Int J Gynecol Cancer 2003, 13, 580586

REVIEW ARTICLE

Chemoradiation: A new approach for the treatment of

cervical cancer
V. LOIZZI*, G. CORMIO*, G. LOVERRO*, L. SELVAGGI*, P. J. DISAIA & F. CAPPUCCINI
*Department of Obstetrics and Gynecology, University of Bari, Bari, Italy; Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of California Irvine Medical Center, Orange, California; and Division of
Gynecology Oncology, Oregon Health & Science University, Portland, Oregon

Abstract. Loizzi V, Cormio G, Loverro G, Selvaggi L, DiSaia PJ,

Cappuccini F. Chemoradiation: A new approach for the treatment of
cervical cancer. Int J Gynecol Cancer 2003;13:580586.
Despite advances in screening, cervical cancer remains a major health
problem worldwide. In an effort to improve loco-regional control, both
neoadjuvant and chemoradiation have been trialed. Recently, five randomized clinical trials performed by the Gynecologic Oncology Group,
the Radiation Therapy Oncology Group and the Southwest Oncology
Group have demonstrated a significant advantage both in progressionfree and overall survival when cisplatin-based chemotherapy was administered during radiation for advanced stages of cervical cancer. Based
on the results of these trials, the US National Cancer Institute released
a Clinical Announcement supporting the concurrent use of cisplatinbased chemotherapy with radiation therapy for high-risk early stage
and locally advanced stage cervical cancer. Subsequently, an additional
prospective randomized trial performed by the National Cancer Institute of Canada was not able to show benefit with the use of chemoradiation compared with radiation alone for patients with locally
advanced stage cervical cancer. This article will analyze these six clinical
trials in order to determine the role of chemoradiation in the management of patients with cervical cancer. Furthermore, as anemia is one of
the most powerful prognostic factors in patients with cervical cancer, we
propose to evaluate the relationship between a decreased level of hemoglobin and treatment outcome.
KEYWORDS:

cervical cancer, chemoradiation, cisplatin.

Cervical cancer remains the third common cancer

affecting women in the world, although it is decreasing in North America and in Europe(1). Yet even in the

Address correspondence and reprint requests to: Fabio Cappuccini,

MD, Division of Gynecologic Oncology, Oregon Health & Science
University, 3181 SW Sam Jackson Park Road, L466, Portland, OR
972013098. Email: cappucci@ohsu.edu

United States and in North America there will be

more than 12,200 new cases in 2003(2), many of them
younger women(3,4). Improvements in prevention,
detection, and treatment are a priority worldwide.
On February 1999, the US National Cancer Institute
released a clinical alert to practicing oncologists based
on research showing significant improvement in
survival when cisplatin-based chemotherapy was
administered during radiation for advantaged stages
# 2003 IGCS

Chemoradiation for cervical cancer

of cervical cancer. This clinical alert outlined the

findings of five clinical trials involving approximately 1800 women; these trials showed a 3050%
improvement in survival when patients with locally
advanced cervical cancer were treated with concomitant chemoradiation(59). Prior studies of various
chemotherapies given before or after radiotherapy
for cervical cancer had not shown any benefit in
survival. An additional sixth randomized trial
performed by the National Cancer Institute of
Canada surprisingly showed no benefit between
chemoradiation compared with radiation alone for
patients with locally advanced stage cervical
cancer(10).
This article will focus on the biologic rationale of
chemoradiation and the results of these six clinical
trials in order to evaluate the role of concurrent chemoradiation in the management of patients with
locally advanced cervical cancer.

Biology of chemoradiation
Radiation therapy and chemotherapy theoretically
should complement each other with different
mechanisms of interaction. These theoretic mechanisms include the simultaneous activity of drug and
radiation in different phases of the cell cycle and
against different tumor cell subpopulations, the
decreased tumor cell repopulation following fractionated radiation, the increased tumor cell recruitment
from G0 phase into a therapy-responsive cell cycle
phase, and inhibition of the repair of sublethal radiation damage(11). Clearly, these are only some of the
possible mechanisms of interaction between chemotherapy and radiotherapy. There are several studies both in vivo and in vitro that have documented
the radiosensitizing property of some chemotherapeutic agents used in cervical cancer chemoradiation
trials such as hydroxyurea, fluorouracil, and cisplatin.
Hydroxyurea is an inhibitor of ribonucleotide
reductase and has been shown to act synergistically
with radiation to synchronize the tumor cells by
inhibiting the entry of cells from the radiosensitive
G1-phase into the radioresistant S-phase. It also has
additive effects with radiation because it has specific
toxicity for S-phase that are considered radioresistant(1214). Furthermore, Phillips et al. showed
the inhibition of the repair of sublethal radiation
damage(15). Hydroxyurea administrated once or
twice per week during external beam irradiation
was included in most of the earliest trials of chemoradiation for cervical cancer(16).

581

5-Fluorouracil (5-FU), a uracil analog, is another

chemotherapeutic agent that has been shown to
enhance radiation cytotoxicity in vitro, probably by
increasing DNA radiation damage and inhibiting
DNA repair(17,18). Subsequent in vivo studies
revealed that the cytotoxicity of radiation markedly
increased with a prolonged exposure time of the
tumor cells to this drug(19,20). In particular, Byfield
et al. showed that in order to achieve radiosensitization, the cells had to be exposed to 5-FU for at least
24 h after the radiation therapy was administered(19).
Diarrhea is the most important dose-limiting toxic
effect of 5-FU and this is a particular concern when
the drug is used in combination with pelvic irradiation. However, close monitoring and the use of field
arrangements that minimize the area of small bowel
in the radiation field may limit this problem in most
patients.
Cisplatin is presently the most active cytotoxic
agent against cervical cancer. Because of this activity
and moderate bone marrow toxicity, cisplatin is the
drug of choice for chemoradiotherapy(21,22). Additional mechanisms of radiosensitizing activity such
as inhibition of the repair of sublethal and potentially
lethal radiation damage and hypoxic cell sensitization
have also been hypothesized(23,24). This drug has also
shown synergy with 5-FU when given concurrently
with radiation in animal models(25). These results
encouraged clinicians to try a variety of cisplatin
schedules, including once every 34 weeks, weekly,
daily, or by continuous infusion, and to explore combinations of cisplatin and 5-FU. The most important
toxicities of these regimens are renal and acute upper
gastrointestinal, although hematologic can also be
limiting. However, because this combination had
increased toxicity and subsequent treatment delays
without improved efficacy, cisplatin is more commonly used as a single agent.

Recent clinical trials

The current practice of treating cervical cancer with
surgery or radiation alone has been challenged by the
recent information from the National Cancer Institute
regarding concurrent chemoradiation for cervical cancer. Results from five randomized phase III trials
showed an overall survival advantage of 30% for
cisplatin-based therapy given concurrently with
radiation therapy. The combined patient population
in these studies included women with FIGO stage
IB2-IVA cervical cancer and women with stage I-IIA
disease with poor prognostic factors at the time of
primary surgery with positive pelvic lymph nodes,
# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

582 V. Loizzi et al.

parametrial disease, or positive surgical margins. The

trials varied in terms of stage of disease, dose of
radiation, and schedule of cisplatin and radiation.
Yet all demonstrated significant survival benefit for
this combined approach. A brief summary of the
recent randomized trials is provided in Table 1.
GOG protocol 85 opened in 1986 and was the first
large randomized trial that included cisplatin-based
concurrent chemotherapy and radiation. Patients with
locally advanced cervical cancer were randomized.
Radiation was combined with both cisplatin and
5-FU or with hydroxyurea. With a median follow-up
of 8.7 years, patients on the cisplatin-containing treatment arm had significantly better progression-free
and overall survival compared with those in the
hydroxyurea treatment arm (P 0.03 and P 0.18,
respectively)(8). Cisplatin was also better tolerated.
Significantly less leukopenia occurred with cisplatin
and 5-FU than that with hydroxyurea. In a subsequent trial (RTOG-9001), patients with stage IB2-IVA
were randomized to receive chemoradiation with cisplatin and 5-FU vs. extended field radiation. This trial
revealed a significant improvement in overall survival
(P 0.0004), disease-free survival (P < 0.001), local
control (P < 0.001), and distant metastasis-free survival (P < 0.001) for patients who received concurrent
chemotherapy. Acute toxicity was more common
with chemoradiation, but the rates of late complications (complications that persisted or occurred more
than 60 days after treatment) were similar. The
median duration of follow-up was 43 months(5). To elucidate the optimal chemoradiation regimen, the GOG
performed a three-arm trial (GOG-120) in patients
with locally advanced cervical cancer comparing
weekly cisplatin vs. cisplatin, 5-FU, and hydroxyurea,
vs. hydroxyurea alone. With a median duration of
follow-up of 35 months, this trial showed an
improved survival for both concurrent cisplatinbased regimens compared with concurrent hydroxyurea alone (P 0.004 for cisplatin alone, P 0.002
for cisplatin-containing regimen). Furthermore, the
toxicity profile of the single agent cisplatin was inferior to the cisplatin-containing regimen(7). In a subsequent trial performed by the Southwest Oncology
Group and GOG (SWOG-8797) patients with stage
IA2-IIA with high risk factors such as nodal metastasis, parametrial extension, or involved margins of
resection following radical hysterectomy, were randomized between radiation therapy with cisplatin and
5-FU vs. radiation alone. This trial differed from the
others in that the administration of the chemotherapy
that was given both concurrently during the radiation
therapy for two cycles and for two cycles after
# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

radiation completion. Women treated with concurrent

chemoradiation showed an improved progressionfree and overall survival compared to women who
received radiation alone (P 0.003 and P 0.007,
respectively) with a median duration of the followup of 42 months. However, grade 3 and 4 hematologic
and gastrointestinal toxicity were more frequent in
the chemoradiaton group(6). In the fifth trial (GOG123), concurrent weekly cisplatin with radiation and
adjuvant hysterectomy was compared with radiation
and adjuvant hysterectomy in patients with stage IB
bulky cervical cancer with negative pelvic and paraaortic lymph nodes. Again, the results of this trial
revealed that women treated with concurrent chemoradiation had an improved progression-free and overall survival compared to those who received radiation
alone (P < 0.001 and P 0.0008, respectively) with a
median duration of follow-up of 36 months(9).
Based on the results of these five experimental
trials, the National Cancer Institute released a clinical
alert to practicing oncologists in February 1999. This
new guideline recommended the incorporation of
concurrent cisplatin-based chemotherapy with radiation for the treatment of cervical cancer. Since that
clinical announcement by the NCI, the Canadian
NCI reported a trial with conflicting results(10). In
this multi-institutional trial, 253 patients with stage
IB and IIA (
5 cm in diameter) and stage IIB-IVA
were randomized to receive radiation with weekly
cisplatin at a dose of 40 mg/m2 vs. radiation therapy
alone. The median follow-up time was 82 months.
The 3- and 5-year survival were not significantly different although all slightly favored the chemoradiation group (69% vs. 66%, 62% vs. 58%, respectively,
P 0.42).
The results of this trial seem on the surface irreconcilable with the positive results of the five previous
trials. The Canadian study was, as the previous five
trials, a randomized and multi-institutional trial
where appropriate doses and schedules of cisplatin
and radiation therapy were used. However, in contrast with four of the five previously reported trials,
the Canadian study did not use surgical staging but
computer tomographic scans to identify and exclude
patients with para-aortic nodal metastasis. Since computer tomography has demonstrated a sensitivity of
only 34% for para-aortic nodal metastasis in patients
with cervical cancer(26), this is a major difference of
this trial. Since para-aortic metastasis occurs in 21% of
stage IIB and in 31% of stage III patients, there should
be a number of patients in the Canadian study with
undiagnosed metastasis in the para-aortic region.
Inclusion of patients with unrecognized para-aortic

10

1991-1996

1992-1997

1992-1996

1992-1997

1990-1997

1986-1990

Accrual Period

127
126

(IIA >5 cm)

186

183

116

176
127

177
173

193

191
195

177

Pts

IB2-IVA

IB bulky

RH with positive
pelvic lymph nodes
or parametria or
margins

IA2, IB, IIA after

IIB-IVA

IIB-IVA or IB,IIA
with tumor >5 cm
or pos pelvic
lymph nodes

IIB-IVA

FIGO Stage

EB and intracavitary radiation with weekly cisplatin

(40 mg/m2) followed by extrafascial hysterectomy
EB and intracavitary radiation followed by extrafascial
hysterectomy
EB and intracavitary radiation with weekly cisplatin
(40 mg/m2)
EB and intracavitary radiation

EB and intracavitary radiation with weekly cisplatin (40 mg/m2)

EB and intracavitary radiation with ciplatin (50 mg/m2),
5-FU (4000 mg/m2) and hydroxyurea (2 mg/ m2)
EB and intracavitary radiation with hydroxyurea (3 mg/ m2)
EB radiation therapy with cisplatin (70 mg/m2) and 5-FU
(4000 mg/m2) infusion
EB radiation therapy

EB and intracavitary radiation with 5-FU

(1000 mg/m2) infusion and CDDP (50 mg/m2)
EB and intracavitary radiation with hydroxyurea (80 mg/kg)
EB and intracavitary radiation with 5-FU (4000 mg/m2)
infusion and CDDP (75 mg/m2)
Extended-field EB (pelvis and para-aortic) and intracavitary
radiation therapy

Regimen

EB External-beam; CDDP Cisplatin; 5-FU 5-Fluorouracil; HT Hematologic; GI Gastrointestinal; RH=Radical Hysterectomy

NCIC

GOG-1239

SWOG-8797

GOG-120

RTOG-9001

GOG-85

Trial

Table 1. Results of six randomized trails.

62%

69%

74%

83%

77%

47%
87%

65%
65%

63%

57%
76%

67%

3-Year Survival

8%

2%

20%

2%

23%
33%

22%
48%

1%

24%
37%

4%

HT

9%

5%

5%

14%

10%

8%
36%

7%
10%

1%

4%
8%

8%

GI

Toxicity (grade 34)

Chemoradiation for cervical cancer

583

# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

584 V. Loizzi et al.

metastasis could have blunted the effect of chemoradiation. Another major difference in this study was
the presence of anemia among the cisplatin-treated
patients. The authors reported a greater decrease of
hemoglobin level during chemoradiation compared
with radiation alone. More specifically, 31% of
patients in the chemoradiation group experienced a
decrease of hemoglobin of more than 15 g/l compared
with only 20% in the radiation group (P 0.003).
Based on the data reported by Grogan et al. on the
relationship of decreasing hemoglobin on overall survival, during radiation therapy, this difference could
have accounted for as much as an 8% reduction in
survival in the chemoradiation group of the Canadian
study(27). Similarly, other authors demonstrated that
local failure after chemoradiation for cervical cancer
was significantly more likely in patients with
hemoglobin values that dropped during treatment,
whereas anemia at presentation was not prognostically significant. As the level of hemoglobin is highly
predictive of response to treatment(2831), this supports greater attention to hemoglobin levels during
radiation therapy.

Chemoradiation-associated anemia
Although anemia is a frequent cancer treatment
related finding, recent studies have focused on its
impact rather than its prevalence among patients
undergoing radiotherapy. For patients with cervical
cancer, the use of both radiation and cisplatin chemotherapy increases the risk of anemia during treatment over radiation alone. As noted before, anemia
is one of the most powerful prognostic factors in
patients with cervical cancer. The relationship
between anemia and treatment outcome is hypothesized to represent an increase in the hypoxic cell fraction of the tumor, a consequence of the anemia, and is
associated with a lowered degree of radiosensitivity(3234). Thus, improving the efficacy of radiation
therapy by controlling anemia and tumor hypoxia
could lead to better locoregional response and prolonged survival. Recent studies have investigated
strategies that reduce anemia and tumor hypoxia
such as transfusions and recombinant human erythropoietin (rh-EPO). Although transfusion is an effective
method of raising hemoglobin levels during chemoradiation, it is used cautiously in the treatment of
moderate (8.010.0 g/dl) and mild (10.0 g/dl to just
to below normal limits) anemia, because of the risks
associated with exposure to allergenic blood products. These risks include acute and chronic reactions,
# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

viral infections, and the possibility of increased tumor

recurrence due to transfusion induced immunosuppression(35). Furthermore, blood transfusions increase
the blood hemoglobin level immediately but only for
a short time. Therefore, multiple transfusions may be
required throughout a treatment program that can
last 56 weeks.
Recently, rh-EPO has been evaluated as an alternative to transfusion in raising the hemoglobin level
of patients with cervical cancer treated with
radical radiation with or without concurrent chemotherapy(36). Rh-EPO is the recombinant form of
the principal hormone responsible for erythrogenesis,
erythropoietin, and acts by stimulating the proliferation of committed erythroid progenitor cells and
effecting their differentiation into morphologically
recognizable normoblasts, thereby increasing hematocrit. A meta-analysis of all randomized studies of
patients with cancer in which rh-EPO was injected
subcutaneously, showed that rh-EPO reduced the
odds of transfusion by a factor of 0.38 compared
with patients managed without rh-EPO(37). However,
evidence is insufficient to determine whether
initiating rh-EPO earlier spares more patients
from transfusion than waiting until the hemoglobin
concentration declines to nearly 10 g/dl. The most
robust evidence that rh-EPO reduces the risk of
transfusion comes from trials in a group of patients
with the mean baseline hemoglobin concentration
of greater than 10 g/dl compared to trials in which
the mean hemoglobin concentration was 10 g/dl
or less(38,39) The use of rh-EPO has been evaluated
in the treatment of patients undergoing radiotherapy. Data from a recent study showed that
rh-EPO safely stimulates autologous hematopoiesis
and rapidly corrects decreased hemoglobin levels in
most patients undergoing radiotherapy; in addition, it
improves the efficacy of radiotherapy(40). Dusenbery
et al. on a series of 15 patients who received rh-EPO
during extended field radiotherapy and concurrent
cisplatin chemotherapy, found that the hemoglobin
level was raised by an average of 5 g/l/week. All
patients were treated with 200 U/kg/day of rh-EPO
subcutaneously(36).
No large randomized study has determined
whether raising hemoglobin can overcome the poor
prognosis associated with low presenting hemoglobin. To evaluate the significance of anemia and the
potential anemia protective effect of rh-EPO in
patients with primary invasive stage IIB-IV cervical
cancer, the GOG, in protocol number 191, is presently
evaluating radiation with weekly cisplatin with or
without rh-EPO.

Chemoradiation for cervical cancer

Summary
For many years, clinicians tried to combine chemotherapy with radiation. Most of the early prospective trials involving the use of neoadjuvant
chemotherapy followed by radiation failed to show
any benefit in survival. More recently, several
multi-institutional groups have explored the use of
concomitant chemotherapy with radiation and found
that some drugs may sensitize tumor cells to the
effects of radiation. Based on the results of these trials,
the use of ciplatin-based chemotherapy concurrently
with radiation therapy has became the new standard
of treatment for patients with locally advanced cervical cancer and for patients with early stage disease
with poor prognostic factors. Although the NCIC
study failed to demonstrate significant differences in
progression-free and overall survival, all outcomes
slightly favored cisplatin chemoradiation. The potential inclusion of para-aortic nodes positive patients
and the significant difference in anemia raises question about this trial results. Thus, strong consideration
should be given to the incorporation of concurrent
cisplatin-based chemotherapy with radiation in
women who require radiation therapy for treatment
of cervical cancer. Additionally, managing anemia
with an approach that minimizes risk to the patient
and reduces undesirable side effects, may hold the
key to further improvements in survival for advanced
cervical cancer patients. Additional studies are
needed to address the relationship between anemia
and tumor/tissue hypoxia and the role of erythropoietin receptor on treatment outcome. Prospective
data must be obtained prior to proposing any recommendations in this clinical setting.

7
8

10

11
12
13
14
15
16
17
18

19

References
1 Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA
Cancer J Clin 1999;49:3364. 1.
2 American Cancer Society. Cancer Facts & Figures, 2003.
3 Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:831. 1.
4 Duenas-Gonzalez, C. Lopez-Graniel, A. Gonzalez-Enciso
et al. Concomitant chemoradiation versus neoadjuvant
chemotherapy in locally advanced cervical carcinoma:
results from two consecutive phase II studies. Ann Oncol
2002;13:12129.
5 Morris M, Eifel PJ, Lu J et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high-risk cervical cancer. N Engl J
Med 1999;340:113743.
6 Peters WA. 3rd, Liu PY, Barrett RJ, 2nd et al. Concurrent
chemotherapy and pelvic radiation therapy compared
with pelvic radiation therapy alone as adjuvant therapy

20
21
22
23
24

585

after radical surgery in high-risk early-stage cancer of

the cervix. J Clin Oncol 2000;18:160613.
Rose PG, Bundy BN, Watkins EB et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced
cervical cancer. N Engl J Med 1999;340:114453.
Whitney CW, Sause W, Bundy BN et al. Randomized
comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA
carcinoma of the cervix with negative para-aortic lymph
nodes: a Gynecologic Oncology Group and Southwest
Oncology Group study. J Clin Oncol 1999;17:133948.
Keys HM, Bundy BN, Stehman FB et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB
cervical carcinoma. N Engl J Med 1999;340:115461.
Pearcey R, Brundage M, Drouin P et al. Phase III trial
comparing radical radiotherapy with and without cisplatin
chemotherapy in patients with advanced squamous cell
cancer of the cervix. J Clin Oncol 2002; 20:96672.
Vokes EE, Weichselbaum RR. Concomitant chemoradiotherapy rationale and clinical experience in patients
with solid tumors. J Clin Oncol 1990;8:91134.
Sinclair WK. Hydroxyurea effects on Chinese hamster
cells grown in culture. Cancer Res 1967;27:297308.
Sinclair WK. The combined effect of hydroxyurea and
x-rays on Chinese hamster cells in vitro. Cancer Res
1968;28:198206.
Piver MS, Howes AE, Suit HD, Marshall N. Effect of
hydroxyurea on the radiation response of C3H mouse
mammary tumors. Cancer 1972;29:40712.
Phillips RA, Tolmach LJ. Repair of potentially lethal damage
in x-irradiated HeLa cells. Radiat Res 1966;29:41332.
Piver MS, Barlow JJ, Vongtama V, Webester J. Hydroxyurea and radiation therapy in advanced cervical cancer.
Am J Obstet Gynecol 1974;120:96972.
Vietti T, Eggerding F, Valeriote F. Combined effect of
x radiation and 5-fluorouracil on survival of transplanted leukemic cells. J Natl Cancer Inst 1971;47:86570.
Berry R. Effetcs of some metabolic inhibitors on x-ray
doseresponse curves for the survival of mammalian
cells in vitro, and on early recovery between fractionated
x-ray doses. Br J Radiol 1966;39:45863.
Byfield JE, Calabro-Jones P, Klisak I, Kulhanian F.
Pharmacologic requirements for obtaining sensitization
of human tumor cells in vitro to combined 5-Fluorouracil
or ftorafur and X rays. Int J Radiat Oncol Biol Phys
1982;8:192333.
Grem JL. Mechanisms of action and modulation of
fluorouracil. Semin Radiat Oncol 1997;7:24959.
Nias AH. Radiation and platinum drug interaction. Int J
Radiat Biol Relat Stud Phys Chem Med 1985;48:297314.
Dewit L. Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and
clinical data. Int J Radiat Oncol Biol Phys 1987;13:40326.
Carde P, Laval F. Effect of cis-dichlorodiammine platinum II and X rays on mammalian cell survival. Int J
Radiat Oncol Biol Phys 1981;7:92933.
Kallman RF, Rapacchietta D, Zaghloul MS. Scheduledependent therapeutic gain from the combination of
fractionated irradiation plus c-DDP and 5-FU or plus
c-DDP and cyclophosphamide in C3H/Km mouse
model systems. Int J Radiat Oncol Biol Phys 1991;20:22732.

# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

586 V. Loizzi et al.

25 Dionet C, Verrelle P. Curability of mouse L1210 leukemia

by combination of 5-fluorouracil, cis-diamminedichloroplatinum (II), and low doses of gamma-rays. Cancer Res
1984;44:6526.
26 Heller PB, Maletano JH, Bundy BN, Barnhill DR,
Okagaki T. Clinical-pathologic study of stage IIB III, and
IVA carcinoma of the cervix: extended diagnostic evaluation for paraaortic node metastasis a Gynecologic
Oncology Group study. Gynecol Oncol 1990;38:42530.
27 Grogan M, Thomas GM, Melamed I et al. The importance
of hemoglobin levels during radiotherapy for carcinoma
of the cervix. Cancer 1999;86:152836.
28 Obermair A, Cheuk R. Horwood K et al. Impact of hemoglobin levels before and during concurrent chemoradiotherapy
on the response of treatment in patients with cervical
carcinoma. preliminary results. Cancer 2001;92:9038.
29 Werner-Wasik M, Schmid CH, Bornstein L, Ball HG,
Smith DM, Madoc-Jones H. Prognostic factors for local
and distant recurrence in stage I and II cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:130917.
30 Hong JH, Chen MS, Lin FJ, Tang SG. Prognostic assessment of tumor regression after external irradiation for
cervical cancer. Int J Radiat Oncol Biol Phys 1992;22:9137.
31 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;16:3742.
32 Nordsmark M, Overgaard M, Overgaard J. Pretreatment
oxygenation predicts radiation response in advanced
squamous cell carcinoma of the head and neck. Radiother
Oncol 1996;41:319.
33 Hockel M, Schlenger K, Hockel S, Vaupel P. Hypoxic
cervical cancers with low apoptotic index are highly
aggressive. Cancer Res 1999;59:45258.
34 Henke M, Bechtold C, Momm F, Dorr W, Guttenberger R.
Blood hemoglobin level may affect radiosensitivity-

# 2003 IGCS, International Journal of Gynecological Cancer 13, 580586

35

35

36

37

38

39

40

preliminary results on acutely reacting normal tissues.

Int J Radiat Oncol Biol Phys 2000;48:33945.
Henke M. Correction of cancer anemia impact on disease course, prognosis and treatment efficacy, particularly for patients undergoing radiotherapy. Onkologie
2001;24:4504.
Seidenfeld J, Piper M, Flamm C et al. Epoetin treatment
of anemia associated with cancer therapy: a systematic
review and meta-analysis of controlled clinical trials.
J Natl Cancer Inst 2001;93:120414.
Dusenbery KE, McGuire WA, Holt PJ et al. Erythropoietin increases hemoglobin during radiation therapy
for cervical cancer. Int J Radiat Oncol Biol Phys 1994;
29:107984.
Seidenfeld J, Piper M, Flamm C, et al. Epoetin treatment
of anemia associated with cancer therapy: a systematic
review and meta-analysis of controlled clinical trials. J
Natl Cancer Inst 2001;93:120414.
ten Bokkel Huinink WW, de Swart CA, van Toorn DW,
et al. Controlled multicentre study of the influence of
subcutaneous recombinant human erythropoietin on
anaemia and transfusion dependency in patients with
ovarian carcinoma treated with platinum-based chemotherapy. Med Oncol 1998:15:17482.
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E,
Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving
nonplatinum chemotherapy: results of randomized,
double-blind, placebo-controlled trial. J Clin Oncol
2001;19:286574.
Henke M, Guttenberger R, Barke A, Pajonk F, Potter R,
Frommhold H. Erythropoietin for patients undergoing
radiotherapy: a pilot study. Radiother Oncol
1999;50:18590.

Accepted for publication May 20, 2003.