The Use of Erythropoietin
in Radiation Oncology
Jin Soo Lee, MD
Erythropoietin can minimize problems with anemia in cancer patients who receive
radiation either alone or in conjunction with chemotherapy. Its use is not
associated with greater thrombocytopenia or other side effects.
Introduction
Anemia is a common problem in patients with advanced cancer. While
the etiology of anemia in cancer patients is often multifactorial,1 blunted
erythropoietin response to anemia is considered one of the most important contributing
factors in newly diagnosed cancer patients.2 Treatment with chemotherapy or
radiotherapy or both contributes to the magnitude of anemia, which results in decreased
functional capacity and quality of life. Because the efficacy of radiation therapy depends
on adequate tissue oxygenation at the time of irradiation, there is continued interest in
the relationship between anemia and the response to radiation therapy.3-6
In the past, red cell transfusion -- with its associated risks,
inconvenience, and cost -- was the only means to correct anemia. With the advances in
molecular biologic techniques, an erythroid growth factor erythropoietin (EPO) was cloned,
and recombinant human erythropoietin (rHuEpo), an erythroid growth factor, is now
available for clinical use.7 In phase III placebo-controlled trials, EPO has
been shown to increase hemoglobin levels, decrease transfusion requirements, and improve
self-perceived quality-of-life parameters in anemic cancer patients undergoing
chemotherapy.8-11 Taken together with the radiobiologic principle of oxygen as
a critical mediator of ionizing radiation effects, it is postulated that the use of EPO
during radiation therapy may improve the efficacy of radiation therapy.
Early clinical trials have proven that EPO is safe and effective in
alleviating anemia during radiation therapy.12-14 Even if the EPO-induced
alleviation of anemia does not result in improvement of tissue oxygenation and subsequent
enhancement of therapeutic efficacy, subjective improvement in the sense of well being7
may motivate patients to better comply with rigorous treatment approaches such as
concurrent chemoradiation therapy.15
Anemia and Radiation Therapy
Over the past several decades, many investigators have examined the
relationships between anemia and response to radiotherapy. Of 25 articles on this subject
compiled by Dische16 in 1991, 23 reported an adverse influence of anemia on the
outcome of radiotherapy. Although the cutoff value for the definition of anemia was
variable, there was evidence that severe anemia, defined as hemoglobin levels of <10.0
g/dL or the requirement of blood transfusion, was associated with poor local control rates
and shorter survival in patients with uterine cervical cancers and head and neck cancers.
Most studies reported the same poor outcome even in patients with moderate anemia
(hemoglobin levels between 10.0 and 12.0 g/dL) compared with those treated who had higher
hemoglobin levels.16 For example, in a series of 1,055 patients with stage IIB
or III uterine cervical cancer, Bush4 observed that anemia during radiation
therapy was associated with higher local relapse rates but not with distant metastasis
rates (Table 1).
Table 1. -- Effects of Average Hemoglobin Levels During Radiotherapy on Log-Rank Adjusted
Local and Distant Relapse Rates |
| Hemoglobin(g/dL) |
Number of Patients |
Local Relapse Rate |
Distant Relapse Rate |
| <10 |
29 |
0.46 |
0.18 |
| 10 - 11.9 |
319 |
0.29 |
0.24 |
| 12 - 13.9 |
578 |
0.20 |
0.16 |
| >=14 |
129 |
0.20 |
0.18 |
| |
| P value |
0.002 |
0.1 |
| |
| From Bush RS.4 |
Similar findings were reported by others not only in patients with
cervical cancers, but also in patients with head and cancers. In a retrospective study of
386 patients with advanced-stage IIB or III cervical cancers, for example, Girinski et al17
reported that a posttreatment hemoglobin level of <10.0 g/dL, but not the pretreatment
hemoglobin level, was associated with a significantly higher risk of locoregional failure.
Patients with at least one posttreatment hemoglobin value below the threshold of 10.0 g/dL
had 1.8 times more risk of locoregional failure than those with all values above the
threshold. This suggests that even relatively short periods of anemia could significantly
increase the risk of locoregional failure and that hemoglobin levels at the time of
radiation rather than the baseline hemoglobin values are more important to the efficacy of
radiation therapy.
More recently, Tarnawski et al18 correlated hemoglobin
levels before and after radiation therapy with the probability of local tumor control in
847 patients with supraglottic squamous cell carcinomas of the larynx who were treated
with radiation therapy alone. A stepwise logistic regression analysis showed that
hemoglobin level at the end of radiotherapy, but not the pretreatment hemoglobin level,
was the most important prognostic factor for the probability of local control. Other
significant prognostic factors were T stage, overall treatment time, female sex, and age.
The decrease of hemoglobin during therapy was a significant prognostic factor for local
treatment failure, but it was less important than the hemoglobin level at the end of
treatment. Fig 1 shows the observed cure rates according to the hemoglobin level at the
end of treatment and the predicted probability of tumor control. More importantly, for the
clinically observed variability range, hemoglobin level at the end of radiation therapy
had a more pronounced correlation with the probability of tumor control than the overall
treatment time. Although the possibility that posttreatment hemoglobin level might reflect
other yet unidentified prognostic factors cannot be excluded, these findings support the
idea that a correlation exists between the hemoglobin level during radiation therapy and
local tumor control.
Transfusion and Radiation Therapy
Investigators at the Princess Margaret Hospital in Toronto, Canada,
addressed the role of anemia on radiation therapy in a randomized trial in which red blood
cell transfusion was given to a group of patients with stage IIB and III cervical cancers
to keep the hemoglobin levels at 13.5 g/dL or above (treatment group) vs a policy of not
administering transfusions unless the hemoglobin level dropped below 10.0 g/dL (control
group).4,19 In a retrospective analysis of the data, 132 patients who were
prospectively enrolled in the original study19 were divided into four
subgroups: (1) treatment group patients who were anemic (hemoglobin <12.5 g/dL) and
given transfusions to keep hemoglobin > or = 12.5 g/dL, (2) treatment group patients
with hemoglobin > or = 12.5 g/dL who were not given transfusions, (3) control
group patients with hemoglobin > or = 12.5 g/dL who were not given transfusions,
and (4) control group patients who were anemic (hemoglobin <12.5 g/dL) and were given
transfusions only if necessary to keep hemoglobin >10.0 g/dL. The log-rank was adjusted
depending on stage and whether radical treatment was completed or not.4
As shown in Table 2, those patients whose hemoglobin was > or =
12.5 g/dL, either with or without transfusion, had similar local relapse rates (0.15,
0.23, and 0.21) while the control group patients who became anemic (hemoglobin <12.5
g/dL) but were transfused only if necessary to keep hemoglobin at >10.0 g/dL had the
highest local relapse rate of 0.44. The difference between subgroups 1 and 4 was
statistically significant (0.15 vs 0.44, P=0.0076). However, there was no
significant difference in the proportion of patients dying of disease between the
transfusion arm and the control arm of the study (0.35 vs 0.49, P=0.2). Obviously,
the result of this retrospective analysis was not definitive in determining whether
transfusion improves the local relapse rate and consequently survival of stage IIB or III
cervical cancer patients. However, the data are consistent with the thesis that there is a
relationship between the hemoglobin level during treatment and the probability of local
relapse. It is noted that raising the hemoglobin level improved the local control rate to
that of the nonanemic patients.
Table 2. -- Effects of Blood Transfusions on the Log-Rank Adjusted Local Relapse Rate in 132
Patients With Stage IIB or III Cervical Cancer of the Uterus |
| Transfusion Policy* |
Group |
Number of Patients |
Adjusted Local Relapse |
| |
| To keep Hb >=13.5 g/dL |
Hb <12.5 g/dL Transfused |
38 |
0.15 |
| |
| |
Hb> =12.5 g/dL Not transfused |
28 |
0.23 |
| |
| To keep Hb >10.0 g/dL |
Hb >=12.5 g/dL Not transfused |
41 |
0.21 |
| |
| |
Hb <12.5 g/dL Transfused |
25 |
0.44 |
| |
| * From Bush RS, et al.19 |
These results have not resolved the lingering skepticism regarding
the role of anemia in the efficacy of radiation therapy. Anemia might simply reflect the
presence of more advanced substage of cancer or aggressive nonresponsive tumors. Patients
with advanced-stage cervical cancers were found to be more anemic than those with
earlier-stage tumors. Thus, 25%, 33%, and 45% of patients with stage I, II, and III
tumors, respectively, had hemoglobin levels of <12.0 g/dL.19
Although other investigators have undertaken similar studies to
assess the effects of transfusion, no other studies have convincingly demonstrated a
significant improvement in radiation therapy outcome.20 The reason for this
difference is not apparent, but it may in part be explained by immunosuppressive effects
of blood transfusion. This notion is further supported by the results from a randomized
study of autologous vs allogeneic blood transfusion in patients undergoing surgery for
colorectal cancer.21 In this study of 120 patients with potentially curative
resectable colorectal cancer, patients who needed allogeneic blood transfusion had a
significantly higher risk of tumor recurrence compared with those who did not, with a
relative risk of 6.18 (95% confidence interval, 2.20 to 17.37; P<.001). The
other two independent predictors of tumor recurrence were pathological T and N stage with
relative risk (95% confidence interval) of 6.61 (1.82 to 23.99; P=.004) and 8.39
(3.15 to 22.33; P<.001), respectively.21 Based on all available data,
it seems prudent to balance the potential radiosensitizing effects of blood transfusion by
improving oxygen-carrying capacity against the potentially deleterious effects of
allogeneic blood transfusion and to look for an alternative means to improve the
oxygen-carrying capacity during radiation therapy. Autologous blood transfusion is an
alternative but has only limited application in cancer patients with anemia.22
Clinical Use of Erythropoietin During Radiation Therapy
Based on the premise that EPO-induced correction of anemia will
increase tissue oxygenation and thereby improve the efficacy of radiation therapy, three
groups have studied the effects of EPO on anemia during radiation therapy.12-14
All three trials selected the patients with hemoglobin levels below certain cutoff values,
as shown in Table 3. In the first reported open-label phase II randomized trial,
Vijayakumar et al12 evaluated the role of EPO in 26 patients undergoing
intensive radiation therapy with or without chemotherapy for breast, lung, cervix, or
prostate cancer. The study entry criteria included low hemoglobin levels (<13.0 g/dL
for men and <12.0 g/dL for women). Fourteen patients were assigned to treatment with
EPO (200 U/kg per day SC five times a week plus 325 mg of ferrous sulfate PO TID), and 12
patients were assigned to a control group. Mean hemoglobin values at baseline were 10.6
g/dL for the control group and 11.4 g/dL for the EPO group. While hemoglobin concentration
declined by a mean value of 0.035 g/dL per week in the control group, it increased by 0.43
g/dL per week in the EPO-treated group.
Table 3. -- Erythropoietin Trials in Radiation Therapy |
| Characteristics of Study Population |
Vijayakumar12(1993) |
Lavey13(1993) |
Dusenbery14(1994) |
| |
| |
Radiation |
>=4 wks XRT No chemotherapy |
1.8-2 Gy/day x 5-8 wks No chemotherapy |
External beam and intracavitary brachytherapy x 2 |
| |
| |
EPO dose |
200 U/kg x 5 per wk then reduce by 50% |
300 U/kg x 3 then 150 U/kg TIW |
200 U/kg x 10 days then TIW |
| |
| |
Tumor types |
Lung, prostate, breast |
Head/neck, lung, CNS, other |
Uterine, cervical |
| |
| |
EPO patients |
14 |
20 |
15* |
| |
| |
Control patients |
12 |
20 |
5* |
| |
| Entry Hb Criteria (g/dL) |
M: <13 |
<13.5 |
<12.5 |
| |
W: <12 |
|
|
| |
| Mean Hb at Entry (g/dL) |
EPO (14) 11.4 |
EPO (20) 11.9 ± 1.3 |
EPO (15) 10.3 ± 1.04 |
| |
[CTR (12) 10.4] |
[CTR (20) 11.8 ± 1.1] |
[CTR (5) 10.7 ± 1.04] |
| |
| Hb Outcome (g/dL) |
á 0.430/wk |
15.1 ± 2.2 (5 ± 3% per wk) |
13.2 ± 1.7 |
| |
[â 0.035/wk] |
[Stable at 11.8 (0 ± 1% per wk)] |
[10.4 ± 1.8] |
| |
| * Except for one in each group, all patients also received
cisplatin (20 mg/m2 per week). |
In another randomized study, Lavey et al13 evaluated the
effect of EPO in 40 patients with a hemoglobin value of <13.5 g/dL. These patients were
scheduled to receive five to eight weeks of radiotherapy for a malignant tumor located
above the diaphragm without evidence of distant metastasis. Twenty patients received EPO
at 300 U/kg x 3, then 150 U/kg 3 times per week SC beginning 0 to 10 days prior to the
first radiation dose with oral ferrous sulfate. The remaining patients received ferrous
sulfate alone and served as controls. The mean baseline hemoglobin value was 11.9 g/dL and
11.8 g/dL for the EPO and control group, respectively. Compared with only 5% of the
controls, 80% of the EPO-treated patients achieved hemoglobin levels greater than 14 g/dL
during radiation therapy. At the end of radiation therapy, the mean ± SD hemoglobin
levels increased to 15.1 ± 2.2 g/dL in the EPO group while the hemoglobin levels in the
control group remained stable at 11.8 g/dL. No toxicity was associated with EPO use in
this study.
In a third study reported by Dusenbery et al,14 20
patients with surgically staged cervical cancer and anemia (hemoglobin <12.5 g/dL) were
enrolled in a phase I/II study. Fifteen were treated with EPO (200 U/kg per day) and
ferrous sulfate 5 to 10 days prior to initiation of external beam radiation therapy,
continuing until the hemoglobin was > or = 14 g/dL or radiation therapy was completed.
Five were treated with ferrous sulfate alone. An additional 61 historical controls who met
the eligibility criteria were analyzed. Cisplatin was given (20 mg/m2 per week)
as a radiosensitizer in 14 EPO patients and four concurrent control patients. In the EPO
group, the mean ± SD hemoglobin rose by 30% over the course of radiation therapy (from
10.3 ± 1.04 g/dL to 13.2 ± 1.7 g/dL). The average increase in hemoglobin was 0.5 g/dL
per week. The average hemoglobin during radiation therapy was 13.4 g/dL. In the study and
historical controls, mean initial hemoglobin levels were 10.7 ± 1.04 g/dL and 11.1 ± 1.3
g/dL, respectively, which remained unchanged over the course of radiation therapy. Average
hemoglobin levels during radiation therapy were 11.1 g/dL in study controls and 11.4 g/dL
in historical controls, significantly lower than EPO-treated patients (P=0.0001).
From these early trials, it is evident that EPO is both safe and effective in raising
hemoglobin levels in anemic cancer patients receiving radiation therapy with or without
concurrent chemotherapy with cisplatin.
EPO Use During Concurrent Chemoradiation Therapy: M.D. Anderson
Experience
Radiation therapy had been the treatment of choice for locally
advanced inoperable non-small cell lung cancer (NSCLC) until 1990, when Dillman et al23
reported the results of the Cancer and Leukemia Group B 84-33 trial, which showed
improvement in overall survival favoring combined-modality treatment (median survival =
9.7 vs 13.8 months; one-year survival = 40% vs 55%; P=0.007). These results are
confirmed by the Radiation Therapy Oncology Group three-arm study (RTOG 88-08).24
Since 1990, we have investigated the concept of concurrent chemoradiation therapy, using a
cisplatin and oral etoposide regimen, which showed both antitumor effects against NSCLC
and radiosensitizing potential, given concurrently with hyperfractionated radiation
therapy to the chest (1.2 Gy bid/total 69.6 Gy in six weeks). In a multi-institutional
trial of 76 patients (RTOG 91-06),15 we observed a median survival of 18.9
months with one-year and two-year survival rates of 67% and 35%, respectively. For a
subgroup of 56 patients with less than 5% weight loss, the median survival was 21.1 months
with one-year and two-year survival rates of 70% and 42%, respectively. This concurrent
chemoradiation therapy strategy was further explored in subsequent RTOG 92-04 (arm 2)25
and RTOG 94-10 (arm 3) trials with a minor modification of the regimen. To avoid excessive
toxicity, the duration of oral etoposide administration was reduced from 14 days to 10
days given only on the day of radiation therapy over the first two-week period of each
cycle.
In contrast to previous experience with chest radiation alone, the
addition of chemotherapy to chest radiation produced significant anemia in most patients.
Of 18 patients who were enrolled for RTOG 92-04 from our institution, anemia defined as
hemoglobin levels of <12 g/dL in women and <13 g/dL in men was noted in 89% of 18
patients during concurrent chemoradiation. Moreover, the nadir hemoglobin value was less
than 10 g/dL in 7 (39%) of 18 patients after the first course and in 15 (83%) of 18
patients over the entire treatment course (unpublished data). The average drop in
hemoglobin was 4.0 g/dL (range = 2.3 to 7.1 g/dL), and 78% of the patients had a greater
than 3.0 g/dL decrease from the baseline pretherapy value.
With these data as a background, a phase II single-arm trial was
initiated to evaluate the efficacy and safety of EPO in this concurrent chemoradiation
setting (Fig 2). The treatment schedule is basically the same as arm 2 of RTOG 92-04
protocol25 and also arm 3 of the concurrently ongoing RTOG 94-10 protocol. This
trial differed from the other two trials in two aspects: (1) EPO 10,000 U/kg was given
subcutaneously 3 times a week for 12 weeks, and (2) patients with weight loss > or = 5%
were allowed. Also, unlike other EPO trials,12-14 all patients were required to
have a relatively normal hemoglobin level of > or = 12.0 g/dL, and the main study
endpoint was to maintain the hemoglobin levels close to normal using 10 g/dL as a cutoff
value. Less than 10 g/dL hemoglobin means grade II or greater anemia. Initially, we did
not intend to give iron supplements. However, on observing a significant drop in
hemoglobin values in the first four patients, the protocol was revised to give 325 mg of
ferrous sulfate orally three times a day throughout the 12-week period of EPO
administration. This change in iron supplement policy had a dramatic effect on the
magnitude of anemia, as shown in Table 4. To date, 19 patients have been enrolled in this
trial of chemoradiation plus EPO. Hematologic toxicity was evaluated in 16 patients. The
results from these 16 patients are compared with the data obtained from 16 patients who
were enrolled in arm 3 of the RTOG 94-10 protocol, who basically received the same
treatment but without the benefit of EPO and iron supplement. The median hemoglobin value
at study entry was 13.2 g/dL for both groups. With EPO, the nadir hemoglobin value was
significantly higher than without EPO (11.5 g/dL vs 9.5 g/dL) with the median drop in
hemoglobin of 1.5 g/dL vs 3.3 g/dL, favoring the EPO-treated group.26 When the
patients who were given both EPO and iron supplements were analyzed separately, this group
of 12 patients had even better results, as shown in Fig 3. While the baseline hemoglobin
values are basically the same (13.2 g/dL), EPO plus iron supplement significantly reduced
the degree of anemia (median nadir hemoglobin = 11.8 vs 9.5 g/dL; grade II or greater
anemia = 1/12 [8%] vs 9/16 [56%]) and the requirement for blood transfusion (1/12 [8%] vs
6/16 [37.5%]) compared with the patients treated without EPO or iron supplement (RTOG
94-10, arm 3). With EPO alone, median hemoglobin nadir was 9.7 g/dL, and two of four
patients developed grade II or greater anemia, but none received transfusion. No other
significant side effects were noticed. More specifically, EPO did not cause
thrombocytopenia, a toxicity that has been reported when other growth factors such as
GM-CSF were given concurrently with chemoradiation therapy.27 Based on these
preliminary results, we recommend iron supplements in patients receiving EPO, even in the
absence of clinical signs of iron deficiency.
Table 4. -- Effects of EPO on Hemoglobin During Chemoradiation Therapy |
| Variables |
RTOG 94-10 Without EPO |
DM 95-186 With EPO |
| |
| Total number of patients |
16 (9M / 7F) |
16 (11M / 5F) |
| |
| Median hemoglobin (range) |
|
| |
Pretherapy |
13.2 (10.9 - 15.0) |
13.2 (11.9 - 16.l) |
| |
Nadir |
9.5 (6.5 - 13.7) |
11.5 (9.0 - 15.8) |
| |
Difference |
3.3 (1.2 - 7.5) |
1.5 (+0.4 - 5.6) |
| |
| Days to nadir |
42 (21 - 98) |
35 (16 - 79) |
Conclusions
Anemia and anemia-associated tissue hypoxia are critically important
for the efficacy of radiation therapy. The results from prior studies, as well as those
from our ongoing study, indicate that EPO is safe to administer, even with concurrent
chemoradiation therapy, and it also is effective in maintaining the hemoglobin levels
above a threshold level. In addition, it also reduces transfusion requirements and has
improved the self-reported quality-of-life parameters. In the past, blood transfusion has
been considered a useful adjuvant to radiation therapy based on the premise that higher
hemoglobin levels would improve tissue oxygenation and thereby enhance the efficacy of
radiation therapy. However, this premise has not been clinically confirmed. Whether the
EPO-induced effects on hemoglobin and improvement in oxygen-carrying capacity will
translate into improvement in overall efficacy of chemoradiation therapy remains to be
studied in a large, prospectively randomized trial.
Compared with red cell transfusion, EPO provides an opportunity to
assess the role of anemia in radiation therapy without the confounding effect of
transfusion-induced immunosuppression. A prospective, randomized trial of EPO is warranted
in patients undergoing intensive combined chemoradiation therapy for locally advanced
inoperable NSCLCs or stage IIB or III cervical cancers.
References
1. Spivak JL. Cancer-related anemia: its causes and characteristics. Semin Oncol.
1994;21:3-8.
2. Miller CB, Jones RJ, Piantadosi S, et al. Decreased erythropoietin response in
patients with anemia of cancer. N Engl J Med. 1990;322:1689-1692.
3. Newall J. The significance of anaemia in radiotherapy. Clin Radiol. 1967;18:140-145.
4. Bush RS. The significance of anemia in clinical radiation therapy. Int J Radiat
Oncol Biol Phys. 1986;12:2047-2050.
5. Withers RH. Biologic basis of radiation therapy. In: Perez CA, Brady LW, eds. Principles
and Practice of Radiation Oncology. Philadelphia, Pa: JB Lippincott; 1992:64-97.
6. Hellman S. Principles of radiation therapy. In: DeVita VTJ, Hellman S, Rosenberg SA,
eds. Principles and Practice of Oncology. 4th ed. Philadelphia, Pa: JB Lippincott;
1993:248-275.
7. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on
clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in
community oncology practice. J Clin Oncol. 1997;15:1218-1234.
8. Miller CB. The use of erythropoietin in cancer patients. Hematol Oncol Ann. 1994;2:288-296.
9. Abels RI. Use of recombinant human erythropoietin in the treatment of anemia in
patients who have cancer. Semin Oncol. 1992;3:29-35.
10. Case DC, Bukowski RM, Carey RW, et al. Recombinant human erythropoietin for anemic
cancer patients on combination therapy. J Natl Cancer Inst. 1993;85:801-806.
11. Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and
chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. Semin
Oncol. 1994;21:21-28.
12. Vijayakumar S, Roach M 3d, Wara W, et al. Effect of subcutaneous recombinant human
erythropoietin in cancer patients receiving radiotherapy: preliminary results of a
randomized, open-labeled, phase II trial. Int J Radiat Oncol Biol Phys. 1993;26:721-729.
13. Lavey RS, Dempsey WH. Erythropoietin increases hemoglobin in cancer patients during
radiation therapy. Int J Radiat Oncol Biol Phys. 1993;27:1147-1152.
14. Dusenbery KE, McGuire WA, Holt PJ, et al. Erythropoietin increases hemoglobin
during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys. 1994;29:1079-1084.
15. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral
etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer:
radiation therapy oncology group protocol 91-06. J Clin Oncol. 1996;14:1055-1064.
16. Dische S. Radiotherapy and anaemia: the clinical experience. Radiother Oncol. 1991;20(suppl):35-40.
17. Girinski T, Pejovic-Lenfant MH, Bourhis J, et al. Prognostic value of hemoglobin
concentrations and blood transfusions in advanced carcinoma of the cervix treated by
radiation therapy: results of a retrospective study of 386 patients. Int J Radiat Oncol
Biol Phys. 1989;16:37-42.
18. Tarnawski R, Skladowski K, Maciejewski B. Prognostic value of hemoglobin
concentration in radiotherapy for cancer of supraglottic larynx. Int J Radiat Oncol
Biol Phys. 1997;38:1007-1011.
19. Bush RS, Jenkin RDT, Allt WEC, et al. Definitive evidence for hypoxic cells
influencing cure in cancer therapy. Br J Cancer. 1978;37(suppl III):302-306.
20. Levine EA, Vijayakumar S. Blood transfusion in patients receiving radical
radiotherapy: a reappraisal. Onkologie. 1993;16:79-87.
21. Heiss MM, Mempel W, Delanoff C, et al. Blood transfusion-modulated tumor
recurrence: first results of a randomized study of autologous versus allogeneic blood
transfusion in colorectal cancer surgery. J Clin Oncol. 1994;12:1859-1867.
22. Surgenor DM. The patient’s own blood is the safest blood. N Engl J Med
1987;316:542-544.
23. Dillman RO, Seagren SL, Propert KL, et al. A randomized trial of induction
chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell
lung cancer. N Engl J Med. 1990;323: 940-945.
24. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG 88-08)
and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III
trial in regionally advanced, unresectable, non-small cell lung cancer. J Natl Cancer
Inst. 1995;87:198-205.
25. Komaki R, Scott C, Ettinger D, et al. Randomized study of chemotherapy radiation
therapy combinations for favorable patients with locally advanced inoperable nonsmall cell
lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04. Int J Radiat Oncol Biol
Phys. 1997;38:149-155.
26. Lee JS, Touroutoglou N, Komaki R, et al. EPO prevents anemia during concurrent
chemoradiation therapy. Proc Annu Meet Am Soc Clin Oncol. (Submitted). 1998.
27. Bunn PA Jr, Crowley J, Kelly K, et al. Chemoradiotherapy with or without
granulocyte-
macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung
cancer: a prospective phase III randomized study of the Southwest Oncology Group. J
Clin Oncol. 1995;13:1632-1641.
DR HORTON
Was there any difference in the incidence of esophagitis in the
erythropoietin-treated vs the nontreated groups?
DR LEE
Even though overall tolerance in the erythropoietin-treated patients
improved, the rate of esophagitis seemed similar.
DR HORTON
My experience with patients receiving concomitant chemotherapy and
radiation for lung cancer is based on those I see in the inpatient service. Esophagitis
can be severe in these patients. Theoretically, one could argue that erythropoietin should
enhance the vascularity of the normal esophagus as well as of the tumor and therefore you
might be enhancing radiation reaction in the esophagus as well as against the tumor.
DR LEE
That was a concern we had, because when radiosensitizers are used,
normal tissue is radiosensitized as well as the tumor. However, the positive effect of
correcting anemia was so overwhelming that patients would tolerate small increases in
esophagitis or other toxicities.
DR DALTON
When did the anemia occur in these patients with concurrent
chemotherapy and radiation, and when did patients reach their nadir?
DR LEE
The nadir of anemia occurred at a median of approximately 42 days,
during or immediately before the end of treatment with radiation therapy and the second
course of chemotherapy. We usually give a second course of chemotherapy at approximately
day 29, and the nadir occurred about 14 days after the second course.
DR ZUCKERMAN
About 10 years ago at the University of Alabama, we were one of the
largest centers participating in the original study in EPO in renal failure. At that time,
we expected virtually 100% of these patients to respond to EPO. Early in the study, we
learned that a small group did not respond. When we studied the iron studies, we found
that there is a cutoff in a non-iron deficient range of a transferrin saturation of about
20% and of a ferritin level of about 100 below which there is an increased proportion of
people who do not respond optimally to EPO. We began to monitor iron studies closely and
to administer iron to whomever fell below those cutoff numbers.
We also observed an interesting effect regarding erythropoietin
response during the course of that study. In our own group of approximately 45 patients at
the University of Alabama, one developed pancreatitis, one broke her hip, three or four
were admitted to the hospital with pneumonia or sepsis, and six required shunt revisions.
Without exception, these patients shut down erythropoiesis completely despite receiving
stable levels of EPO. As soon as the episode was over, they started responding once again
to the same doses of EPO they were taking before.
DR BENNETT
AIDS-related malignancies provided our first clue that EPO was
beneficial. The endogenous EPO level was clearly related to response. So now there are at
least two models in which the lower the serum EPO level, the more likely a response will
occur.
DR SABA
Since carboplatin has considerable myelotoxicity but cisplatin has
less, why do cisplatin-treated patients develop more anemia, especially without azotemia?
DR BENNETT
Anemia is one of the most common hematopoietic side effects of
cisplatin. In some cases, decreased production of erythropoietin seems to be independent
of renal function, but I think that is anecdotal. About 15 years ago, some reports
suggested that cisplatin could act like a heavy metal and cause a kind of sideroblastic
anemia, but again, that was anecdotal. I do not know if any studies have investigated that
problem.
DR SPIVAK
Two studies suggested that cisplatin may not directly act on the
erythroid progenitor cell. Another study, from Albany, showed that there was a more
substantial effect on the kidney than suspected. You can dissect the endocrine and the
exocrine function of the kidney, especially in diabetics, and show that patients who have
minimal creatinine elevations have lost the relationship between hemoglobin and
erythropoietin. This is an effect that could be missed in clinical biochemical testing.
DR BALDUCCI
It is not commonly known, but a study was done, I believe in Japan,
showing that the DNA adducts caused by cisplatin persisted longer in older people than in
younger people. So there may be some selective toxicity as well.
DR ZUCKERMAN
I am unaware of any studies addressing this, but people who receive
cisplatin develop anemia quickly, too fast to account for it on the basis of even ceasing
all bone marrow function. That indicates that there has to be either hemolysis or a
dilutional effect.
DR SABA
What is the effect of cisplatin on erythropoietin release? My
feeling is that erythropoietin is shut down quickly, followed by a drop in hemoglobin.
DR ZUCKERMAN
It can’t be just a shutdown of erythropoietin; that is a
longer-term effect. As Dr Spivak noted, if you could abolish all erythropoietin activity
today, you would not notice anemia in these people a week from today, based on the
lifespan of the red cell. In 12 days, you would lose only 10% of red cell mass.
DR DALTON
We’re talking about the effects of
chemotherapeutic drugs on red cells in anemia. I’d like to address the converse: the
influence of anemia on the effect of cytotoxic drugs, principally considering their
pharmacokinetics. In an Italian study done in the early 80s with doxorubicin, patients who
were anemic at the time of drug administration had more profound myelosuppression compared
with those who were not anemic. Many drugs do, in fact, bind to red cells. David Alberts
at Arizona showed that mitoxantrone and anthracycline binds significantly to red cells,
which will change the free amount -- the drug-free availability -- and might possibly
increase toxicity. The bottom line is that if you have anemic patients, you might want to
administer transfusions before giving the chemotherapy rather than treating them while
they are profoundly anemic.
From The University of Texas M.D. Anderson Cancer Center.
Address reprint requests to Jin S. Lee, MD, Professor of Medicine,
The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX
77030.
Dr Lee receives grant support from Ortho Biotech, Inc.
Back to Cancer Control Journal Supplement Volume 5 Number 2