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

Drs. Shasha and Harrison provide an excellent review of the problem of anemia in patients receiving definitive radiotherapy. They also summarize their own original research on the prevalence of anemia in a typical radiation oncology practice. Their study confirms that there is an "epidemic" of anemia among oncology patients and suggests that the issue requires far more attention than it has received.

A Prognostic Indicator

It is well recognized that anemia is associated with decreased response, local control, and/or survival after radiotherapy, and the authors supply numerous references to support this premise. Many of these studies addressed the condition in the setting of radiotherapy alone, but is anemia still an important prognostic factor now that concurrent chemoradiation has supplanted radiotherapy alone for many-if not most-epithelial cancers? The Austrian experience cited by Drs. Shasha and Harrison is thus very important in support of this hypothesis.[1]

At the University of Pennsylvania Medical Center, we have observed a strong relationship between hemoglobin level and response to preoperative chemoradiation in patients with bulky stage IIIA non-small-cell lung carcinoma.[2] We treated 41 patients (all with mediastinoscopy-proven bulky stage IIIA disease) with neoadjuvant radiotherapy (45-50 Gy) and concurrent chemotherapy (either etoposide/cisplatin [Platinol] or carboplatin [Paraplatin]/paclitaxel [Taxol]). Our results are listed in Table 1. Pathologic complete or near-complete (only tiny microscopic residual foci) responses were seen in 12 of 23 patients with hemoglobin levels of  12.5 g/dL or more  vs 3 of 18 responses in patients with hemoglobin levels < 12.5 g/dL. More studies are needed to determine the significance of anemia in the setting of concurrent chemoradiation.

A Frequently Uncorrected Problem

In light of the strong evidence of a relationship between anemia and outcome, why isn’t more emphasis placed on the correction of anemia? Drs. Shasha and Harrison provide several possible reasons, including:

• A lack of recognition of the problem;
• The perception that the problem of anemia pales in comparison with other treatment toxicities, such as infection and esophagitis;
• The well-known infectious and immunologic risks of transfusion; and
• The cost and logistical difficulties associated with the use of recombinant human erythropoietin (epoetin alfa, Epogen, Procrit), including the modest rate at which it increases hemoglobin.

Perhaps the most significant reason why the correction of anemia is still not a standard intervention is the failure of the academic and clinical research communities to prove that there is indeed a cause-and-effect relationship between anemia and poor tumor control. In Figure 1 of their article, Drs. Shasha and Harrison describe the traditional hypothesis that anemia leads to hypoxia, which, in turn, leads to radioresistance and poor outcome. However, an alternative explanation is that anemia/hypoxia-which may be present for months to years prior to cancer diagnosis and treatment-stimulates angiogenesis[3] and, thus, tumor invasion and metastasis. In the angiogenesis model, correcting anemia at this late stage in a cancer’s natural history may be ineffective.

Finally, it is possible that anemia is merely a "marker" of a patient’s underlying comorbidity and performance status rather than an independent predictor of outcome. In fact, our experience in treating early-stage laryngeal cancer showed a strong correlation between anemia and death from intercurrent disease or second primary cancers.[4]

Few Relevant Trials

Only large, prospective randomized trials can adequately answer these questions. To date, there have been few such studies. The most widely cited trial-in which local control and survival of anemic cervical cancer patients were improved with transfusion[5]-has been criticized for its small size and inconclusive results when analyzed by intent-to-treat analysis.[6] Preliminary results of a small randomized study of erythropoietin in head/neck cancer patients from the University of Chicago were disappointing.[7] On a more positive note, a recent phase III trial (in a chemotherapy-alone setting) showed not only improved quality of life, but a trend toward improved survival for patients randomized to erythropoietin vs placebo.[8]

The Radiation Therapy Oncology Group (RTOG) is conducting a large randomized trial in head and neck cancer, in which 372 patients will be randomized to erythropoietin or control. The design of this trial (RTOG 99-03), including stratification variables, is shown in Figure 1. The study is currently undergoing amendment to open accrual (with appropriate stratification) of patients who will receive concurrent cisplatin chemotherapy. Prospective studies such as RTOG 99-03 are critical to determining whether the correction of anemia significantly improves tumor control and survival as well as quality of life. Radiation oncologists should welcome and support these studies wholeheartedly.

References:

1. Glaser CM, Millesi W, Kornek GV, et al: Impact of hemoglobin level and use of recombinant erythropoietin on efficacy or preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 50:705-715, 2001.

2. Robnett TJ, Hahn SM, Shrager JB, et al: Pathologic response to preoperative chemoradiation worsens with anemia in non-small-cell lung cancer (NSCLC) patients (abstract 256). Proceedings of the annual meeting of the Radiologic Society of North America, Chicago, November 2000.

3. Dunst J, Pigorsch S, Hansgen G, et al: Low hemoglobin is associated with increased serum levels of vascular endothelial growth factor (VEGF) in cancer patients. Strahlenther Onkol 175:93-96, 1999.

4. Canady DJ, Regine WF, Mohiuddin M, et al: The significance of pretreatment hemoglobin level in patients with T1 glottic cancer. Radiat Oncol Invest 7:42-48, 1999.

5. 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.

6. Fyles AW, Milosevic M, Pintilie M, et al: Anemia, hypoxia, and transfusion in patients with cervix cancer: A review. Radiother Oncol 57:13-29, 2000.

7. Rosen FR, Haraf D, Brockstein B, et al: Multicenter randomized phase II study of 1-hour infusion paclitaxel, fluorouracil, and hydroxyurea with concomitant hyperfractionated radiotherapy with or without erythropoietin for advanced head and neck cancer (abstract 902). Proc Am Soc Clin Oncol 20:226a, 2001.

8. Littlewood TJ, Bajetta E, Nortier JWR, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized double blind placebo controlled trial. J Clin Oncol 19:2865-2874, 2001.