ht. 1. Radiotim Oncology Bid. Phys., Vol. 5, pp. 317-322 0364L3016/79/0301-03 17/$02.

00/O
@ Pqpmon Rress Ltd., 1979. Printed in the U.S.A.

0 Original Contribution

HYDROXYUREA OR PLACEBO COMBINED WITH RADIATION TO

TREAT STAGES IIIB AND IV CERVICAL CANCER CONFINED TO
THE PELVISt

MYROSLAW M. HRESHCHYSHYN, M.D.

Professor, Department of Gynecology and Obstetrics, Head, Division of Gynecologic Oncology, State
University of New York at Buffalo, NY 14203, U.S.A.

BERNARD S. ARON, M.D.

Professor of Radiology, Director, Division of Radiation Therapy, University of Cincinnati College of
Medicine, Cincinnati, OH 45267, U.S.A. American Cancer Society, Professor of Clinical Oncology.

RICHARD C. BORONOW, M.D.

Clinical Professor, Department of Obstetrics and Gynecology, University of Mississippi Medical School,
Jackson, MS 39216, U.S.A.

ERNEST W. FRANKLIN, III, M.D.

Director, The Foundation of Gynecologic Oncology, Inc., Atlanta, GA 30342, U.S.A.

HUGH M. SHINGLETON, M.D.

Professor of Gynecology and Assistant Professor of Pathology, University of Alabama Medical Center,
Birmingham, AL 35294, U.S.A.

and

JOHN A. BLESSING, Ph.D.

Group Statistician, Gynecologic Oncology Group, Roswell Park Memorial Institute, Buffalo, NY 14263,
U.S.A.

In a prospective study by the Gynecologic Oncology Group (GOG), 104 evahtable patients with cervical
squamous cell carcinoma Stages RIB and IVA were randomly assigned to treatment with hydroxyurea or
placebo in combination with radiation. There were no deaths resulting from the treatment. Hematologic
toxicity was more common and more severe in patients who received hydroxyurea. Response was evaluated in
terms of complete tumor regression, duration of progression-free interval and survival probability. By all those
parameters the response was significantly better in the groups of patients receiving hydroxyurea.

Carcinoma of the cervix, Hydroxyurea, Radiation.

tparticipating institutions and the National Cancer In-
stitute grants supporting this study: University of Missis-
sippi Medical Center (CA 13633), University of Alabama
Hospitals and Clinics (CA 12484), Emory University School
of Medicine (CA 08121), New York Medical College (CA
12483), University of North Carolina (CA 23073), Uni-
versity of Southern California Medical Center (CA 13641),
Milton S. Hershey School of Medicine of Pennsylvania
State University (CA 16386), University of Colorado Medical
Center (CA 15975), Duke University Medical Center (CA
12534), Wayne State University School of Medicine (CA
12477). George Washington University Medical Center (CA
13446), University of California at Los Angeles (CA 13630),
University of Utah Medical Center,S Brown AfRliated Hos-
317
pitals (Roger Williams Hospital) (CA 12481), Hospital of the
University of Pennsylvania (CA 15977), Roswell Park
Memorial Institute (CA 12535), Walter Reed Army Medical
Center (CA 19189), State University of New York at Buffalo
(CA 12476) and the Gynecologie Oncology Group (CA 10378
and CA 19189).
SSupported in part by the Gynecologic Oncology Group
grant CA 19189.
Reprint requests to: Gynecologic Oncology Group
Headquarters, P.O. Box 60, Philadelphia, PA 19105, U.S.A.
Acknowledgement-The authors gratefully acknowledge
the assistance of the GOG Statistical Office and
Headquarters Office in the preparation of the manuscript.
Accepted for publication 6 October 1978.
318 Radiation Oncology 0 Biology 0 Physics
INTRODUCTION
Patients with advanced cervical cancer have a poor
prognosis when they are treated with radiotherapy
alone, frequently because of failure to control local
disease. Since neither surgery nor conventional
modalities of radiation can be expected to alleviate
this problem, hydroxyurea appeared to be an ap-
propriate agent to potentiate the effect of radio-
therapy.
When it was administered alone hydroxyurea had
an antitumor effect in patients with a variety of
cancers, including squamous cell carcinoma.“.‘2 When
single oral doses of hydroxyurea, were given,
80 mg/kg, maximum serum concentration of the drug
reached within 2 hr and the drug disappeared from
the serum within 24 hr.6 Hematopoietic toxicity was
the dose limiting factor with daily drug adminis-
tration. Lerner and Beckloff’ reported a reduction in
the toxicity without decrease in the antitumor effect
when the drug was administered orally every third day.
In tissue culture studies with Hela cells, Young and
Hodas13 found that hydroxyurea inhibited incor-
poration of thymidine into DNA and suggested that
its action resulted from interference with ribo-
nucleotide (diphosphate) reduction. Sinclair,” worked
with asynchronous cultures of Chinese-hamster lung
cells (V79 line); he found that hydroxyurea damaged
or destroyed the cells during the “S” phase, thus
synchronizing the cells. He also suggested that it may
act as a radiation sensitizer. Phillips and Tolmach’
observed no effect on HeLa S3 cells exposed to
sublethal doses of hydroxyurea prior to irradiation;
however, when the same dose was added to postir-
radiated G, cells, it inhibited the repair processes of
radiation-induced cellular damage.
In a small group of patients with advanced cervical
carcinoma, Hreshchyshyn found the combination of
radiation with hydroxyurea apparently more effective
than radiation alone especially when the disease was
confined clinically to the pelvis.2*3 These results
agreed with those reported for head and neck cancer
treated with radiation and hydroxyurea.’ However,
the relatively small number of patients involved in the
study, and the possible subtle variations in the tumor
extent, radiation dose and other parameters preven-
ted a definitive assessment of this therapeutic ap-
proach; these factors led to the initiation of a ran-
domized prospective study4 by the Gynecologic
Oncology Group (GOG) which is the subject of this
report.
METHODS AND MATERIALS
The study was initiated on 25 June 1970 and was
closed to patient entry on 4 June 1976.
tInternational Federation of Gynecologists and Obstetricians.
March 1979, Volume 5, No. 3
The following patients were eligible for the study:
all those with previously untreated, histologically
confirmed, invasive squamous cell carcinoma of the
uterine cervix clinically (FIGO)‘? Stages IIIb and IVa
(confined to the pelvis) who had not undergone sur-
gical staging. 190 patients were entered into the study
of which 146 were Stage IIIb, 34 were Stage IVa, 5
were Stage IIb (exclusions) and 5 other early
exclusions had no stage specified.
Prestudy evaluation of these patients included:
physical examination, complete blood count and
blood urea nitrogen (BUN), alkaline phosphatase,
urinalysis, intravenous pyelogram (IVP) and chest
X-ray; other studies were optional.
The following patients were excluded from the
study: patients with other than squamous cell car-
cinomas, including mixed squamous and adenocar-
cinema; patients with septicemia or severe infection;
those with severe gastrointestinal symptoms; patients
with impaired hepatic (elevated alkaline phosphatase)
or renal function (BUN greater than 25); and patients
whose circumstances would not permit completion of
the study or the required follow-up.
Hydroxyurea was administered orally at a dosage
of 80 mg/kg of body weight (calculated to the nearest
500 mg) to a maximum dose of 6grams per dose
starting on the first day of irradiation and every 3
days for a period of 12 weeks or at least for the
duration of radiotherapy (Fig. 1).
Patients received at least 5000 rad minimum tumor
dose to the whole pelvis by external radiation if
intracavitary application was planned, or at least
6000 rad minimum tumor dose if intracavitary ap-
plication was not planned. This was delivered at a
rate of 200 rad per day. The dose distribution de-
livered not less than 180 rad per day to the point 7 cm
lateral to the midline of the pelvis in the widest
transverse diameter of the pelvis at the level of the
pelvic brim.
The treatment was to be completed in from 5 to 8
weeks. Brachytherapy was to begin within 2 weeks
of completion of external beam radiation therapy.
Radiation sources employed in this study produced
a peak photon energy of 1 MeV or more, or were 6oCo
units with a source surface difference (SSD) of
80 cm or more. Intracavitary radiation was delivered
by radium, cesium or cobalt sources in standard or
commonly used applicators which provided accept-
able radium dosimetry. The intracavitary dosage was
at least 2000 rad to Point A in one continuous ap-
plication.
External beam verification films and radium dosi-
metry films were obtained. Points of calculation in-
cluded point A and B bilaterally, the points of radia-
 Cervical cancer study with hydroxyurea or placebo with RT 0 M. M. HRESHCHYSHYN et al. 319

Randomize

Hydroxyurea 80 mg/kg q 3 days/12 wks.

+
External Irradiation 5000 rad to pelvis/5-8 wks.
+
Intracavitary Radium 3000 rad to Point A
L

Placebo 80 mg/kg q 3 days/l2 wks.

+
REGIMEN II External Irradiation 5000 rad to pelvis/5-8 wks.
+
Intracavitary Radium 3000 rad to Point A
:

Fig. 1.

Table 1. Patient accession data

No. evaluable
No. No. No. No. evaluable Unable to for survival
Treatment entered ineligible inevaluable for toxicity tolerate RX and PFI

Hydroxyurea 94 10 27 57 6 51
Placebo 96 16 33 47 1 46
- - -
Total 190 26 60 104 7 97

tion in the anterior recta1 and posterior bladder walls. Reactivation of the disease or increased tumor
The Radiologic Physics Center under the sponsorship growth was documented clinically by palpation or by
of the American Association of Physicists and Medi- roentgenolic detection of metastases on two con-
cine supervised dosimetry controls. secutive visits at least 2 weeks apart.
Treatment modifications included the following: All study forms, pathology slides and radiotherapy
Therapy was discontinued temporarily if severe data including verification films of radiation portals
diarrhea, vomiting or skin reactions occurred. If in- (Fig. 1) were submitted to the GOG Central Office
terruptions of more than 21 days occurred, the patient and the Statistical Office. The data was reviewed by
was withheld from analysis. Radiation and drug ad- the appropriate Quality Control Committee as well as
ministration were discontinued when the WBC the Pathology and Radiotherapy Committees. Only
decreased to less than 2500 or the platelets to less entries with full documentation including pathology
than 75,000, and resumed when the WBC and plate- slides and films of radiation portals were analyzed for
lets returned to above 3500 and 150,000, respec- this report.
tively. The administration of androgen or prednisone
to patients whose WBC was less than 2500 cm3 was RESULTS
permitted. Table 1 shows patient accession data. This consists
Both treatments were discontinued in the presence of 94 patients who were treated with radiation and
of severe gastrointestinal symptoms, bleeding or hydroxyurea and 96 patients treated with radiation
severe infection. In no case were the radiation and and placebo. Of this group, 86 patients were ineligible
drug treatments extended beyond the three month or inevaluable; the reasons appear in Tables 2 and 3.
proposed study period. Of 104 patients who were evaluable for toxicity, 97
All patients were examined monthly and preferably were evaluable for progression-free interval (PFI)
weekly for side effects, including hemoglobin, white and survival. 51 of these received hydroxyurea (42
blood count, and platelet counts for the duration of Stage IIIb and 9 Stage IV) and 46 received placebo
radiotherapy and chemotherapy. At the completion of (42 Stage IIIb and 4 Stage IV). There were 90 patients
treatment, the patients were examined with complete evaluable for response.
blood count and BUN, alkaline phosphatase, Table 4 details WBC and platelet toxicity. As
urinalysis, IVP and chest X-ray. expected the bone marrow depression was more
All patients were then followed with examination at common and more severe in patients who received
3 month intervals for up to 5 years. A chest X-ray hydroxyurea. There was significantly more Grades 3
and an IVP were done every 6 months for 2 years and and 4 WBC toxicity in the hydroxyurea regimen
annually thereafter. (p < 0.02). All patients who experienced Grades 3 or 4
320 Radiation Oncology 0 Biology 0 Physics March 1979, Volume 5, No. 3

Table 2. Ineligible patients by treatment toxicity subsequently recovered. Other toxicity, pri-
marily related to radiation, was the same in both
Treatment groups. No patient died as a result of toxicity.
Table 5 presents response in terms of tumor
Reason ineligible Hydroxyurea Placebo Total regression determinable in 90 patients. Complete
tumor regression was observed in 68.1% for
Clerical error 2 0 2
Wrong stage 7 hydroxyurea, compared to 48.8% for placebo: this
4 11
Wrong cell type 3 3 6 difference was statistically significant (p < 0.05).
Recurrent at entry 1 0 1 Survival and duration of progression-free interval
Benign 0 1 1 were significantly different at the 0.05 level between
BUN elevated at entry 0 5 5 the two groups favoring hydroxyurea (Figs. 2 and 3).
- - -
The estimated median survival for all patients who
Total 10 16 26
received hydroxyurea was 19.5 months, while for

Table 3. Inevaluable patients by treatment

Treatment

Reason inevaluable Hydroxyurea Placebo Total

Not double-blinded 1 1 2
Refused treatment 9 11 20
Removed by investigator 2 0 2
Chemotherapy violation 0 2 2
Periaortic nodes irradiated 8 6 14
Improper radiation dose 1 : 2
Excessive duration of radiation 0 3
therapy
Improper field of radiation 2 5 7
Inadequate data 3 1 4
Explored while on protocol 1 2 3
Inadequate pathology materials 0 1 1
- -
Total 27 33 60

Table 4. WBC toxicityt by treatment

Toxicity grade

Life
Treatment None (0) Mild (1) Moderate (2) Severe (3) threatening (4) Total
Hydroxyurea 20 10 20 5 2 57t
Placebo 31 11 5 0 0 47
- - - -
Total 51 21 25 5 2 104

tHematologic toxicity is defined below.

Grade WBC Granulocytes Platelets

None (0) dOO0 ~1500 2 150,ooo

Mild (1) 3ooo-3999 1000-1499 1oo,ooo-149,999
Moderate (2) 2000-2999 500-999 5o,ooo-99,999
Severe (3) 1000-1999 250-499 25,000-49,999
Life- <loo0 <250 <25,000
Threatening (4)

*Of the 57 evaluable patients who received hydroxyurea, 3 had grade 1 platelet toxicity
and 2 had grade 2. Only 1 of 47 evaluable patients who received placebo had platelet toxicity
(grade 2).
 Cervical cancer study with hydroxyurea or placebo with RT 0 M. M. HRESHCHYSHYN et al. 321

Table 5. Response? by therapy

Treatment

Response category Hydroxyurea Placebo Total

No. (%) No. m
Stable disease 1
Partial response 9
Complete response 32
Progression 5 (10.6) 8 (18.6) 13

Total 47 (100.0) 43 (100.0) 90

tThe following is taken from the GOG Protocol Procedures
Manual.
(a) Complete Response is disappearance of all gross evidence of
disease for at least 1 month.
(b) Partial Response is a 50% or greater reduction in the
product obtained from measurement of each lesion for at least 1
month.
(c) Progressive Disease is a 50% or greater increase in the
product from any lesion documented on two separate examinations
at least 2 weeks apart or the appearance of any new lesion within 3
months of entry into study.
(d) Stable Disease is disease not meeting any of the above three
criteria.

those who received placebo it was 10.7 months. The

corresponding estimated durations of PFI were 13.6
and 7.6 months, respectively. Similar differences, also - Hydroxyurea 32151 (4)
significant at the 0.05 level, were observed when ---Placebo 34146 (3)
survival and progression-free interval were compared
by therapy among Stage IIIb patients (Figs. 4 and 5).

DISCUSSION
This study indicates the value of hydroxyurea
combined with radiation compared to radiation alone
in the treatment of patients with Stages IIIb and IVa \
L----
squamous cell carcinoma of the cervix, both in terms
of progression-free interval and patients’ survival. I I I I
12 24 36 4s
The results might have been improved if only patients Monfhsfrom aneefof profoc0l
with advanced disease truly confined to the pelvis had
Fig. 3.

- Hydraxyurea 22/42 (4)

- Hydmxyurea 29/51(4) --- Placeha 26/42 (4)
- -- Placebo 30146 (4)

I I I I I
\ 46 I2 24 3s 4s
Months from onset of protocd Months from onset af profocoI
Fig. 2. Fig. 4.
322 Radiation Oncology 0 Biology 0 Physics March 1979, Volume 5, No. 3

been treated. Approximately one-third of patients

with clinical Stage IIIb and IVa disease might be
- Hydroxyuna 25142 (4) expected to have tumor spread outside the pelvis.’
- - - Placebo 30142 (3) This would render radiation to the pelvis alone rather
ineffective. Thus, the impact of improved local con-
trol within the pelvis was obscured partially by death
from distant disease. Surgical staging was not an
established procedure when this study was initiated
but now,’ in the absence of accurate non-invasive
techniques for determining nodal tumor spread, is
being incorporated into the design of all future
studies involving treatment of primary advanced car-
I I 1 1 cinoma of the uterine cervix. In addition, comparative
12 24 36 48
trial of other potential sensitizers of radiation therapy
Months from onset of protocol
(e.g. Misonidazole or Metronidazole (Flagyl) should
Fig. 5. be considered for future studies.

REFERENCES
1. Gynecologic Oncology Group Protocol 19. Exploratory 8. Report presented by the Cancer Committee to the
Celiotomy for Surgical Staging of Invasive Carcinoma General Assembly of FIGO, New York, April, 1970. H.
of the Cervix, to be published. L. Kottmeier, M.D., Chairman of the Committee. Znt. J.
2. Hreshchyshyn, M.M.: Hydroxyurea with irradiation for Gynecol. Obstet. 9: 172-179, 1971.
cervical carcinoma-preliminary report. Cancer Che- 9. Richards, Jr., G.J., Chambers, R.G.: Hydroxyurea: a
motherapy Rept. 52: 601-602, Sept. 1968. radiosensitizer in the treatment of neoplasms of the
3. Hreshchyshyn, M.M.: Hydroxyurea and radiation in head and neck. Am. J. Roentgen. Radium Ther. Nucl.
advanced cervical carcinoma. Data included in study, Med. 105: 555-565, 1969.
background, to be published. 10. Sinclair, W.K.: Hydroxyurea: differential lethal effects
4. Hreshchyshyn, M.M.: Gynecologic oncology report I on cultured mammalian cells during the cell cycle.
and II. .I. Gynecol. Oncol. 3: 251-257, Sept. 1975. Science 150: 1729-1731, 1965.
5. Lerner, H.J., Beckloff, G.L.: Hydroxyurea administered 11. Sterns, B., Losee, K.A., Bernstein, J.: Hydroxyurea: a
intermittently. J. Am. Med. Assoc. 192: 1168-1170, new type of potential antitumor agent. J. M. Chem. 6:
1%5. 201, March 1%3.
6. Lerner, H.J., Beckloff, G.L., Godwin, M.C.: Hydroxy- 12. Thurman, W.G., Bloedow, C., Howe, C.D., Levin,
urea (NSC-32065) intermittent therapy in malignant W.C., Davis, P., Lane, M., Sullivan, M.P., Griffiths,
diseases. Cancer Chemotherapy Rept. 53: 385-395, K.M.: Phase I study of hydroxyurea. Cancer Chemo-
1%9. therapy Rept. 29: 103-107, 1%3.
7. Phillips, R.A., Tolmach, L.J.: Repair of potentially 13. Young, C.W., Hodas, S.: Hydroxyurea: inhibitory
lethal damage in X-irradiated HeLa cells. Radiat. Res. effects on DNA metabolism. Science 146: 1172-1174,
29: 413432, 1%6. 1964.