapy. However, 30% of national patients and 56% of Iowa patients received < 85% of their relative DI chemotherapy regimen. Indeed, myelosuppression was one of the main reasons for the reduction/delay in therapy. “This alarming statistic did not vary by the type of treatment facility. Complications, however, did vary by the doctor’s familiarity with the regimen, and little use of preventive or secondary prophylaxis for neutropenia or thrombocytopenia was observed,” Dr. Scott explained. He continued, “Across the nation, there is evidence of toxicity-associated reduced and delayed chemotherapy dosing in patients with potentially curable disease, rather than maintenance of the necessary DI needed for curative treatment, as cited in the literature. It is therefore important to identify patients at risk for neutropenia and thrombocytopenia, and implement prophylactic growth factor therapy early, to achieve and maintain the DI needed for potential cure.”

Chemotherapy Regimen Modification in Non-Hodgkin’s Lymphoma
Similar to the case in breast cancer, Devita and colleagues (1989) showed that overall survival rates dropped by over 40% when the initial dose of CHOP therapy is halved in patients with NHL. As part of the OPPS trial, data from patients with intermediate-grade NHL were analyzed by the same methods as those with breast cancer. The results indicated that there was no difference in average relative DI between disease stages for those patients planned to receive CHOP or CNOP chemotherapy. Overall, 43% of patients with potentially curable NHL received suboptimal therapy. “Either the regimen was suboptimal as planned or the delivery of the planned regimen was suboptimal,” Dr. Scott explained. The speaker pointed out that 56% to 59% of dose reductions and delays were related to neutropenia and 7% to 10% to thrombocytopenia.

Conclusion
In summary, Dr. Scott pointed out that the OPPS trial, using a relatively representative group of patients, showed that delivery of chemotherapy regimens for early-stage breast and intermediate-grade NHL appears to be suboptimal throughout much of the United States. “To ensure optimal survival outcomes, clinicians need to utilize the primary and secondary prophylactic measures to minimize hematologic toxicities, and ensure adequate DI is delivered to these patients with potentially curable disease,” he concluded.

Impact on Patient Care

While use of proper dose-intense chemotherapy regimens is a critical factor in the ability to cure, it also results in the toxicities that may result in dose reduction or delay. “In 2002, we have the answers to many of these toxicities, and as oncology nurses, we need to facilitate the translation of that knowledge into clinical practice,” said Barbara I. Damron, PhD, RN, Clinical Nurse Specialist, Educational Psychologist, and President, Damron Oncology Consulting, Santa Fe, New Mexico. According to Dr. Damron, oncology nurses need to take the available data on managing treatment-induced toxicity, and advocate for change within their own institutions. Indeed, it may be beneficial to apply the model used today for the prevention and minimization of nausea and vomiting to the side effect of thrombocytopenia, she said.

Identifying High-Risk Patients and Treatment Goals
It is the responsibility of oncology nurses to utilize their knowledge, critical-thinking skills, and communication skills to develop an ongoing approach to integrate new advances into clinical practice, Dr. Damron said. “When we know that many patients are receiving < 85% of recommended chemotherapy doses, we need to address the hematologic toxicities that are causing dose reductions and delays,” she pointed out. A first step in addressing thrombocytopenia is identifying which patients are at high risk for this side effect. Second, treatment goals need to be set with the physician and patient. Are the goals for a complete response, long-term remission, or palliation? “If the goal is one of cure, then oncology nurses must ensure that each therapeutic intervention taken is such that it supports this goal,” Dr. Damron explained. Reducing or delaying chemotherapy doses unnecessarily is an action that does not match with the goal of cure, she said. Often, intervention strategies may be followed out of familiarity or habit. “In the case of patients with low platelet counts, the old strategy was to reduce or delay therapy and to give platelet infusions. Today, growth factors afford a more effective way to minimize the effect of low platelet levels, while maintaining appropriate chemotherapy doses,” the speaker noted. At the foundation of the effort to integrate change into clinical practice are effective communication and patient advocacy.

Communicating Effectively with Physicians and Patients
Nursing strategies must consider first and foremost the best interest of the patient. Today, more than ever, patients wish to be informed of their disease, treatment options, and expected side effects. To ensure that patients are able to participate actively in their own care and decision making, oncology nurses need to communicate (and help physicians to communicate) the needed information in a way in which the patient can understand it.

Studies have shown that a number of elements may influence the exchange of information. For example, patients are more likely to report new, upsetting symptoms than chronic, non-specific, or mild symptoms. Patients who are female or who are well educated may ask more questions of their healthcare providers, thereby receiving more information. Nurses and physicians also vary in their interest in and ability to elicit relevant information from their patients. Levinson and Roter, researchers in the field of healthcare communication, found that patients disclose more emotional and social functioning issues when the healthcare provider has a positive attitude toward these aspects of care. Similarly, Maguire and colleagues found that patients disclosed less psychosocial information when providers’ questions are close-ended or focused primarily on physical issues. Finally, structural factors, such as location and time pressure, may play a role in whether patients disclose important health-related information.

In 1999, Epstein described an approach by which nurses and physicians might attend in a nonjudgmental way to their own physical and mental processes during everyday tasks. This approach, termed “mindful practice,” allows providers to reflect critically on their thoughts and actions, listen more attentively to patients’ distress, and make evidence-based decisions. Mindful practice may be achieved on six levels, ranging from 0 to 5 (Table 1). “Indeed, studies have shown that the more in tune physicians or nurses are with themselves, the more likely patients are to understand the information received,” Dr. Damron said.

Unfortunately, studies show that patients with cancer receive less information than they would like from their healthcare providers (Holmes 1996). Because of the life-and-death nature of cancer, communication efforts may be met with unique problems. “Thus, nurses and physicians need to work collaboratively to ensure that the patient understands his or her disease, and treatment and symptom management options. In addition, instead of accepting an outdated method of addressing important treatment-related toxicities, such as thrombocytopenia, nurses or physicians can inform their colleagues and work to introduce new evidence-based strategies into clinical care,” Dr. Damron noted.

“Ultimately, effective communication between nurses, physicians, and patients is an important key to ensuring that optimal treatment and symptom management is provided and that patients are empowered in their own care,” the speaker concluded.

Table 1. The Components of “Mindful Practice”

Allows practitioners to
 • Listen attentively to patients’ distress
 • Recognize own errors
 • Refine technical skill
 • Make evidence-based decisions
 • Clarify own values so they can act with compassion, technical competence, presence, and insight
Levels of mindful practice
 • Level 0: denial and externalization
 • Level 1: imitation, behavioral modeling
 • Level 2: curiosity, cognitive understanding
 • Level 3: curiosity, emotions and attitudes
 • Level 4: insight
 • Level 5: generalization, incorporation, and presence

Source: Epstein 1999