Orthopedics

Commentary 

Blood Management Challenges in Orthopedic Oncology

Kenneth Jaffe, MD

Abstract

Although substantive progress has been made in the management of benign and malignant bone and soft tissue neoplasms, one challenge still faced by orthopedic oncologists is the anemic state of the patient in the perioperative period. Anemia results bom from systemic effects of the disease and, as a major side effect, from multiagent chemotherapy and radiation therapy. Anemia can reduce a patient's tolerance for continued therapy and can jeopardize the efficacy of radiation therapy. Further, the prospect of significant blood loss during tumor resection may exacerbate the anemic state of these patients. Thus, the orthopedic oncologist must meet the challenges of managing anemia in the perioperative setting.

ANEMIA OF CANCER

A majority of patients diagnosed with cancer already have or will develop anemia, either from the disease itself or as a result of radiotherapy or multiagent chemotherapy. There are many factors that either cause or contribute to chronic anemia in these patients, including increased cytokine production,' impairment of erythroid precursors,2 reduced erythropoietin production,3 iron deficiency or improper iron utilization, and the toxicity of cancer therapy.

Anemia may adversely affect the efficacy of cancer therapy and longterm survival rates.4,5 Anemic patients undergoing radiation therapy, for instance, are more likely to exhibit local recurrence of tumor growth and shortened survival.4,6 Likewise, chemotherapy also is associated with anemia and may impair the patient's function and quality of life.7-8 In a review of cervical cancers by Dische,4 anemia was associated with an impaired tumor response to radiation therapy in 23 of 25 (92%) cases. Moreover, a hemoglobin (Hb) level of < 10 g/dL was an independent prognostic indicator of mortality in a study of 401 patients with squamous cell cervical carcinoma.5 Multivariate analysis in a study of 735 patients with glottic cancer demonstrated that pretreatment Hb level was a predictor of local failure of radiotherapy.6 Given that pretreatment Hb levels, independent of other known prognostic factors, are significantly predictive of local tumor response and overall survival following radiation therapy, interventions aimed at increasing pretreatment Hb levels are recommended for treating all cancers that are expected to respond to radiation therapy.

SURGICAL BLOOD MANAGEMENT OPTIONS IN ORTHOPEDIC ONCOLOGY

Allogeneic Blood Transfusion. Surgery for aggressive bone tumors of the extremities is often accompanied by significant blood loss, which in turn exacerbates the anemic state of the patient. Allogeneic blood transfusion is the standard treatment for increasing perioperative Hb concentrations in anemic surgery patients undergoing radiation therapy or chemotherapy. Despite the apparent advantages of allogeneic blood transfusion on pretreatment Hb levels, however, it has been suggested that routine allogeneic transfusion of chronically anemic patients is not justified.9 In addition, there is growing evidence that allogeneic blood transfusion modulates the immune system.10-14 The immunosuppressive effects of allogeneic blood transfusion appear to be mediated by transfused allogeneic passenger leukocytes.12,15

Although transfusion-induced immunomodulation may be beneficial in some clinical settings, such as in renal transplantation,16,17 immunomodulation in the oncology setting has been associated with an increase in cancer recurrence.14,18,22 Furthermore, perioperative transfusion with allogeneic blood has been associated with reductions in long-term survival rates in patients with colorectal cancer.21,23 Similarly, allogeneic blood transfusion has exhibited prognostic significance in lung,18 breast,19,24 and resected gastric cancers.25

The role of perioperative blood transfusion in tumor recurrence has generally been under- investigated in patients' soft-tissue sarcomas of the extremities. Rosenberg and colleagues26 investigated the relationship between allogeneic blood transfusions and overall and continuous disease-free survival in patients with high grade soft-tissue sarcomas of the extremities. Overall 5 -year survival was markedly lower in patients who had been transfused compared with patients who had not been transfused (63% versus 85%, P < .004). Similarly, 5-year…

Although substantive progress has been made in the management of benign and malignant bone and soft tissue neoplasms, one challenge still faced by orthopedic oncologists is the anemic state of the patient in the perioperative period. Anemia results bom from systemic effects of the disease and, as a major side effect, from multiagent chemotherapy and radiation therapy. Anemia can reduce a patient's tolerance for continued therapy and can jeopardize the efficacy of radiation therapy. Further, the prospect of significant blood loss during tumor resection may exacerbate the anemic state of these patients. Thus, the orthopedic oncologist must meet the challenges of managing anemia in the perioperative setting.

ANEMIA OF CANCER

A majority of patients diagnosed with cancer already have or will develop anemia, either from the disease itself or as a result of radiotherapy or multiagent chemotherapy. There are many factors that either cause or contribute to chronic anemia in these patients, including increased cytokine production,' impairment of erythroid precursors,2 reduced erythropoietin production,3 iron deficiency or improper iron utilization, and the toxicity of cancer therapy.

Anemia may adversely affect the efficacy of cancer therapy and longterm survival rates.4,5 Anemic patients undergoing radiation therapy, for instance, are more likely to exhibit local recurrence of tumor growth and shortened survival.4,6 Likewise, chemotherapy also is associated with anemia and may impair the patient's function and quality of life.7-8 In a review of cervical cancers by Dische,4 anemia was associated with an impaired tumor response to radiation therapy in 23 of 25 (92%) cases. Moreover, a hemoglobin (Hb) level of < 10 g/dL was an independent prognostic indicator of mortality in a study of 401 patients with squamous cell cervical carcinoma.5 Multivariate analysis in a study of 735 patients with glottic cancer demonstrated that pretreatment Hb level was a predictor of local failure of radiotherapy.6 Given that pretreatment Hb levels, independent of other known prognostic factors, are significantly predictive of local tumor response and overall survival following radiation therapy, interventions aimed at increasing pretreatment Hb levels are recommended for treating all cancers that are expected to respond to radiation therapy.

SURGICAL BLOOD MANAGEMENT OPTIONS IN ORTHOPEDIC ONCOLOGY

Allogeneic Blood Transfusion. Surgery for aggressive bone tumors of the extremities is often accompanied by significant blood loss, which in turn exacerbates the anemic state of the patient. Allogeneic blood transfusion is the standard treatment for increasing perioperative Hb concentrations in anemic surgery patients undergoing radiation therapy or chemotherapy. Despite the apparent advantages of allogeneic blood transfusion on pretreatment Hb levels, however, it has been suggested that routine allogeneic transfusion of chronically anemic patients is not justified.9 In addition, there is growing evidence that allogeneic blood transfusion modulates the immune system.10-14 The immunosuppressive effects of allogeneic blood transfusion appear to be mediated by transfused allogeneic passenger leukocytes.12,15

Although transfusion-induced immunomodulation may be beneficial in some clinical settings, such as in renal transplantation,16,17 immunomodulation in the oncology setting has been associated with an increase in cancer recurrence.14,18,22 Furthermore, perioperative transfusion with allogeneic blood has been associated with reductions in long-term survival rates in patients with colorectal cancer.21,23 Similarly, allogeneic blood transfusion has exhibited prognostic significance in lung,18 breast,19,24 and resected gastric cancers.25

The role of perioperative blood transfusion in tumor recurrence has generally been under- investigated in patients' soft-tissue sarcomas of the extremities. Rosenberg and colleagues26 investigated the relationship between allogeneic blood transfusions and overall and continuous disease-free survival in patients with high grade soft-tissue sarcomas of the extremities. Overall 5 -year survival was markedly lower in patients who had been transfused compared with patients who had not been transfused (63% versus 85%, P < .004). Similarly, 5-year continuous disease-free survival was decreased in transfused patients versus nontransfused patients (48% versus 70%, P = .007). Further, an inverse relationship was noted between the number of allogeneic units transfused and the 5-year overall and disease-free survival. The investigators concluded that allogeneic transfusion is associated with increased tumor recurrence and decreased survival (i.e., poor prognosis) in patients with high-grade soft-tissue sarcomas of the extremities.

While a multivariable analysis showed that blood transfusion appeared to be linked to survival because of its strong association with large tumor size and deep tumor invasion (thereby resulting in more perioperative blood loss), other investigators have found no causal relationship between allogeneic blood transfusion and tumor recurrence.27'30 A separate study of risk factors contributing to tumor recurrence and survival in 232 primary high-grade extremity sarcoma patients found blood transfusion to be unfavorable in a univariable analysis.27 There may be other subtle factors leading to the requirements for blood transfusion that are not yet apparent.

Autologous Blood Donation. Irrespective of the effect of allogeneic blood transfusion on tumor recurrence, under most conditions the patient's blood (i.e., autologous blood) is considered the safest. Autologous blood donation, a widely adopted alternative to allogeneic blood transfusion, involves the predonation of autologous blood units, perioperative salvage of blood loss, or acute normovolemic hemodilution. In the oncology setting, however, perioperative salvage is contraindicated because of concerns related to the risk of hematogenous spread of the cancer. Thus, allogeneic blood is administered frequently in patients with cancer, despite the risks associated with it.

Other Options for Treating Perioperative Anemia. Because of limitations associated with conventional blood management techniques (i.e., allogeneic and autologous blood transfusion) in treating anemia in the oncology setting, there is a well-defined need for improvement in blood management and Hb support in oncology patients, and clinicians have sought alternatives to blood transfusion. The effectiveness of recombinant human erythropoietin (Epoetin alfa) in treating preoperative anemia has been established in orthopedic settings,31-34 and Epoetin alfa has been successfully employed in treating the anemia of cancer.35-38 Thus, Epoetin alfa may have an important role in the treatment of orthopedic oncologic patients undergoing surgery.

There may also be a role for Epoetin alfa in managing oncology patients during radiation therapy and in preparation for tumor resection. In contrast to allogeneic transfusion, elevation of Hb levels with Epoetin alfa eliminates the risks of immunosuppression and the adverse effects of allogeneic transfusion. In a placebocontrolled trial, Hb values increased during radiation therapy from a mean of 11.9 ± 1.3 g/dL to > 14 g/dL in 16 of 20 (80%) patients treated with Epoetin alfa, compared with 1 of 20 (5%) patients treated with placebo.39 It has also been reported that Epoetin alfa is effective in correcting anemia induced by platinum-based chemotherapy in 60% to 80% of patients.40 Further studies are required, however, to determine what effect increasing Hb levels with Epoetin alfa treatment may have on local tumor response to radiation therapy, transfusion requirements, and overall survival rates.

We have begun to investigate the use of Epoetin alfa treatment in orthopedic oncology patients preparing to undergo tumor resection. Because some tumors, such as giant cell tumors and aneurysmal bone cysts, exhibit aggressive growth, the freedom to delay resection is limited: resection must occur within 2 to 3 weeks. Malignant bone tumors of the extremities, such as chondrosarcomas, also require rapid surgical scheduling. Therefore, we have developed a protocol for Epoetin alfa treatment for patients with accelerated surgical timelines (within 2 or 3 weeks). Hematocrit levels and transfusion requirements will provide quantitative measures of treatment efficacy. The results will be presented after. completion of the study.

SUMMARY

Because anemia is associated with reduced long-term survival, and because allogeneic transfusion is linked to increased recurrence of disease and reduced rates of long-term survival, alternative options for managing anemia in the orthopedic oncologic patient have been sought. Managing the anemia of cancer is particularly challenging given the many obstacles to employing conventional blood management options. One potential means of treating perioperative anemia in orthopedic oncologic patients involves the use of Epoetin alfa. The clinical utility of Epoetin alfa in this setting, however, must be determined in controlled trials.

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29. Blumberg N, Heal JM. Noncausai relationship between cancer recurrence and perioperative blood transfusions. Ann Surg. 1995; 222:757-758.

30. Busch OR, Hop WC, Marquet RL. Jeekel J. Prognostic impact of blood transfusions on disease-free survival in colorectal carcinoma. Scand J Gastroenterol Suppl. 1993; 200:21-23.

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32. de Andrade J, Jove M, Landon G, et al. Baseline hemoglobin as a predictor of risk of transfusion and response to Epoetin alfa in orthopedic surgery patients. Am J Orthop. 1996; 25:533-542.

33. Faris P, Ritter M, Abels R, The American Erythropoietin Study Group. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. J Bone Joint Surg Am. 1996; 78-A:62-72.

34. Goldberg MA, McCutchen JW, Jove M, et al. A safety and efficacy comparison study of two dosing regimens of Epoetin alfa in patients undergoing major orthopedic surgery. Am J Orthop. 1996; 25:544-552.

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38. Pangalis GA, Poziopoulos C, Angelopoulou MK, Kiakantaris MP, Panayiotidis P. Effective treatment of diseaserelated anaemia in B-chronic lymphocytic leukaemia patients with recombinant human erythropoietin. Br J Haematol. 1995; 89:627629.

39. Lavey RS, Dempsey WH. Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys. 1993;27:1147-1152.

40. Rosso R, Del Mastro L, Venturini M, et al. [Use of erythropoietin in oncology]. Tumor. 1997; 83(suppl 2, pt 4):S26-S30.

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