Commentary (Komaki)-Anemia Treatment and the Radiation Oncologist: Optimizing Patient Outcomes

This article reviews the recent literature documenting that anemia is one of the important prognostic factors among cancer patients. The authors suggest that anemia could be correlated with quality of life in addition to outcomes factors such as locoregional control and disease-free survival. They emphasize articles published between 1989 and 2001 that report the significance of anemia among patients treated with radiation therapy and describe the potential strategies for overcoming hypoxia by correcting the anemia.

Original Reports

The main criticism of this review is that the authors neglected the original articles describing the relationship between hemoglobin levels and local control rate in patients with carcinoma of the cervix and larynx.[1,2] Anemia associated with high risk of local failure was thought to be related to decreased oxygen supply to the tumor, which reduced radiosensitivity in patients with cervical or head and neck cancer. Therefore, the suggestion by Drs. Shasha and Harrison that "the prevalence and nature of anemia in the radiation oncology setting have been inadequately characterized" is not quite correct.

More recent articles have documented quality of life and prognostic factors associated with anemia among patients receiving chemotherapy, with or without other treatment modalities. I would like to remind oncologists to read the original study published by Dr. Raymond S. Bush and his colleagues in 2,803 patients with cervical cancer treated by radiation therapy at the Princess Margaret Hospital.[3] These investigators clearly noted that anemia was related to patient outcomes especially among those with more advanced disease (eg, stage IIB and III). In their randomized trial, intervention to increase hemoglobin levels prior to initiating radiation therapy produced markedly positive results.

Study patients had stage IIB or III carcinoma of the uterine cervix and hemoglobin levels between 10 and 12.5 g/dL. They were randomized to receive a red blood cell transfusion to raise their hemoglobin levels above 12.5 g/dL prior to standard pelvic radiation therapy vs observation. Patients given transfusions showed a significant increase in local control and disease-specific survival rates, compared to those who were observed without transfusion (P < .01).[3] However, this improvement was not significant among those with early-stage cervical cancer.

Erythropoietin

Over the next decade, major concerns developed regarding blood transfusions because of the transmission of hepatitis and HIV.[4] Moreover, whether the improvement in locoregional control would lead to improvement in outcome was also questioned. It was suggested that patients who presented with low hemoglobin levels may have a poor outcome despite subsequent improvement in hemoglobin levels via transfusion. These concerns became less important once recombinant human erythropoietin (Epogen, Procrit) with ferrous sulfate was shown to significantly increase hemoglobin levels (without a blood transfusion).[5] Over 400 anemic cancer patients were enrolled in prospective randomized clinical trials that compared subcutaneous erythropoietin to placebo. Some patients received chemotherapy concurrently. In one such trial, the quality of life of patients who received erythropoietin improved significantly, compared to patients given placebo.[6]

We have accumulated sufficient evidence demonstrating that the maintenance of hemoglobin levels above 12 g/dL will improve locoregional control and disease-free survival in patients with cervical, head and neck, non-small-cell lung, and bladder cancer. There is still some controversy, however, regarding whether hypoxia of the tumor is correlated to hemoglobin level. This question can be answered by direct measurement of the oxygenation of the tumor or through fluorodeoxyglucose positron-emission tomography (FDG-PET) correlated to hemoglobin levels and responsiveness to radiation therapy. The imaging of hypoxia and the results of trials of hypoxic sensitizers have been gradually improving.

Conclusions

In summary, it is important to maintain hemoglobin levels, especially among patients who have received multimodality treatment such as induction chemotherapy with or without radiotherapy followed by surgery, surgery followed by radiation therapy with or without chemotherapy, or chemoradiotherapy alone. Recent trends in cancer management emphasize a multidisciplinary approach that could cause anemia in many more patients than those who present with the condition at the time of cancer diagnosis. At the very least, we can improve the quality of life of cancer patients by maintaining hemoglobin levels.

References:

1. Taskinen PJ: Radiotherapy and TNM classification of cancer of the larynx. Acta Radiol (suppl 287):1-21, 1969.

2. Hierlihy P, Jenkin RDT, Stryker JA: Anaemia as a prognostic factor in cancer of the cervix. Can Med Assoc J 100:1100-1102, 1969.

3. Bush RS, Jenkin RDT, Allt WEC, et al: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37:302-306, 1978.

4. Walker RH: Special report: Transfusion risks. Am J Clin Pathol 88:374-378, 1987.

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

6. Abels RI: Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. Semin Oncol 19(suppl 8):29-35, 1992.