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The Treatment of Carcinoma of the Cervix During Pregnancy
Am.erican Journal of Obstetrics and Gynecology VOL.
48
OC'fOBER,
1944
Xo.4
Original Communications THE TREATMENT OF CARCINOMA OF THE CERVIX DURING PREGNANCY HOWARD
\V.
JOKES, .JR.,
M.D.,
A~D WILLIAM ~EILL, .JR., ~1.D.,
BALTIMORE, :\iD.
(From the Kelly Clinic)
T HE
treatment of carcinoma of the cervix occurring during pregnancy is complicated by the conflicting fucts that radium irradiation is the most trustworthy method of therapy for careinoma of the cervix, but can damage the developing fetus, especially when used in the early months of gestation. Because of this danger to the child, many observers have concluded that irradiation in any form or dosage is contraindicated, so long as the pregnancy is allowed to continue. Leopold Goldstein and Douglas l\'Iurph,v 1 in a series of papers in 1928 and 1929 brought together the existing literature, whieh clearly demonstrated that therapeutic pelvic irradiation during pregnancy is extremely likely to injure the growing fetus and that such injury may result in the birth of a seriously defective child; in 75 instances of irradiation during pregnancy, there was an uncorrected figure of 50.7 per cent defee1ive children. However, a closer analysis or the data reveals extenuating circumstances in many eases; for example, in some instances substantial high voltage roentgen dosage was delivered to a pregnant uterus in the mistaken belief that it was a myoma. This faet, along with our own and the varying experience:,; of others with cervical (mlll~er, has led us to believe that the COllelusion of Goldstein and ~Iurphy, while indicating the danger of irradiation during pregnancy, does not necessarily outweigh its advantage in treating careinoma of the cervix. Contributors to the literature have resolved themselves into two principle groups-those who do not permit irradiat:on of cervix cancer if pregnancy is allowed to eontinue, and those who feel that properly applied radium irradiation is justifiable and safe. Bither point of view NOTE: The Editors accept no responsibility for the viewR and statements of authors as publisheu in their "Original Communications."
H7
448
.'\ MERICAN JOCRSAI, OF ORHTETRJCS AXD GYNECOLOGY
is often supported by a single case report issued almost before the patient leaves the hospital so that an estimation of the five-year salvage, or the ultimate outcome for the baby is impossible. There are well over 200 references to this subject in the Quarterly Cumulative Index .Medicus, but scare'ely more than a dozen reports that fulfill the essential requirement of an elapsed time of five years so necessary in a discussion of carcinoma. Thus, many reports are invalid in a discussion of the results of treatment in carcinoma of the cervix, and are also worthless from the standpoint of prognosis for the infant, as it is well known that one of the most serious deformities caused by irradiation, microcephaly, is often not recognizable at birth. A period of about three years must elapse before one ean he sure that this distressing condition does not exist. Our own experience with carcinoma of the cervix during pregnancy, and a study of the reported cases, in so far as they are helpful, has led us to believe that the treatment of sueh patients must be individualized; one general rule of therapy, which either allows radiation and continuation of pregnancy, or dictates interruption of the pregnancy as a necessary part of the treatment is not applicable. If there is a probability of obtaining a norma,l child in treated cases, and if the circumstances of the case so justify it, the attending physician must indicate this possibility to the patient. In a multipara with adequate family, it would be unwise to assume even a slight hazard of fetal injury, provided interruption of the pregnancy will not endanger the prognosis for the mother. Many patients pregnant for the first time would desire to entertain a reasonable risk of an abnormal baby, if their own chanee of cure was not compromised. Our problem therefore, is to estimate the risk of an abnormal fetus following irradiation for (~arcinoma of the cervix during pregnancy, and to examine the prognosis for the mother with and without interruption. The Risk of Fetal Abnonnality Following Radium Irradiation for Carcinoma. of the Cervix In order to estimate the risk of fetal damage with radium in the treatment of cervix cancer during pregnancy, we have collected all cases of this condition and added our own experience. This mat~rial is summarized in Tables I and II. Some of the cases herein reported were previously described by NeilP but are included with additional follow-up notes. There are 48 cases, exclusive of our own, in which irradiation was used sometime following conception and prior to delivery. One may arbitrarily set three years as the time which must elapse in order to be sure about the occurrence of microcephaly. There are reported only seven normal children which fulfill these requirements. There are 28 indeterminate cases, that is, cases reported prior to three years after delivery. Practically an of these children are quoted as normal.
.JO:-'ES, JR., A:-'D NEILL, JR.:
CARCIXOMA OF CERVIX
449
There are five examples of abnormal offspring. Two of these five treated many years ago, received x-ray therapy and therefore should be excluded. Two are macerated fetuses. One of these two was irradiated at 4 months and the other at 3; both went almost to term. There remain.'l but a single reported case prior to our own of a living child with microcephaly following radium treatment for carcinoma of the cervix. This patient was treated at 6 months, and both patient and child were living 11 years at the time of the report. There are also eight reported cases of neonatal deaths due to incidental causes such as measles, pyloric obstruction and pneumonia. Our own material (Table II and Case Reports) includes 8 instances of prenatal irradiation. There are five children living and normal from three to fifteen years of age. There are two instances of microcephaly, but one of these contracted tuberculosis and died at the age of four years. There is one child who seemed normal in every way, but who died of measles at the age of 18 months. Combining 0111' own material and the literature, there are twelve children irradiated prenatally who are living and normal more than three years of age. There are 28 children living and apparently normal but reported before three years. There are nine children who died of some unrelated disease before three years. There arc three cases of microcephaly. It is difficult, due to limitation of numbers, to express the risk of microcephaly percentage-wise. If only determinate cases are considered, there are three seriously abnormal children in a total of 15 live births. or 20 per cent. If the entire group is considered, the figure would be three in fifty-two, or 6 per cent. Pive months is sometimes cited as the earliest time at which irradiation should be applied. At that time the fetus is higher in the abdomen, thus affording greater distance from the source of irradiation. There is also said to be less likelihood of abortion , if ovarian function be destroyed at that time. There is little real evidence to support snch view although it may well be correct. Of the 4f1 reported cases, 8 were treated prior to five months. Two of these went to term and delivered macerated fetuses. One is living and well at eight years. Five arc said to be living and well, but under three years of age. There arc 40 reported cases treated later than 5 months. These yielded 6 children living and normal more than 3 years after delivery, 23 living and normal but reported prior to 3 years of age, 8 children dead of undetermined causes and 3 abnormal children. Two of these last three were treated with high voltage roentgen therapy and can be eliminated tor our purposes; the third one treated at 6 months is a living microcephalic 11 years of age at time of report. Three of our cases were treated prior to 5 months. Two of these were microcephalic, one of which is still living at 3% years of age. Five were treated after 5 months, and none of these developed microcephaly.
5 months months
(7)
34
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Hoffmann, II.'
Pouey,"
Couvelaire,7
41
29
3:1
Van Rooy, A. \V.IO
Paroli, G.l1
ZimmermaIl., H.12
Hadium
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4,200 mg. h. 6/9/:13 Hadium
I
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4 months
;;,GOO mg. h.
34
Berkley, C."
1 or IT
48 me. rl. in 10 days 1800 x 4 postpartum
'7 months
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Spontaneous
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Spontaneous 20 hours labor
11 /28/2;3 4;{.2 mc. d. in S days RadilUll
Hpontaneous
Hpontaneous
9/15/38
Ce~arean ~e('.tion
DELIVEIlY
-.. - - - - - - - - -
Hadium
Radium
( f) I
I
1,ROO mg. h. eaeh week for il weeks 6/12/38
mRADIA'l'lOX
Titus,S
;) months
II
I
CLINICAL STAGE
Condamine, H. 7
Ii months
(i ~
5 months
(')
Herold, K.4
25 weeks
DURATION OF PREGNANCY
33
AGE
Mundell3
AUTHOR
'l'AflL~;
\Yell under 5 years
Living an. I well 20 years
Died 18 months, l'eeurrenep in broad liganl<'nt
Living- Unu0l' five years ,")/1/27
Living under five years 4/1S/39
!':ND ftl<;ST:UI' MOTHER
Living and normal
Living and normal
Well under 3 years
Living and normal 20 years
Pvlorie stpnosis. vnied from operatjon
Xormal
Xormal
Xormal
loliving- and nonna] 5/1/27, IllllJ'(' than :~ yeal'~
Kormal
:Xormal
Living and normal 4/18/39
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Petenyi, G.16
Gol, F.11
Goldstein, I.., and Murphy, D. P.1
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Metzger awl Leguen 20
Hartman, H., and }'arber, S.21
Roy,22
Condamine, R.23
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Amico-Roxas, S.13
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nle. <1.
Forceps
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3/23/23
Cesarean section
6/21/16
Spontaneolls
Spontaneous
Spontaneous
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Cesarean section
Cesarean section and hysterectomy
47 me. d. in ij months
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IS mc. d.
3,000 mg. h.
1 00 mg. for 24 hours
19Hi
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Radium
Radium
Died I () days Dil'd from (liflicult delivery
Died from laceraHan of ecrvix after delivery
Living and normal 2 months
Living alltl normal 20 months
Died
Living with growth 2 months
Died of recurrence 18 months
Died soon after delivery
Died 2 years; recurrence
11
and
Dipd 3 hours
years
~Iicrocephaly
Microcephaly
eye damage
Mi(~roeephaly
Died 3 days; atelectasis
Died postoperative
Living and well 11 years
Died 18 months
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DURATION (W PRF.GNANCY 3 months
39
A.24
AGE
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AUTHOR 40 me. d.
24 me. d.
IRRADIATION
II
Spontaneous
Spontaneous
Cesarean section and hysterec· tomy 3 days after radium treatment
Cesarean section at term 4/3/20
Spontaneous 4/26/19
Cesarean sor,Uon at term
Spontaneous
Cesarean section
Spontaneous
DELIVERY
Living and weU 1 year
Living and well ] 0 months
Died postoperative
Died of eclampsia 4/16/20
Died 6/17/20
Died] year
Living and well fi years
END RESULT MOTHER Died 9 months
Living Cesarean section and hysterec· __ _ _ ~~my at _~e rm ____ . .
68 me. d. 15 days
55 mg. for 24 hourA
100 mg. for 72 hours
Radium
:1,613 mg. h.
7,230 mg. h. March 3 to 26, 1919
50 mg. for 24 hours repeated 5 times in 8 days
"Early' , 55 mg. for 24 hours
CLINICAl. STAGF.
T ABLE I -CONT 'D
Living
Living and normal 1 year
Living and normal 10 months
Living under :1 years
Normal; died of pneumonia 2~· months
Living and well :l years
Living and normal i-i years
Living and normal (j years
END RESUI,T CHILD Macerated at birth
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Condamine, R., Voron and Molin 23
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Infanti7.7.i8
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Diiderlein,
Diiderlein,
Kirtz, L. P., and Pareira, M. D. 36
36
Hauch, E.33
32
30
36
Porte and deNabias 32
7 months
7 months
7 months
5 months
7 months
5 months
7 months
7 months
I
:1,350 mg. h.
Extensive 2,440 mg. h. x 3
2,440 mg. h.
40 mc. d.
Radium
25 mc. d.
Radium
27.5 mc. d. 5 days
Radium
Radium
9 months
7 months
32 mc. d.
5t months
Living
Died with metastases
CCRarean section
Spontaneous
Spontaneou8
SpontaneouB
Spontaneous
Spontaneous
Cesarean section at term
Cesarean section and hysterectomy
Living and normal 9 years Living and normal :l years
Living under 5 yearH
Li vi ng and normal ;>, year8
Living and normal
Died 1 year
Died 2 years
Died 1 year
Died 1 month Living and well 3 months
Living
~ormal
Died
Normal
Living and normal
Died 4 days postoperative
Cesarean section and hysterectomy Cesarean section and hysterectomy 8 months
Living and normal 1 year
Living and well 1 year
Cesarean section 8t months
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AMERICAN ,J01:HXAL OF OBSTETRIC'S AND GYNECOLOGY
Our own material more than t.he literature tends to support the opinion that irradiation is much safer for the fetus, if used after 5 lllonths. 'Ve are, therefore, gr'catly influenced by the duration of gestation in recommending tl'eatmen1. At times abortion oceurs from 1 to 60 days following thc application of radium to the cel'Vix, and there are about 15 such eases reported: about half or these were treated before the pregnancy had progressed five months. 1t is likely that many lllore sneh cases have never been reported. Manipulation of the cel'vix incident to the treatment ('(Juld be more responsible for abortion than injury to 1.11e ('hild, or destruction of ovarian fundion. Dosage of radium is important, but none of the eases with abnormal fetuses received excessive treatment considering the growth. Furthermore, normal children v,ere born to mothers who received as much or higher dosage. It was impossible in our own cases to correlate in any way dosage estimated to be delivered in the region of the child's head with the occurrenee of microcephaly.
Risk to the Mother An estimation of the possible risk which the mother may suffer from the interruption or continnation of the pregnancy is essential in planning treatment. This figure can best be determined hy a study of comparable series treated on one hand by irradiation and continuation of pregnancy, and on the other by irradiation with interruption of pregnancy. In discussing the risk to the child, it was pointed out that case reports were issued too soon to be of real value in determining the health of the child; this is likewise true in determining the ultimate outcome for the mother. In the treated uninterrupted eases ('rable I), there are only three mothers living and well more than five years. There are 18 mothers dead, most of these wit.hin the first 18 months following treatment. In 24 instances reports of living mothers were issued prior to five years following treatment. Our own results (Table II) show seven mothers treated during eight pregnancies. 'rwo are dead, one is living at three years, and foul' mothers treated during five pl'egnaneies are living and well five years or more after treatment. l;nsatisfaetory as al'e these figures, the number of published ca.'.::es treated with radium plus abortion either spontaneous or induced, is even more meager. Phillipp 37 has reported a case living seven years. She was treated at four months and had a spontaneous abortion at 6112 months. Danforth 38 reports a case well for seven years in whom a very early pregnaney was eurctted from the utel'us just priol' to inserting the radium. On the other hand, there are at least two reported cases (MoriS,a9 Danforth 38 ) of instrumental abortion followed by death from infection. Most of the case reports are issued far too soon for an
2S
32
29
30
35
36
33
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O. II." ] 73;')5
M . B.* 22599
A.W.-" 24792
S.B. 30042
H.B. 31471
H .B. 3J471
M. L. 3:1975
J.H. 34894
4 month s
4 months
1 months
6 months
7 months
6 monthR
5 months
6 months
I
10/12/39 ]0/1 6/39 10/23/3 9 1I / 13/3 9
2/25/:19 3/ 4/39 4/ 2/39
2/ JO/38
4/ 16/37
2/23/3 6
I
1
11/ 28/3 1 1/ 9/32
5/ 13/30
12/18/2 6
J,072 1,064 506 fj]8 mc. mc. mc. mc.
h. h. h. h.
1,752 mc. h. 1,001 me. h. 1,.169 mc. h.
:1,204 me. h.
1,614 me. h.
2,940 me. h.
2,671 me. h. 843 me. h.
:1,109 me. h.
1,762 mc. h.
TREA'l'l£E:>T
I
IT
II
Dl;HATlOX Ob' CLI:>WAL J>REGNANCY STAGE
11
,J a n., 19'10 Cesarean Hcet ion
6/ 4/:19 Cesarean se(,tion
7/ 19/ 37 Cesarean seetion
6/24/37 Cesarean Hection
6/19/30 Cesarean :section
2/11/ 32 Cesarean section
9/ 12/3 0 Cesarean section
1/1(i/27 Cesarean section
DELIVERY
'Previously r eported by N ciil." i\'L .1. OUST, & GY!'>EC. 30: 414, 1935.
AGE
NAME
TABU;
Living' 3/ J2/ 4:)
l'eeUrrellee
Died July, ] 941-
Living and well, ]943
Living and well, 1943
Livin g- and well, 194:)
Living and well, ]943
Living and well, 1942
Died met. Sept., 1930
l'O[,LOW-UP MOTHER
Living and normal, 3/12/43
xlierocephaly
Mic,"oeephaly Died tuberculoRis, 8/4/42
Died 18 months Meu:sles
Living and normal, 1943
Living and normal, 1943
Living and n ormal, 1942
Living and normal, 3/31/42
BABY
~'OLLOW-UP
2/ 13/ 40·- 690 Ille. h. pluA 2,000 1'. times 4
2/12/30 500 me. h.
POH1'-PARTUl\1 THEA'J'MENT
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AMEHlCAX .JOURNAL OF OBSTETRICS A~D GYXECOI,OGY
estimation of the rure ratc. Therc are also probably many cases with spontaneous abortion following' treatment which have not found their way into the literature. These considerations make it impossible to estimate statisti{'ally the relative merits and dangers of abortion in the treatment of cervix eanrer. It is certain however, that continuation of the pregnancy by no means precludes a cure as indicated by the literature and our own experience. Thc influcncc of pregnancy on tumors in gcneral is problcmatical. The alteration in circulation contingent upon thc intcrruption of pregnancy may cxert an unfavorable influence in curing the cervical growth; this possibility is suggestcd by the very poor prognosis in ca~es treated at term by llecessity with cesarean section, before the treatment of the cervix cancer. It is only fair to say however, that in this latter group the eases are genet'ally more advanced than those seen earlier in pregnancy. In this discussion yery little has been said about the extent of disease in relation to CUl'C. Obviously, this consideration is as important here as in uncomplicated cervix carcinoma. The number of reported cases is too few to makc such a correlation of significance. It is to be notcd that the majority of prenatal cases is not more advanced than I,eague of Kations Stage n. The neglected extensive cases are not encountered until term when delivery of the child is imperative. In estimating the proper therapcutic procedure in a particular case, due weight must be given to the clinical stage of the disease. One would hesitate to accept for trcatment with a view to carrying to term a patient with disease more extensive than Stage II. Because of thc pregnancy with its attendant examination most cases will be discovered relativcly early.
Techlrlque -of Treatment If it is decided to treat during pregnancy with a view to obtaining a normal living child at term, certain points in technique may be stressed. It is important that no high voltage roentgen-ray therapy be employed because of the obvious dangers of substantial depth dosage in the region of the developing child. I"urthermore, it has been our practice to omit the usc of tubes within the cervical canal. This is done for the twofold purpose of se<~uring all possible distance from the baby and also to guard against the onset of lahor by dilating the cervix. The entire treatment is carried out by tubes held in a cloth plaque against the cervix. The details of treatment in uncomplicated cervix cancer have been previously dcscribed. 4o As an additional precaution against stimulating utcrine contractions by prolonged packing against the cervix, we have preferred to use a large amount of radium for a correspondingly short period of time. This means the use of 2.5 to 3 grams of radium. While it is by no means necessary to have available such a quantity of radium for the successful treatment of these cases, the fact that we
JONES, JR., AND NEII.L, JR. :
CARCIXOMA OF CERVIX
457
have in no case stimulated uterine contractions leads us to believe that this is not an unimportant point. The dosage is subject to more variation than in uncomplicated cervix carcinoma. This variation is allowable in an effort to spare thc fetus all possible treatment and must be determined by clinical experience. In the cases herein reported, the dose varied from 1,614 me. hr. to 3.922 millicurie hours. Following delivery it is often desirable to administer additional radium and x-ray. Operative Treatment Irradiation is by far the most common method of treatment for uncomplicated carcinoma of the cervix. In spite of this, many cases complicated by pregnancy have been treated by panhysterectomy. This is probably because panhysterectomy seems expedient if abdominal section for delivery of the child is necessary. ~evertheless, one should be hesitant in accepting this as a suitable method of therapy in view of the unsatisfactory results from panhysterectomy in uncomplicated eervix carcinoma even in carefully selected material. 41 The reported cases based on this method are too few to express the cure rate statistically, but Newell and Scrivner,42 Stacey and Thompson,43 Stoekl,44 Miller/~ Chalfont,46 Bir0 47 and many others have reported such cases both at term and before with an alarmingly high operative mortality. Furthermore, most of these rcports have appeared before an elapsed time of five years so that an estimation of carcinoma of cervix curability is not possible. In our opinion, any necessary abdominal operation either before or following irradiation of eervix ('arcinoma should be confined to evacuation of the uterus. Pregnancy at Term If the baby is viable when the carcinoma is discovered, the problcm of injury to the fetus by irradiation need not be considered. Under these circumstances, the child can and often must be delivered by cesarean section. The prognosis under these circumstances has been very poor. There are approximately 40 reported cases to which we have added four treated by various methods including irradiation, panhysterectomy or both; as far as we are aware, the two cases rcported by Bir0 47 are the only ones which have survived more than five years. The poor prognosis was in many instances due to the advanced stagc of the growth. However, the profound circulatory changes following parturition may be an unfavorablc influence in arresting the disease. The impression received from reviewing the cases of this group, emphasized by the experience of our own four cases, is of a lost opportunity on the part of the attending physician to diagnose and treat an early carcinoma. Almost without cxception, the possibility of making an early diagnosis was dissipated by failure to usc such simple diagnostic
'1-58
.\MEIUCAN JOUR~Afj OF OBf:;TETRf($ AN I) GYKECOLOGY
procedures as speculum examination ~llIJ biop!:!y even after the appearall<~e of such all alarming sign as slight vaginal hleeding during pregnancy. Prenatal tare through it~ 1'outine periodic examinations offers an unequaled opport unity to diagnose carcinoma of the cervix at an early stage.
Summary and Conclusions In forlnulatillg a plan for a clinical situation a!:! rare as the association of pregnancy and elll'cinoma ot cervix, one must draw upon the collective experience of the literature as well as upon one's own eases. It is therefore to be regTeUed that ill so many instanecs, ease reports have been issued too soon to he of value in estimating the ultimate outcome either for mother or baby. }fany more detailed reports of this condition are needed, but these should not be published before the patient has died, or five years after treatment has elapsed. -VVe have come to beli()ve that a general 1'1Ile for the handling of these cases must take into aeconnt th0 obstetl'ie and social haekground as expressed in the desire of the prospective parents for the child, as well as the extent of the disease. If there are other childl'en, or if the parents do not care to assume the ever present risk of an abnormal chi ld, we see no l'ca!:!on 1.0 advise any course except illtel'1'upt.ion of the pregnancy and adequate irradiation therapy. The risk of an abnormal fetns cannot be stat.istically stated at the present time withcert.ainty, hut it seems probable that its upper limit. is 20 pCI' eent. I f' the parents and physician for any reason wish to assume this risk, it is justifiable, in our opinion, to proceed with irradiation during pregnaney with a view to obtaining a living child at term. ]f the pregnaucy is at the fift h month or beyond, the risk of an abnormal ehild is substalltially les..<;. As indicated above, the risk to the mot.her is probably not in('reased by this procedure as eompared with int.erruption of the pregnan('y. The mother 's prognosis is intimately related to the clinical extent of the disease. The genel'v.J experience has been that most euse!:! ~tr(~ diseovered early (League of' ~ations I 01' II), and the prognosis has heen parallel hut somewhat low('[' than for eOl'l'rsponding but uncomplicated groups. The prognosis of eal'einoma diagnosed at term and treated by eCSIIeb simple elinical methods as speeul um examination and biopsy, even in t.he presence of vaginal bleeding during pregnancy. Case Reports CA8t; 1.-0. 11 ., 17855, aged 2H, four living children, youngest 3 years. Had il'l'egulal' vaginal spotting for 3 months. Did not remem ber missing any periods, but on examination December 18, 1926, she was estimated to be 6 months pregnant. At another hospital, it was thought
JONES, JR., AND NEILL, .JR.:
CARCI~O:lfA 010' CERVIX
4ii!l
that she had a small cervical fibroid which was" removed 12/1/26. Pathologic examination however, showed squamous-eell epithelioma. , At the examination December 18, the entire {'ervix was in vol ve,d and there was some extension of the growth on the vaginal wall . . :\fo parametrial extension by rectal examination. Treatment: 12/18/ 26-2,644 me. against the cervix by 7-tube plaque for 40 minutes. Patient went. into labor spontaneously 1/ 16/ 27 and was delivered by cesarean section. Patient got along very well until 1930, when there was a recurrence. In spite of further treatment with radium and x-ray, the patient died September 12, 1930,frorri the disease. l<'emale child was examined 1-Iarch 31, 1942, and round t6 he normal in every way. She was above average in her school work. CASE 2.-C. B., 22599, aged 32, 3 living child['en. 1J. 11. P. 12/ 16/ 29. Three months prior to May, 1930, there was irregular bleeding and discharge. On examination 5/ 13/ 30, it was estimated that she was 5 to 6 months pregnant. On the anterior Jip of the cervix, llrincipally on thc left side, there was a hard growth. It extended somewhat on to the vaginal wall. Rectal examination showed that thcr'e waR some induration in the right broad ligament. B,iopsy revealedsquamolls-ecll eareinoma. Treatment: 5/13/30-3,109 mc. by 7-tube plaque against the cervix lor one hour. Pregnancy progressed norma1ly and t.he cervix healed. On September 12, 1930, she was delivered hy cesaI'ean section. At operation, the broad ligaments were carefully palpated, and no maRS could be felt. Following delivery, there was a recurrence of the normal menstrual flow which was abolished by x-ray in .Tnne, 1931. Patient has been examined at interva~s since then, the la<;t time heing .Tune 12,1942, at which time she was well. The female ('hild was also examined June 12, 1942, and found to be normal in <'very respect. She waR doing well in her school work. CASE 3.-A. W., 24792, aged 29. Four normal pregnancies during the last. six years. All children living. Patient has never menstruated between pregnancies. In January, 1931, had some spotty va~inal bleeding. There was a little staining caeh day. In September, 1931, 'she bled rather profusely for 5 days. 1o'irst seen November 23, 1931. AbdOniinal examination showed pregnancy which was estimated to be hetween six and seven months. Vaginal examination revealed a friable mass confined to the posterior lip of the cervix with no extension on to the vaginal wall. Rectal examination demonstrated no parametrial involvement. Biopsy showed squamous-cell carcinoma. Treatment: On Kovembel' 28, 1931, the patient received a 7-tube plaque containing 952 me. against the cervix for one hour. She was given also four permanent gold radon implants for a total of 20.6 me. On January 9, 1932, pat.ient reeeived a G-tuhe plaque containing 1,606 me. for 30 minutes. The regression was very satisfaetory. On February 11, 1932, a classical cesarean section was performed. At the time of operation no mass could be palpated in the hroad ligament region. Since operation, the patient has had no£\fr.t'ber treatment and is well as of November 1, 1941. The female child"was also examined on that date and was normal and getting along in srhool hetter than the average for her age. CASE 4.-S. B." 30042, aged 30. Nine pregnancies and five living children. L. M. P. stated to be Odober 1, 1935; however, at the time of
460
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
examination, l<'ebruary 23, 1936, it was estimated that she was 7 months pregnant. On February 9, she first noted a slight bloody discharge and on February 12, had rather severe bleeding. On the anterior lip of the cervix there was a granular uleer. There was little or no extension on to the vaginal vault. The posterior lip of the cervix seemed normal. Rectal examination revealed no apparent extension into the broad ligaments. Biopsy showed squamous-cell careinoma. Treatment: 1,960 mc. divided into 1 tube in the cervical canal and a 5-tube plaque against the cervix for l'i2 hours. Following this, the lesion healed and on April 30, 1936, the cervix appeared grossly normal. On June 5, 1936, a female child was delivered by classical cesarean section. March 12, 1943, mother alive and well, and child living and normal, walked at 11 months. CASE 5.-H. S., 31471, aged 35, five previous pregnancies; ;) living children. Ij. M. P. October 8, 1936. First noticed vaginal spotting in the latter part of March. 1937. ~ever had any irregular bleeding prior to this time. IJost 8 pounds in weight. Examination showed a pregnancy estimated to be 5 months. On the left side of thc cervix, there was an ulcer about 2 cm. in diameter. No extension all to the vaginal wall. No involvement of the parametria. Biopsy showed squamous-cell carcinoma of the cervix. 'l'reatment: On April 16, 1937, received 2,150 mc. against the cervix with a 5-tube plaque for % of an hour. Pollowing the treatment, there was rapid healing of the lesion. Cesarean section on June 24, 1937. Following delivery, it was noted that there was some induration of the right side of the cervix. The patient was given an appointment to report back for further treatment but was very slow in doing so and in February, 1938, when she reported for examination, she was found to be again four months pregnant. Biopsy again showed squamous-cell carcinoma which involved the entire cervix but had not involved the vaginal walls or the parametria. On February 10, 1938, she received 2,746 mc. against the cervix for 1 hour and 10 minutes. For a second time, there was a rapid healing of the lesion and at term a second eesarean section was done. She has been followed at intervals since that time, and there has been no recurrence of the growth. The first child died at the age of 18 months. It was in good health until it contracted measles and died. The second child was mentally defective. She entered the Polk (Pa.) State School May 19, 1942. She was classed as an imbecile with an I.Q. of 43. Soon after admission, she showed evidence of active tubereulosis and died August 4, 1942. CASE 6.-J. H., 34894, aged 38. Four previous pregnancies, the last one 10 years ago. All children living and well. First seen October 12, 1939. Patient complained of intermenstrual bleeding of one year's duration. She was estimated to have a pregnancy of four months. The right side of the cervix was involved in a growth, biopsy of which showed squamous-cell carcinoma. The left side of the cervix was normal, and there was no spread on to the vaginal mucosa or into the parametria. Treatment: 10/12/39, 1,072 mc. foI' one hour. 10/16/39, 1,847 mc. against the cervix for 35 minutes. 10/23/39, 1,012 mc. against the cervix for 30 minutes. 11/13/39, 1,236 mc. against the cervix for 30 minutes. There was improvement in the lesion and the patient had a cesarean section in January, 1940. On March 12, 1943, the mother was alive and well, and the child was normal.
JONES, JR .., AND NEILL, JR . :
CARCINOMA OF CERVIX
461
CASE 7.-M. L., 33975, aged 33. Patient has 8 living children. L M. P. October, 1938. First seen February 2fi, 1939. Examination February 25, 1939, showed a pregnancy which was estimated to be four months. There was a granular growth involving the posterior lip of the cervix and cervical canal. The anterior lip was also thought to be involved as it was stony hard although the overlying mucous membrane appeared normal. Rectal examination showed no invoh'ement. of the parametrium. Treatment: February 25, 1939, 2,628 me. divided into tube in cervical canal and a 5-tube plaque against the cervix for 40 minutes. 3/ 4/ 39, 2,003 mc. similar set up for 30 minutes. 4/ 2/ 39, 2,338 me. with a plaque against the cervix for 30 minutes. Cesarean section June 3. 1939. Careful palpation of the parametrium at the time of operation revealed no induration. The baby appeared grossly normal. 'l'here was a recurrence of the growth in Xovember, 1939, and she received a course 01' x-ray therapy of 8,000 r. through six portals around the pelvis (250 k.v. 30 Ma. 1 mm. copper plus 1 mm. aluminum-15 by 10 portals; 50 cm. S. T. D.; r. measured with scattering) . She also received 1,380 me. for 30 minutes against the cervix. However, she did not do well and died in July, 1941, from the disease. The baby was examined several times and was found to be mentally deficient. By March. 1943, she was not able to talk. CASE 8.-T. K., 23125, aged 35. August 24, 1930. had normal spontaneous delivery. This was the tenth child. There had been some bleed· ing during the latte!' part of the pregnancy. Examination September 23, 1930, revealed the entire vault of the vagina to be filled with a large growth. There was extension into both broad ligament regions but no firm fixation. Biopsy showed squamous-cell carcinoma. Treatment: October 4, 1930, 3,660 me. 2 tubes in cervical canal and a 5-tube plaque against cervix for 50 minutes. There was some improvement, but patient died of the disease in July, 1934, in spite of subsequent treatment with x-ray and radium. CASE 9.-M. H., 24229, aged 38. Multipara 3-0-1-2. L. M. P. September 15, 1930. Pregnancy was normal until February 22, 1931, when she began to bleed in small amounts. Examination June 5, 1931, showed pregnancy of 8Y2 months' duration. There was a nodular cervix with a growth confined entirely to the portio vaginalis. Biopsy revealed squamous-cell carcinoma. The broad ligaments seemed to be free. As the ehild was viable, immediate cesarean section was advised and carried out on June 6, 1931. Patient did not receive radium treatment until July 12, 1931. At that time there had been some increase in the size of the growth which was still limited to the cervix. The fornices were clear. There did seem to be some thickening of the right broad ligament region, although at the time of the cesarean section, careful palpation did not reveal any involvement of the broad ligament regions. Treatment: .July 12, 1931, 1,498 me. for 2 hours with a seven-tnbe plaque against the cervix.
X-ray 7/ 16/ 31, 1,000 r. 7 by 7 suprapubic portal. 7/ 23/31, 1,000 r. 7 by 7 right lateral and left lateral pubic and 1,000 r. on perineal porta1. 7/ 30/ :n, 10 by 10 portal 1,000 r. right lateral sacral and 1,000 r. left lateral sacral. Factors as in Case 7.
462
AMERICAN JOrnXAl. OF OU::>TE'l'RIC8 AXD QYXECOLOny
There was improvement bill on Sepicm bel' 30, I !):~1. t1wI'e was still an ulceration ]112 cm. in dianwter which on hiopsy showed artjvc growth. Two gold points eu{'h eontaining 6.8 11Ie. or radon \\,PI'C inserted into this area. On l\ovembcr 1, 1931, pati('Jlt received 1,060 Jll<':. in thr' eel'vieal canal for 57 minutes. Patient ditl nol improve awl ~he die(l of the disease on April 23, 1932. CASJ<: 10.--B . V, 242HO} aged 39. Patient has had 6 ehildren and two miscarriages. All children living. At term tIl<' patient had a ('('sarean section on December la, J 929, at another hospital. Apparently. it was a classical cesarean seetion and a supravaginal hyst.erectomy. It was not until ,Tuly 25, ] 931, that she came under our observation. There had been no bleeding from the time of the cesarean section until Alay, when it recurred and has continued to the time of examination. A large mass protruded from the <~er\'ix and extended on to th e vaginal wall: Both parametria were involved to the pelvic wall, and thrr'e was fixation to the l'cetum. It was a very ('xtensivc easc. Treatment: July 25 and 26) re('eived 1,000 1'. of x-ray through 10 by 10 portals, 9 fields around the pelvis. Factors as in Case 7. August 3, 19:3], received 2,67:J me. in aIHI on t.he eCl'vix for 67 minutes. On August 17, 1931, she died l'athrr sndd0IIly. . CASE 11.--1\1. K., 84297, aged :n. First Heen }lay 11, 1939. Eight months previously patient had had 11 ('CS8ol'ean f;retion hcrause of an undilatable cervix. After s(lvrral hours in lahor, there was no progress and section was derided upon. Following this, therc (~ontinucd to he some vaginal discharge until the diagnosis of <:ar(~inoma of cervix was made. At this time, the growth was rather massive and had spread into both parametrial regions. Treatment was hegun by x-ray and she received 8,000 r. through four portals from May 9, 1989, to May 18, 1939. J~'actors as in Case 7. On .June 1, 1939, 1,212 me. in and on the cervix for] hour. June 22, ]939. 2,361 mc. on the cervix for 35 minutes. 1"01lowing this, she reeeived many other radium and x-ray treatments, hut the growth eonId not he enred, and she died Angust 15, 1941.
References 1. 2. :1. 4. :'i.
6. i. S.
n.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. il2.
Goldstein) L.} and Murphy, D. P.: A~L J . OUST. & GYXEC. 18: IS9, 192!l. Neill, W., Jr.: A.M .. r. OBST. & GYSEl:. 30: 414, .\93;;. Mundell, J .•r.: AM. 'J. On ST. & GYXEC. 38: 130, ]9:W. Herold, K.: Zen tralbl. 'f. 'Gynak. 59: 2655} 1935. Hofmann, H.: ZentralbL f. Gynak. 58: 1886, 1934. Pouey, H.: Bull. Soc. gynec. et .de d 'obst. 16: 702, HI:!7. Condamine, R.: Gyneeologie 27: 577} 1928. Brouha, -'1:., and GosHelin~ -0.: Bull. Acad. roy. tie Illod. de Belgique 13: 499, 1933. Berkley, C.: J. Obst. & Gynaec. Brit. Emp. 41: 402, 1934. Van Rooy, A. W.: J. Oust. & Gynaec. Brit. Emp. 41: 404, 1934. Paroli, G.: Arch. di ostet. e ginec. 20: 316, 1933. Zimmerman, R.: Strahlenth erapie 29: 108, 1928. Amico-Roxas, S.: Riv. d'ostet. e ginec. pl·at. 18: 9f\ 1936. Fagioli} }f.: Ann. di oste1. e ginec. 58: 1I35} 1936. Smith, F. R.: A~f. J. OUST. & GYNEC. 34: 616} 1937. Petenyi} G.: Klin. Wchnschr. 2: 566} 1923. Gol, }'.: Verhandl. d. ungar arztl. GeselJsch. 3: 79, .Ill:!3 . Schilling, N.: AM. J. OnST. & GYNEC. 7: 440} 1924. Strauss, A.: Am. J. Roentgenol. 43: 552, ]940. Metzger and Leguen~ .,Bull. Soc. gynec. et de d 'obst. 12: 188, 1923. Hartman, H., and Farber, S.: Bull. Soc. gynec. et de d'obst. 12: 167, 1923. Roy: Bull: Soc. gynoo. 'et de d 'obst. 17: 653, 1928.
JOXE1', JR., AXD X£I1.L, JH.:
23. 24. 2;3. 26. 27. 2R. 29.
:lI!.
:ll. :-\2. ;l3.
:l4. il5. 30. :17. a8. 30. .to. 41. 42. 4:3. 44. 45. 46. 47.
('.\HCIXO:\IA OJ<' CERVIX
46:\
Condamine, R., Voron and :Molin: Bull. Soc. gynee. et de d 'obst. 17: 862, 1021-1. McGlinn, .r. A.: A~I..r. OBST. & GY~EC. 18: 502, If)20. Heuze: Liege mCd. 22: 632, 1020. Karg, C.: Strahl
48
OC'fOBER,
1944
Xo.4
Original Communications THE TREATMENT OF CARCINOMA OF THE CERVIX DURING PREGNANCY HOWARD
\V.
JOKES, .JR.,
M.D.,
A~D WILLIAM ~EILL, .JR., ~1.D.,
BALTIMORE, :\iD.
(From the Kelly Clinic)
T HE
treatment of carcinoma of the cervix occurring during pregnancy is complicated by the conflicting fucts that radium irradiation is the most trustworthy method of therapy for careinoma of the cervix, but can damage the developing fetus, especially when used in the early months of gestation. Because of this danger to the child, many observers have concluded that irradiation in any form or dosage is contraindicated, so long as the pregnancy is allowed to continue. Leopold Goldstein and Douglas l\'Iurph,v 1 in a series of papers in 1928 and 1929 brought together the existing literature, whieh clearly demonstrated that therapeutic pelvic irradiation during pregnancy is extremely likely to injure the growing fetus and that such injury may result in the birth of a seriously defective child; in 75 instances of irradiation during pregnancy, there was an uncorrected figure of 50.7 per cent defee1ive children. However, a closer analysis or the data reveals extenuating circumstances in many eases; for example, in some instances substantial high voltage roentgen dosage was delivered to a pregnant uterus in the mistaken belief that it was a myoma. This faet, along with our own and the varying experience:,; of others with cervical (mlll~er, has led us to believe that the COllelusion of Goldstein and ~Iurphy, while indicating the danger of irradiation during pregnancy, does not necessarily outweigh its advantage in treating careinoma of the cervix. Contributors to the literature have resolved themselves into two principle groups-those who do not permit irradiat:on of cervix cancer if pregnancy is allowed to eontinue, and those who feel that properly applied radium irradiation is justifiable and safe. Bither point of view NOTE: The Editors accept no responsibility for the viewR and statements of authors as publisheu in their "Original Communications."
H7
448
.'\ MERICAN JOCRSAI, OF ORHTETRJCS AXD GYNECOLOGY
is often supported by a single case report issued almost before the patient leaves the hospital so that an estimation of the five-year salvage, or the ultimate outcome for the baby is impossible. There are well over 200 references to this subject in the Quarterly Cumulative Index .Medicus, but scare'ely more than a dozen reports that fulfill the essential requirement of an elapsed time of five years so necessary in a discussion of carcinoma. Thus, many reports are invalid in a discussion of the results of treatment in carcinoma of the cervix, and are also worthless from the standpoint of prognosis for the infant, as it is well known that one of the most serious deformities caused by irradiation, microcephaly, is often not recognizable at birth. A period of about three years must elapse before one ean he sure that this distressing condition does not exist. Our own experience with carcinoma of the cervix during pregnancy, and a study of the reported cases, in so far as they are helpful, has led us to believe that the treatment of sueh patients must be individualized; one general rule of therapy, which either allows radiation and continuation of pregnancy, or dictates interruption of the pregnancy as a necessary part of the treatment is not applicable. If there is a probability of obtaining a norma,l child in treated cases, and if the circumstances of the case so justify it, the attending physician must indicate this possibility to the patient. In a multipara with adequate family, it would be unwise to assume even a slight hazard of fetal injury, provided interruption of the pregnancy will not endanger the prognosis for the mother. Many patients pregnant for the first time would desire to entertain a reasonable risk of an abnormal baby, if their own chanee of cure was not compromised. Our problem therefore, is to estimate the risk of an abnormal fetus following irradiation for (~arcinoma of the cervix during pregnancy, and to examine the prognosis for the mother with and without interruption. The Risk of Fetal Abnonnality Following Radium Irradiation for Carcinoma. of the Cervix In order to estimate the risk of fetal damage with radium in the treatment of cervix cancer during pregnancy, we have collected all cases of this condition and added our own experience. This mat~rial is summarized in Tables I and II. Some of the cases herein reported were previously described by NeilP but are included with additional follow-up notes. There are 48 cases, exclusive of our own, in which irradiation was used sometime following conception and prior to delivery. One may arbitrarily set three years as the time which must elapse in order to be sure about the occurrence of microcephaly. There are reported only seven normal children which fulfill these requirements. There are 28 indeterminate cases, that is, cases reported prior to three years after delivery. Practically an of these children are quoted as normal.
.JO:-'ES, JR., A:-'D NEILL, JR.:
CARCIXOMA OF CERVIX
449
There are five examples of abnormal offspring. Two of these five treated many years ago, received x-ray therapy and therefore should be excluded. Two are macerated fetuses. One of these two was irradiated at 4 months and the other at 3; both went almost to term. There remain.'l but a single reported case prior to our own of a living child with microcephaly following radium treatment for carcinoma of the cervix. This patient was treated at 6 months, and both patient and child were living 11 years at the time of the report. There are also eight reported cases of neonatal deaths due to incidental causes such as measles, pyloric obstruction and pneumonia. Our own material (Table II and Case Reports) includes 8 instances of prenatal irradiation. There are five children living and normal from three to fifteen years of age. There are two instances of microcephaly, but one of these contracted tuberculosis and died at the age of four years. There is one child who seemed normal in every way, but who died of measles at the age of 18 months. Combining 0111' own material and the literature, there are twelve children irradiated prenatally who are living and normal more than three years of age. There are 28 children living and apparently normal but reported before three years. There are nine children who died of some unrelated disease before three years. There arc three cases of microcephaly. It is difficult, due to limitation of numbers, to express the risk of microcephaly percentage-wise. If only determinate cases are considered, there are three seriously abnormal children in a total of 15 live births. or 20 per cent. If the entire group is considered, the figure would be three in fifty-two, or 6 per cent. Pive months is sometimes cited as the earliest time at which irradiation should be applied. At that time the fetus is higher in the abdomen, thus affording greater distance from the source of irradiation. There is also said to be less likelihood of abortion , if ovarian function be destroyed at that time. There is little real evidence to support snch view although it may well be correct. Of the 4f1 reported cases, 8 were treated prior to five months. Two of these went to term and delivered macerated fetuses. One is living and well at eight years. Five arc said to be living and well, but under three years of age. There arc 40 reported cases treated later than 5 months. These yielded 6 children living and normal more than 3 years after delivery, 23 living and normal but reported prior to 3 years of age, 8 children dead of undetermined causes and 3 abnormal children. Two of these last three were treated with high voltage roentgen therapy and can be eliminated tor our purposes; the third one treated at 6 months is a living microcephalic 11 years of age at time of report. Three of our cases were treated prior to 5 months. Two of these were microcephalic, one of which is still living at 3% years of age. Five were treated after 5 months, and none of these developed microcephaly.
5 months months
(7)
34
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Hoffmann, II.'
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41
29
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Paroli, G.l1
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I
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4 months
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34
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1 or IT
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9/15/38
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DELIVEIlY
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CLINICAL STAGE
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DURATION OF PREGNANCY
33
AGE
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AUTHOR
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Living under five years 4/1S/39
!':ND ftl<;ST:UI' MOTHER
Living and normal
Living and normal
Well under 3 years
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Xormal
Xormal
Xormal
loliving- and nonna] 5/1/27, IllllJ'(' than :~ yeal'~
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3/23/23
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6/21/16
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Cesarean section
Cesarean section and hysterectomy
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19Hi
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"
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Radium
Died I () days Dil'd from (liflicult delivery
Died from laceraHan of ecrvix after delivery
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Living alltl normal 20 months
Died
Living with growth 2 months
Died of recurrence 18 months
Died soon after delivery
Died 2 years; recurrence
11
and
Dipd 3 hours
years
~Iicrocephaly
Microcephaly
eye damage
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Died 3 days; atelectasis
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35
Karg, 0.26
Heurotey and Oheval a1
R,30
Hi month s
( f)
Bottaro, and Mengoa,8
8 month!:'
8 months
7 months
7 months
6j months
6 months
6 months
30
4 months
Karg, C.26
31
DURATION (W PRF.GNANCY 3 months
39
A.24
AGE
Heuze,2f.i
McGlinn, J.
AUTHOR 40 me. d.
24 me. d.
IRRADIATION
II
Spontaneous
Spontaneous
Cesarean section and hysterec· tomy 3 days after radium treatment
Cesarean section at term 4/3/20
Spontaneous 4/26/19
Cesarean sor,Uon at term
Spontaneous
Cesarean section
Spontaneous
DELIVERY
Living and weU 1 year
Living and well ] 0 months
Died postoperative
Died of eclampsia 4/16/20
Died 6/17/20
Died] year
Living and well fi years
END RESULT MOTHER Died 9 months
Living Cesarean section and hysterec· __ _ _ ~~my at _~e rm ____ . .
68 me. d. 15 days
55 mg. for 24 hourA
100 mg. for 72 hours
Radium
:1,613 mg. h.
7,230 mg. h. March 3 to 26, 1919
50 mg. for 24 hours repeated 5 times in 8 days
"Early' , 55 mg. for 24 hours
CLINICAl. STAGF.
T ABLE I -CONT 'D
Living
Living and normal 1 year
Living and normal 10 months
Living under :1 years
Normal; died of pneumonia 2~· months
Living and well :l years
Living and normal i-i years
Living and normal (j years
END RESUI,T CHILD Macerated at birth
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7 months
5 months
7 months
5 months
7 months
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:1,350 mg. h.
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2,440 mg. h.
40 mc. d.
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25 mc. d.
Radium
27.5 mc. d. 5 days
Radium
Radium
9 months
7 months
32 mc. d.
5t months
Living
Died with metastases
CCRarean section
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Spontaneou8
SpontaneouB
Spontaneous
Spontaneous
Cesarean section at term
Cesarean section and hysterectomy
Living and normal 9 years Living and normal :l years
Living under 5 yearH
Li vi ng and normal ;>, year8
Living and normal
Died 1 year
Died 2 years
Died 1 year
Died 1 month Living and well 3 months
Living
~ormal
Died
Normal
Living and normal
Died 4 days postoperative
Cesarean section and hysterectomy Cesarean section and hysterectomy 8 months
Living and normal 1 year
Living and well 1 year
Cesarean section 8t months
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454
AMERICAN ,J01:HXAL OF OBSTETRIC'S AND GYNECOLOGY
Our own material more than t.he literature tends to support the opinion that irradiation is much safer for the fetus, if used after 5 lllonths. 'Ve are, therefore, gr'catly influenced by the duration of gestation in recommending tl'eatmen1. At times abortion oceurs from 1 to 60 days following thc application of radium to the cel'Vix, and there are about 15 such eases reported: about half or these were treated before the pregnancy had progressed five months. 1t is likely that many lllore sneh cases have never been reported. Manipulation of the cel'vix incident to the treatment ('(Juld be more responsible for abortion than injury to 1.11e ('hild, or destruction of ovarian fundion. Dosage of radium is important, but none of the eases with abnormal fetuses received excessive treatment considering the growth. Furthermore, normal children v,ere born to mothers who received as much or higher dosage. It was impossible in our own cases to correlate in any way dosage estimated to be delivered in the region of the child's head with the occurrenee of microcephaly.
Risk to the Mother An estimation of the possible risk which the mother may suffer from the interruption or continnation of the pregnancy is essential in planning treatment. This figure can best be determined hy a study of comparable series treated on one hand by irradiation and continuation of pregnancy, and on the other by irradiation with interruption of pregnancy. In discussing the risk to the child, it was pointed out that case reports were issued too soon to be of real value in determining the health of the child; this is likewise true in determining the ultimate outcome for the mother. In the treated uninterrupted eases ('rable I), there are only three mothers living and well more than five years. There are 18 mothers dead, most of these wit.hin the first 18 months following treatment. In 24 instances reports of living mothers were issued prior to five years following treatment. Our own results (Table II) show seven mothers treated during eight pregnancies. 'rwo are dead, one is living at three years, and foul' mothers treated during five pl'egnaneies are living and well five years or more after treatment. l;nsatisfaetory as al'e these figures, the number of published ca.'.::es treated with radium plus abortion either spontaneous or induced, is even more meager. Phillipp 37 has reported a case living seven years. She was treated at four months and had a spontaneous abortion at 6112 months. Danforth 38 reports a case well for seven years in whom a very early pregnaney was eurctted from the utel'us just priol' to inserting the radium. On the other hand, there are at least two reported cases (MoriS,a9 Danforth 38 ) of instrumental abortion followed by death from infection. Most of the case reports are issued far too soon for an
2S
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29
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35
36
33
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M . B.* 22599
A.W.-" 24792
S.B. 30042
H.B. 31471
H .B. 3J471
M. L. 3:1975
J.H. 34894
4 month s
4 months
1 months
6 months
7 months
6 monthR
5 months
6 months
I
10/12/39 ]0/1 6/39 10/23/3 9 1I / 13/3 9
2/25/:19 3/ 4/39 4/ 2/39
2/ JO/38
4/ 16/37
2/23/3 6
I
1
11/ 28/3 1 1/ 9/32
5/ 13/30
12/18/2 6
J,072 1,064 506 fj]8 mc. mc. mc. mc.
h. h. h. h.
1,752 mc. h. 1,001 me. h. 1,.169 mc. h.
:1,204 me. h.
1,614 me. h.
2,940 me. h.
2,671 me. h. 843 me. h.
:1,109 me. h.
1,762 mc. h.
TREA'l'l£E:>T
I
IT
II
Dl;HATlOX Ob' CLI:>WAL J>REGNANCY STAGE
11
,J a n., 19'10 Cesarean Hcet ion
6/ 4/:19 Cesarean se(,tion
7/ 19/ 37 Cesarean seetion
6/24/37 Cesarean Hection
6/19/30 Cesarean :section
2/11/ 32 Cesarean section
9/ 12/3 0 Cesarean section
1/1(i/27 Cesarean section
DELIVERY
'Previously r eported by N ciil." i\'L .1. OUST, & GY!'>EC. 30: 414, 1935.
AGE
NAME
TABU;
Living' 3/ J2/ 4:)
l'eeUrrellee
Died July, ] 941-
Living and well, ]943
Living and well, 1943
Livin g- and well, 194:)
Living and well, ]943
Living and well, 1942
Died met. Sept., 1930
l'O[,LOW-UP MOTHER
Living and normal, 3/12/43
xlierocephaly
Mic,"oeephaly Died tuberculoRis, 8/4/42
Died 18 months Meu:sles
Living and normal, 1943
Living and normal, 1943
Living and n ormal, 1942
Living and normal, 3/31/42
BABY
~'OLLOW-UP
2/ 13/ 40·- 690 Ille. h. pluA 2,000 1'. times 4
2/12/30 500 me. h.
POH1'-PARTUl\1 THEA'J'MENT
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AMEHlCAX .JOURNAL OF OBSTETRICS A~D GYXECOI,OGY
estimation of the rure ratc. Therc are also probably many cases with spontaneous abortion following' treatment which have not found their way into the literature. These considerations make it impossible to estimate statisti{'ally the relative merits and dangers of abortion in the treatment of cervix eanrer. It is certain however, that continuation of the pregnancy by no means precludes a cure as indicated by the literature and our own experience. Thc influcncc of pregnancy on tumors in gcneral is problcmatical. The alteration in circulation contingent upon thc intcrruption of pregnancy may cxert an unfavorable influence in curing the cervical growth; this possibility is suggestcd by the very poor prognosis in ca~es treated at term by llecessity with cesarean section, before the treatment of the cervix cancer. It is only fair to say however, that in this latter group the eases are genet'ally more advanced than those seen earlier in pregnancy. In this discussion yery little has been said about the extent of disease in relation to CUl'C. Obviously, this consideration is as important here as in uncomplicated cervix carcinoma. The number of reported cases is too few to makc such a correlation of significance. It is to be notcd that the majority of prenatal cases is not more advanced than I,eague of Kations Stage n. The neglected extensive cases are not encountered until term when delivery of the child is imperative. In estimating the proper therapcutic procedure in a particular case, due weight must be given to the clinical stage of the disease. One would hesitate to accept for trcatment with a view to carrying to term a patient with disease more extensive than Stage II. Because of thc pregnancy with its attendant examination most cases will be discovered relativcly early.
Techlrlque -of Treatment If it is decided to treat during pregnancy with a view to obtaining a normal living child at term, certain points in technique may be stressed. It is important that no high voltage roentgen-ray therapy be employed because of the obvious dangers of substantial depth dosage in the region of the developing child. I"urthermore, it has been our practice to omit the usc of tubes within the cervical canal. This is done for the twofold purpose of se<~uring all possible distance from the baby and also to guard against the onset of lahor by dilating the cervix. The entire treatment is carried out by tubes held in a cloth plaque against the cervix. The details of treatment in uncomplicated cervix cancer have been previously dcscribed. 4o As an additional precaution against stimulating utcrine contractions by prolonged packing against the cervix, we have preferred to use a large amount of radium for a correspondingly short period of time. This means the use of 2.5 to 3 grams of radium. While it is by no means necessary to have available such a quantity of radium for the successful treatment of these cases, the fact that we
JONES, JR., AND NEII.L, JR. :
CARCIXOMA OF CERVIX
457
have in no case stimulated uterine contractions leads us to believe that this is not an unimportant point. The dosage is subject to more variation than in uncomplicated cervix carcinoma. This variation is allowable in an effort to spare thc fetus all possible treatment and must be determined by clinical experience. In the cases herein reported, the dose varied from 1,614 me. hr. to 3.922 millicurie hours. Following delivery it is often desirable to administer additional radium and x-ray. Operative Treatment Irradiation is by far the most common method of treatment for uncomplicated carcinoma of the cervix. In spite of this, many cases complicated by pregnancy have been treated by panhysterectomy. This is probably because panhysterectomy seems expedient if abdominal section for delivery of the child is necessary. ~evertheless, one should be hesitant in accepting this as a suitable method of therapy in view of the unsatisfactory results from panhysterectomy in uncomplicated eervix carcinoma even in carefully selected material. 41 The reported cases based on this method are too few to express the cure rate statistically, but Newell and Scrivner,42 Stacey and Thompson,43 Stoekl,44 Miller/~ Chalfont,46 Bir0 47 and many others have reported such cases both at term and before with an alarmingly high operative mortality. Furthermore, most of these rcports have appeared before an elapsed time of five years so that an estimation of carcinoma of cervix curability is not possible. In our opinion, any necessary abdominal operation either before or following irradiation of eervix ('arcinoma should be confined to evacuation of the uterus. Pregnancy at Term If the baby is viable when the carcinoma is discovered, the problcm of injury to the fetus by irradiation need not be considered. Under these circumstances, the child can and often must be delivered by cesarean section. The prognosis under these circumstances has been very poor. There are approximately 40 reported cases to which we have added four treated by various methods including irradiation, panhysterectomy or both; as far as we are aware, the two cases rcported by Bir0 47 are the only ones which have survived more than five years. The poor prognosis was in many instances due to the advanced stagc of the growth. However, the profound circulatory changes following parturition may be an unfavorablc influence in arresting the disease. The impression received from reviewing the cases of this group, emphasized by the experience of our own four cases, is of a lost opportunity on the part of the attending physician to diagnose and treat an early carcinoma. Almost without cxception, the possibility of making an early diagnosis was dissipated by failure to usc such simple diagnostic
'1-58
.\MEIUCAN JOUR~Afj OF OBf:;TETRf($ AN I) GYKECOLOGY
procedures as speculum examination ~llIJ biop!:!y even after the appearall<~e of such all alarming sign as slight vaginal hleeding during pregnancy. Prenatal tare through it~ 1'outine periodic examinations offers an unequaled opport unity to diagnose carcinoma of the cervix at an early stage.
Summary and Conclusions In forlnulatillg a plan for a clinical situation a!:! rare as the association of pregnancy and elll'cinoma ot cervix, one must draw upon the collective experience of the literature as well as upon one's own eases. It is therefore to be regTeUed that ill so many instanecs, ease reports have been issued too soon to he of value in estimating the ultimate outcome either for mother or baby. }fany more detailed reports of this condition are needed, but these should not be published before the patient has died, or five years after treatment has elapsed. -VVe have come to beli()ve that a general 1'1Ile for the handling of these cases must take into aeconnt th0 obstetl'ie and social haekground as expressed in the desire of the prospective parents for the child, as well as the extent of the disease. If there are other childl'en, or if the parents do not care to assume the ever present risk of an abnormal chi ld, we see no l'ca!:!on 1.0 advise any course except illtel'1'upt.ion of the pregnancy and adequate irradiation therapy. The risk of an abnormal fetns cannot be stat.istically stated at the present time withcert.ainty, hut it seems probable that its upper limit. is 20 pCI' eent. I f' the parents and physician for any reason wish to assume this risk, it is justifiable, in our opinion, to proceed with irradiation during pregnaney with a view to obtaining a living child at term. ]f the pregnaucy is at the fift h month or beyond, the risk of an abnormal ehild is substalltially les..<;. As indicated above, the risk to the mot.her is probably not in('reased by this procedure as eompared with int.erruption of the pregnan('y. The mother 's prognosis is intimately related to the clinical extent of the disease. The genel'v.J experience has been that most euse!:! ~tr(~ diseovered early (League of' ~ations I 01' II), and the prognosis has heen parallel hut somewhat low('[' than for eOl'l'rsponding but uncomplicated groups. The prognosis of eal'einoma diagnosed at term and treated by eCS
JONES, JR., AND NEILL, .JR.:
CARCI~O:lfA 010' CERVIX
4ii!l
that she had a small cervical fibroid which was" removed 12/1/26. Pathologic examination however, showed squamous-eell epithelioma. , At the examination December 18, the entire {'ervix was in vol ve,d and there was some extension of the growth on the vaginal wall . . :\fo parametrial extension by rectal examination. Treatment: 12/18/ 26-2,644 me. against the cervix by 7-tube plaque for 40 minutes. Patient went. into labor spontaneously 1/ 16/ 27 and was delivered by cesarean section. Patient got along very well until 1930, when there was a recurrence. In spite of further treatment with radium and x-ray, the patient died September 12, 1930,frorri the disease. l<'emale child was examined 1-Iarch 31, 1942, and round t6 he normal in every way. She was above average in her school work. CASE 2.-C. B., 22599, aged 32, 3 living child['en. 1J. 11. P. 12/ 16/ 29. Three months prior to May, 1930, there was irregular bleeding and discharge. On examination 5/ 13/ 30, it was estimated that she was 5 to 6 months pregnant. On the anterior Jip of the cervix, llrincipally on thc left side, there was a hard growth. It extended somewhat on to the vaginal wall. Rectal examination showed that thcr'e waR some induration in the right broad ligament. B,iopsy revealedsquamolls-ecll eareinoma. Treatment: 5/13/30-3,109 mc. by 7-tube plaque against the cervix lor one hour. Pregnancy progressed norma1ly and t.he cervix healed. On September 12, 1930, she was delivered hy cesaI'ean section. At operation, the broad ligaments were carefully palpated, and no maRS could be felt. Following delivery, there was a recurrence of the normal menstrual flow which was abolished by x-ray in .Tnne, 1931. Patient has been examined at interva~s since then, the la<;t time heing .Tune 12,1942, at which time she was well. The female ('hild was also examined June 12, 1942, and found to be normal in <'very respect. She waR doing well in her school work. CASE 3.-A. W., 24792, aged 29. Four normal pregnancies during the last. six years. All children living. Patient has never menstruated between pregnancies. In January, 1931, had some spotty va~inal bleeding. There was a little staining caeh day. In September, 1931, 'she bled rather profusely for 5 days. 1o'irst seen November 23, 1931. AbdOniinal examination showed pregnancy which was estimated to be hetween six and seven months. Vaginal examination revealed a friable mass confined to the posterior lip of the cervix with no extension on to the vaginal wall. Rectal examination demonstrated no parametrial involvement. Biopsy showed squamous-cell carcinoma. Treatment: On Kovembel' 28, 1931, the patient received a 7-tube plaque containing 952 me. against the cervix for one hour. She was given also four permanent gold radon implants for a total of 20.6 me. On January 9, 1932, pat.ient reeeived a G-tuhe plaque containing 1,606 me. for 30 minutes. The regression was very satisfaetory. On February 11, 1932, a classical cesarean section was performed. At the time of operation no mass could be palpated in the hroad ligament region. Since operation, the patient has had no£\fr.t'ber treatment and is well as of November 1, 1941. The female child"was also examined on that date and was normal and getting along in srhool hetter than the average for her age. CASE 4.-S. B." 30042, aged 30. Nine pregnancies and five living children. L. M. P. stated to be Odober 1, 1935; however, at the time of
460
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
examination, l<'ebruary 23, 1936, it was estimated that she was 7 months pregnant. On February 9, she first noted a slight bloody discharge and on February 12, had rather severe bleeding. On the anterior lip of the cervix there was a granular uleer. There was little or no extension on to the vaginal vault. The posterior lip of the cervix seemed normal. Rectal examination revealed no apparent extension into the broad ligaments. Biopsy showed squamous-cell careinoma. Treatment: 1,960 mc. divided into 1 tube in the cervical canal and a 5-tube plaque against the cervix for l'i2 hours. Following this, the lesion healed and on April 30, 1936, the cervix appeared grossly normal. On June 5, 1936, a female child was delivered by classical cesarean section. March 12, 1943, mother alive and well, and child living and normal, walked at 11 months. CASE 5.-H. S., 31471, aged 35, five previous pregnancies; ;) living children. Ij. M. P. October 8, 1936. First noticed vaginal spotting in the latter part of March. 1937. ~ever had any irregular bleeding prior to this time. IJost 8 pounds in weight. Examination showed a pregnancy estimated to be 5 months. On the left side of thc cervix, there was an ulcer about 2 cm. in diameter. No extension all to the vaginal wall. No involvement of the parametria. Biopsy showed squamous-cell carcinoma of the cervix. 'l'reatment: On April 16, 1937, received 2,150 mc. against the cervix with a 5-tube plaque for % of an hour. Pollowing the treatment, there was rapid healing of the lesion. Cesarean section on June 24, 1937. Following delivery, it was noted that there was some induration of the right side of the cervix. The patient was given an appointment to report back for further treatment but was very slow in doing so and in February, 1938, when she reported for examination, she was found to be again four months pregnant. Biopsy again showed squamous-cell carcinoma which involved the entire cervix but had not involved the vaginal walls or the parametria. On February 10, 1938, she received 2,746 mc. against the cervix for 1 hour and 10 minutes. For a second time, there was a rapid healing of the lesion and at term a second eesarean section was done. She has been followed at intervals since that time, and there has been no recurrence of the growth. The first child died at the age of 18 months. It was in good health until it contracted measles and died. The second child was mentally defective. She entered the Polk (Pa.) State School May 19, 1942. She was classed as an imbecile with an I.Q. of 43. Soon after admission, she showed evidence of active tubereulosis and died August 4, 1942. CASE 6.-J. H., 34894, aged 38. Four previous pregnancies, the last one 10 years ago. All children living and well. First seen October 12, 1939. Patient complained of intermenstrual bleeding of one year's duration. She was estimated to have a pregnancy of four months. The right side of the cervix was involved in a growth, biopsy of which showed squamous-cell carcinoma. The left side of the cervix was normal, and there was no spread on to the vaginal mucosa or into the parametria. Treatment: 10/12/39, 1,072 mc. foI' one hour. 10/16/39, 1,847 mc. against the cervix for 35 minutes. 10/23/39, 1,012 mc. against the cervix for 30 minutes. 11/13/39, 1,236 mc. against the cervix for 30 minutes. There was improvement in the lesion and the patient had a cesarean section in January, 1940. On March 12, 1943, the mother was alive and well, and the child was normal.
JONES, JR .., AND NEILL, JR . :
CARCINOMA OF CERVIX
461
CASE 7.-M. L., 33975, aged 33. Patient has 8 living children. L M. P. October, 1938. First seen February 2fi, 1939. Examination February 25, 1939, showed a pregnancy which was estimated to be four months. There was a granular growth involving the posterior lip of the cervix and cervical canal. The anterior lip was also thought to be involved as it was stony hard although the overlying mucous membrane appeared normal. Rectal examination showed no invoh'ement. of the parametrium. Treatment: February 25, 1939, 2,628 me. divided into tube in cervical canal and a 5-tube plaque against the cervix for 40 minutes. 3/ 4/ 39, 2,003 mc. similar set up for 30 minutes. 4/ 2/ 39, 2,338 me. with a plaque against the cervix for 30 minutes. Cesarean section June 3. 1939. Careful palpation of the parametrium at the time of operation revealed no induration. The baby appeared grossly normal. 'l'here was a recurrence of the growth in Xovember, 1939, and she received a course 01' x-ray therapy of 8,000 r. through six portals around the pelvis (250 k.v. 30 Ma. 1 mm. copper plus 1 mm. aluminum-15 by 10 portals; 50 cm. S. T. D.; r. measured with scattering) . She also received 1,380 me. for 30 minutes against the cervix. However, she did not do well and died in July, 1941, from the disease. The baby was examined several times and was found to be mentally deficient. By March. 1943, she was not able to talk. CASE 8.-T. K., 23125, aged 35. August 24, 1930. had normal spontaneous delivery. This was the tenth child. There had been some bleed· ing during the latte!' part of the pregnancy. Examination September 23, 1930, revealed the entire vault of the vagina to be filled with a large growth. There was extension into both broad ligament regions but no firm fixation. Biopsy showed squamous-cell carcinoma. Treatment: October 4, 1930, 3,660 me. 2 tubes in cervical canal and a 5-tube plaque against cervix for 50 minutes. There was some improvement, but patient died of the disease in July, 1934, in spite of subsequent treatment with x-ray and radium. CASE 9.-M. H., 24229, aged 38. Multipara 3-0-1-2. L. M. P. September 15, 1930. Pregnancy was normal until February 22, 1931, when she began to bleed in small amounts. Examination June 5, 1931, showed pregnancy of 8Y2 months' duration. There was a nodular cervix with a growth confined entirely to the portio vaginalis. Biopsy revealed squamous-cell carcinoma. The broad ligaments seemed to be free. As the ehild was viable, immediate cesarean section was advised and carried out on June 6, 1931. Patient did not receive radium treatment until July 12, 1931. At that time there had been some increase in the size of the growth which was still limited to the cervix. The fornices were clear. There did seem to be some thickening of the right broad ligament region, although at the time of the cesarean section, careful palpation did not reveal any involvement of the broad ligament regions. Treatment: .July 12, 1931, 1,498 me. for 2 hours with a seven-tnbe plaque against the cervix.
X-ray 7/ 16/ 31, 1,000 r. 7 by 7 suprapubic portal. 7/ 23/31, 1,000 r. 7 by 7 right lateral and left lateral pubic and 1,000 r. on perineal porta1. 7/ 30/ :n, 10 by 10 portal 1,000 r. right lateral sacral and 1,000 r. left lateral sacral. Factors as in Case 7.
462
AMERICAN JOrnXAl. OF OU::>TE'l'RIC8 AXD QYXECOLOny
There was improvement bill on Sepicm bel' 30, I !):~1. t1wI'e was still an ulceration ]112 cm. in dianwter which on hiopsy showed artjvc growth. Two gold points eu{'h eontaining 6.8 11Ie. or radon \\,PI'C inserted into this area. On l\ovembcr 1, 1931, pati('Jlt received 1,060 Jll<':. in thr' eel'vieal canal for 57 minutes. Patient ditl nol improve awl ~he die(l of the disease on April 23, 1932. CASJ<: 10.--B . V, 242HO} aged 39. Patient has had 6 ehildren and two miscarriages. All children living. At term tIl<' patient had a ('('sarean section on December la, J 929, at another hospital. Apparently. it was a classical cesarean seetion and a supravaginal hyst.erectomy. It was not until ,Tuly 25, ] 931, that she came under our observation. There had been no bleeding from the time of the cesarean section until Alay, when it recurred and has continued to the time of examination. A large mass protruded from the <~er\'ix and extended on to th e vaginal wall: Both parametria were involved to the pelvic wall, and thrr'e was fixation to the l'cetum. It was a very ('xtensivc easc. Treatment: July 25 and 26) re('eived 1,000 1'. of x-ray through 10 by 10 portals, 9 fields around the pelvis. Factors as in Case 7. August 3, 19:3], received 2,67:J me. in aIHI on t.he eCl'vix for 67 minutes. On August 17, 1931, she died l'athrr sndd0IIly. . CASE 11.--1\1. K., 84297, aged :n. First Heen }lay 11, 1939. Eight months previously patient had had 11 ('CS8ol'ean f;retion hcrause of an undilatable cervix. After s(lvrral hours in lahor, there was no progress and section was derided upon. Following this, therc (~ontinucd to he some vaginal discharge until the diagnosis of <:ar(~inoma of cervix was made. At this time, the growth was rather massive and had spread into both parametrial regions. Treatment was hegun by x-ray and she received 8,000 r. through four portals from May 9, 1989, to May 18, 1939. J~'actors as in Case 7. On .June 1, 1939, 1,212 me. in and on the cervix for] hour. June 22, ]939. 2,361 mc. on the cervix for 35 minutes. 1"01lowing this, she reeeived many other radium and x-ray treatments, hut the growth eonId not he enred, and she died Angust 15, 1941.
References 1. 2. :1. 4. :'i.
6. i. S.
n.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. il2.
Goldstein) L.} and Murphy, D. P.: A~L J . OUST. & GYXEC. 18: IS9, 192!l. Neill, W., Jr.: A.M .. r. OBST. & GYSEl:. 30: 414, .\93;;. Mundell, J .•r.: AM. 'J. On ST. & GYXEC. 38: 130, ]9:W. Herold, K.: Zen tralbl. 'f. 'Gynak. 59: 2655} 1935. Hofmann, H.: ZentralbL f. Gynak. 58: 1886, 1934. Pouey, H.: Bull. Soc. gynec. et .de d 'obst. 16: 702, HI:!7. Condamine, R.: Gyneeologie 27: 577} 1928. Brouha, -'1:., and GosHelin~ -0.: Bull. Acad. roy. tie Illod. de Belgique 13: 499, 1933. Berkley, C.: J. Obst. & Gynaec. Brit. Emp. 41: 402, 1934. Van Rooy, A. W.: J. Oust. & Gynaec. Brit. Emp. 41: 404, 1934. Paroli, G.: Arch. di ostet. e ginec. 20: 316, 1933. Zimmerman, R.: Strahlenth erapie 29: 108, 1928. Amico-Roxas, S.: Riv. d'ostet. e ginec. pl·at. 18: 9f\ 1936. Fagioli} }f.: Ann. di oste1. e ginec. 58: 1I35} 1936. Smith, F. R.: A~f. J. OUST. & GYNEC. 34: 616} 1937. Petenyi} G.: Klin. Wchnschr. 2: 566} 1923. Gol, }'.: Verhandl. d. ungar arztl. GeselJsch. 3: 79, .Ill:!3 . Schilling, N.: AM. J. OnST. & GYNEC. 7: 440} 1924. Strauss, A.: Am. J. Roentgenol. 43: 552, ]940. Metzger and Leguen~ .,Bull. Soc. gynec. et de d 'obst. 12: 188, 1923. Hartman, H., and Farber, S.: Bull. Soc. gynec. et de d'obst. 12: 167, 1923. Roy: Bull: Soc. gynoo. 'et de d 'obst. 17: 653, 1928.
JOXE1', JR., AXD X£I1.L, JH.:
23. 24. 2;3. 26. 27. 2R. 29.
:lI!.
:ll. :-\2. ;l3.
:l4. il5. 30. :17. a8. 30. .to. 41. 42. 4:3. 44. 45. 46. 47.
('.\HCIXO:\IA OJ<' CERVIX
46:\
Condamine, R., Voron and :Molin: Bull. Soc. gynee. et de d 'obst. 17: 862, 1021-1. McGlinn, .r. A.: A~I..r. OBST. & GY~EC. 18: 502, If)20. Heuze: Liege mCd. 22: 632, 1020. Karg, C.: Strahl