Acute leukemia following chlorambucil therapy of advanced ovarian and fallopian tube carcinoma
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Transcript of Acute leukemia following chlorambucil therapy of advanced ovarian and fallopian tube carcinoma
GYNECOLOGIC ONCOLOGY 6, 115-120 (1978)
CASE REPORT
Acute Leukemia following Chlorambucil Therapy of Advanced Ovarian and Fallopian Tube Carcinoma’
JOHN MORRISON, LCDR, MC USN,* AND JOSEPH L. YON, CAPT, MC USNtx2
*Department of Internal Medicine, Hematology-Oncology Branch, and TDirector, Division of Gynecologic-Oncology, Naval Regional Medical Center, San Diego,
California 92 134
Received May 9, 1977
Acute leukemia developed in two patients, one with advanced ovarian carcinoma and the other with advanced carcinoma of the fallopian tubes. Both patients received chlorambucil as a part of their treatment regimen. The literature is reviewed and updated since the report of Sotrel et a/. [O&et. Gynecol. 47, No. I (Suppl.), 67s-71s (1976)], and a rationale for the use of high-dose intermittent chlorambucil therapy in the treatment of ovarian carcinoma is presented for consideration.
In a recent report, Sotrel el al. [I] summarized the nine known cases of acute leukemia occurring after chemotherapy of advanced ovarian carcinoma. Since that report, four additional cases have occurred; two of these have been reported elsewhere [21, and the remaining two are reported herein. Pertinent aspects of the cases are shown in Table I.
Case I CASE REPORTS
A 47-year-old Caucasian female was seen in consultation by the Hematology Department in July 1974 for pancytopenia. Past medical history and examination of medical records showed that she underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy in December 1972 for Stage III ovarian carcinoma. At the time of surgery, a papillary cystadenocarcinoma of the right ovary invading the right meso-ovarium was found. Postoperatively, she received 3000 rad (cobalt-60) to the midplane of the abdomen and 5000 rad to the midplane of the pelvis. X-ray therapy was completed in February 1973. In May 1973, chlorambucil therapy was begun at a dose of 2 mg po daily and continued at this dose level until July 1973, when the dose was reduced to 2 mg po qod. In August
I The opinions or assertions expressed herein are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the naval service at large.
E Address reprint requests to Joseph L. Yon, CAPT, MC USN, Director, Division of Gynecologic-Oncology, Naval Regional Medical Center, San Diego, California 92134.
0090-8258/78/0061-01 ISSOl .00/O Copyright @ 1978 by Academic Press. Inc.
All rights of reproduction in any form reserved.
TABL
E I
REPO
RTED
CA
SES
OF
ACUT
E LE
UKEM
IA
AFTE
R CH
EMOT
HERA
PY
FOR
OVAR
IAN
CARC
INOM
A,
1976
-1977
Inter
val
from
Do
se
of pr
imar
y to
PlW.e”
Ce
Leng
th of
chem
o-
seco
ndary
Su
rviva
l tim
e Ca
se
Initia
l of
prim
ary
chem
othera
py
therap
y Ty
w
of m
align
ancy
aft
er
diagn
osis
tum
or
on r
e-
num
ber
Refer
ence
Ag
e m
align
ancy
Tr
eatm
ent
(mon
ths)
(mg)
leu
kem
ia (ye
ars)
(mon
ths)
eXplO
Mi0”
IO
2 39
Ov
aria”
Su
rger
y, 30
IO
-12
Eryth
ro-
4 7
Not
report
ed
carci
nom
a, ch
loram
bucil
daily
leuke
mia
stage
III
II
2 62
Po
orly
differ
entia
ted
Surg
ery,
50
6 da
ily Er
ythra
- 4
2 No
t rep
orted
ad
enoc
arcino
ma,
4ooo
rad
leuke
mia
right
“va
ry to
pelvis
, ch
loram
bucil
Pres
ent
- 47
Pa
pillar
y Su
rger
y, 4
7-w
Acute
2.7
5 IO
Ye
s (a
t po
st-
case
I
CYSt%
k”O-
8MlO
rad
, da
ily x
3 “ly
elo-
(No.
12)
mor
tem
) ca
rcino
ma,
chlor
ambu
cil m
onths
; 2
cytic
sta
ge
III
@
x leu
kem
ia I
mon
th Pr
esen
t -
45
Papil
lary
Surg
ery,
I9 16
PO Ac
ute
2.5
Still
living
No
(on
ca
se
2 alV
eOlW
ch
loram
bucil
daily
x un
differ
entia
ted
(No.
13)
in re
miss
ion
seco
nd
look)
aden
ocarc
inoma
2
mon
ths;
8 leu
kem
ia of
fallop
ian
po
daily
tubes
, x
17 m
onths
sta
ge
III
CANCER CHEMOTHERAPY AND ACUTE LEUKEMIA 117
1973, therapy was discontinued because of leukopenia. A bone marrow examina- tion was performed at the time of initial consultation in July 1974. The marrow was markedly damaged and hypocellular without any evidence of leukemia or lym- phoma.
The patient was next seen on September 17, 1974, when she was hospitalized with a 2-week history of fever, “cold sores” on the lower lip, and ulcerations of the uvula and the soft palate. Initial CBC showed a leukocyte count of 37,000/mm3 with 6% blast forms, 32% atypical monocytoid forms, 18% polymorphonuclear leukocytes, 22% band forms, and 22% lymphocytes, a platelet count of 61 ,OOO/ mm3, and a Hct of 24%. Repeat bone marrow examination revealed a hypercellular marrow with 50% blasts, some of which contained Auer rods. A diagnosis of acute granulocytic leukemia was made, and she was started on chemotherapy with 6-thioguanine and Ara-C. After a stormy course complicated by sepsis, she was discharged in November 1974, in complete remis- sion.
Relapse of the leukemic process occurred in February 1975. Weekly pulses of cyclophosphamide, Ara-C, and methotrexate again resulted in complete remission of the leukemic process. This time, however, the course was complicated by sepsis with Escherichia coli and Klehsiella. The patient was finally discharged on April 29, 1975.
The last admission, for gastrointestinal bleeding and progressive abdominal distention, occurred on May 22, 1975. The patient expired on May 27, 1975. At postmortem examination, the pathologic findings were: metastatic adenocar- cinema to the liver, abdominal soft tissue and hilar lymph nodes, bilateral pleural effusions, and multiple abdominal adhesions with functional bowel obstruction. A bone marrow examination revealed 8% blast forms.
Case 2
A 42-year-old G,P,A, Caucasian female was admitted to the hospital in May 1974, with the clinical impression of bilaterial adnexal masses. Exploratory celiotomy revealed a 7-cm left adnexal mass and a 6-cm right adnexal mass. Frozen section revealed adenocarcinoma. A total abdominal hysterectomy, bilat- eral salpingo-oophorectomy, open biopsy of the sigmoid colon, biopsy of the retroperitoneal para-aortic nodes, and sigmoid colostomy were performed.
The pathologic report showed papillary alveolar adenocarcinoma of the fallopian tubes with metastasis to the ovary and retroperitoneal nodes. The colon wall showed endometriosis. Peritoneal washings were positive for malignancy.
Postoperatively, in May 1974, the patient was begun on continuous chemotherapy with chlorambucil, 16 mg po daily. This was continued until July 1974. At this time, an uneventful reanastomosis of the sigmoid colon was per- formed. The patient was again placed on chlorambucil at a dose of 8 mg po daily, and she continued chemotherapy until December 1975. She did not become overly suppressed hematologically during this period and did not discontinue chemotherapy.
A second-look operation was performed in January 1976. Cell washings and multiple biopsies failed to reveal any evidence of tumor persistence. Chemotherapy was discontinued.
118 MORRISON AND YON
The patient did well until February 1977, when she presented to the Gynecologic Oncology Outpatient Clinic with a 2-month history of malaise, a 3-week history of fever and pain over the right maxillary sinus, and a five-day history of petechial lesions over the trunk and lower extremities. A routine blood count showed a leukocyte count of 82,00O/mm”, hematocrit of 30%, and platelet count of 19,00O/mm”. Peripheral smear revealed 80% of the leukocytes to be blast forms, and the patient was admitted to the hospital.
The admission physical examination was normal with the following exceptions: T = 100(O); gums around both upper and lower molars bilaterally swollen with purplish discoloration; tenderness over the right maxillary sinus; and petechial lesions of the trunk, buttocks, and upper and lower extremities. Bone marrow examination revealed a hypercellular marrow with 80% blast forms which failed to stain with Sudan Black B or with periodic acid-Schiff. A diagnosis of acute undifferentiated leukemia was made, and the patient was treated with Doxorubi- tin and Ara-C. A complete remission was achieved, and the patient is currently doing well as an outpatient in complete remission.
DISCUSSION
The oncogenic properties of X-ray therapy and of many commonly used chemotherapeutic agents have been well shown experimentally, but extrapolation of these data to human cases has been more difficult. At the present time, the role of these agents as inducers of secondary malignancy in humans is strongly suspect [3-51 but not proven.
Reports of acute leukemia complicating the course of advanced ovarian car- cinoma continue to accrue. In all of the cases reported to date [I, 2, 6-91 chemotherapy has been a part of the treatment regime; in one of our cases and in two others in the literature [6,9] X-ray therapy was also administered. Even more disturbing is the observation that in five of these cases [ 1,6,7,93, including one of our cases, complete eradication of the primary malignancy was achieved with the chemotherapy employed.
Since the last six patients reported in the literature (our cases included) have received continuous therapy with chlorambucil prior to the development of their leukemia, it may be advantageous in future cases to place these patients on a high-dose intermittent chlorambucil regime similar to the high-dose intermittent phenylalanine mustard regime used to treat myeloma and ovarian carcinoma. One regime used in the treatment of chronic lymphocytic leukemia employs chloram- bucil in doses of 0.4-0.5 mg/kg body weight as a single po dose which is repeated at 2-week intervals [IO].
Such a dose schedule, if effective, would offer the patient a possible advantage. It would allow time for recovery of both cellular and humoral immune function which had been suppressed by the agent employed and would allow the “rebound-overshoot” phenomenon of immune recovery to occur [ 111. The latter phenomenon has been associated with a good response of solid tumors to the chemotherapeutic agent employed [ 111. Moreover, it has been suggested that with continuous chemotherapy, one runs the risk of suppressing those elements of the immune response necessary for tumor destruction [12, 131.
CANCER CHEMOTHERAPY AND ACUTE LEUKEMIA 119
At present, the optimal length of time to achieve a chemotherapeutic cure of advanced ovarian carcinoma is unknown. The length of time may vary and may depend on the type of chemotherapeutic agent or agents employed, the dose of the drug used, and the timing of drug administration. It is apparent that answers to the above questions will be forthcoming only through the use of prospective, con- trolled trials employing judicious use of ultrasound, peritoneoscopy, and, if neces- saw , “second-look” procedures.
ADDENDUM: CASE REPORT
We have recently encountered a case of di Guglielmo’s syndrome in a 56-year- old Caucasian female successfully treated with high-dose pulse phenylalanine mustard (Alkeran) therapy for Stage III serous cystadenocarcinoma of the ovaries.
The patient, a G,P,A, female with LMP in 1967, presented in February 1975 with abdominal bloating and superficial thrombophlebitis of the right leg. At the time of her surgery in April 1975, 2 liters of abdominal ascitic fluid and serous cystadenocarcinoma of both ovaries with studding of the small bowel and omen- turn was found. After a total abdominal hysterectomy, bilateral salpingo- oophorectomy, and omentectomy, the patient was begun on high-dose pulse Alkeran therapy. Therapy consisted of 30-46 mg of Alkeran taken over a 2-day period, with repeat courses every 3 to 4 weeks. Between May 1975 and November 1976, the patient received 14 courses of chemotherapy, with no evidence of tumor recurrence. The patient received no chemotherapy after November 1976 because of persistent pancytopenia.
Hematologic consultation was obtained in May 1977 because of a slowly falling hematocrit in the absence of bleeding or hemolysis. At this time, a Hemogram revealed an RBC count of 2.41 million/mm3, hemoglobin of 6.5g %, hematocrit of 20. I%, MCV of 83 pm”, platelets of 82,000/mm3, reticulocyte count of 0.6%, and WBC of 3200/mm” with 39 polymorphonuclear leukocytes, 56 lymphocytes, 3 monocytes, and 1 myelocyte/lOO white cells. Peripheral smear showed a dual population of cells; one was normochromic, normocytic and the other hypo- chromic, microcytic. Peripheral smear also showed severe anisocytosis and poikilocytosis, nucleated red blood cells, and target cells; granulocytes were decreased with an absolute count of 1248/mm” and occasional myelocytes were noted; and platelets were decreased with numerous large bizarre forms. Bone marrow examination revealed a fat to cell ratio of 5 to 95, a myeloid to erythroid ratio of less than 1 to 10, and a hypercellular bone marrow with markedly increased, severely dysplastic erythropoiesis, markedly decreased granulopoiesis with few mature forms, dysplastic megakaryopoiesis, and increased iron with numerous ringed sideroblasts. Cytochemistries showed a large number of erythroid precursors containing cytoplasmic periodic acid-Schiff globules ringing the nuclei of the cells. Sudan black stain showed only a very small number of myeloid precursors.
At the present time the patient is being followed with serial bone marrow examinations, and her hematocrit is maintained with transfusions of packed leukocyte poor blood at approximately S-week intervals.
120 MORRISON AND YON
REFERENCES
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2. Khandekar, J., Kurtides, S., and Stalzer, R. Acute erythroleukemia complicating prolonged chemotherapy for ovarian carcinoma, Arch. Intern. Med. 137, 355-356 (1977).
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