Current cancer chemotherapy in obstetrics and gynecology

CURRENT DEVELOPMENTS

Current cancer chemotherapy

in obstetrics

and gynecology RANDALL Brooklyn,

D. New

BLOOMFIELD,

M.D.

York

As OBSTETRICIANS and gynecologists, we have become increasingly aware of the limitations of the surgical and radiotherapeutic approach to the treatment of malignant diseaseswhich confront us. In general, for surgery to succeed, the malignancy has to be regional, and for radiation to cure, the diseasemust be radiosensitive. Added to those constraints are the complications attendant upon their use. Brewer42 commented that radiation therapy may cause small bowel perforation or obstruction, rectovaginal or vesicovaginal fistulas, septicemia, or anemia. He noted that surgical treatment can be complicated by hemorrhage, shock, or ureterovaginal fistula. Nelson312observed the marked variation in the incidence of ureterovaginal fistula, the be^tenoire of radical surgery. After radical hysterectomy, the incidence has varied from 1.4 to 14.2 per cent. He attributed this wide range to the experience of the surgeon and the technical modifications employed. Moreover, when the diagnosis of cancer is made late and the disease is widespread or when inadequate radiation or surgery has been performed, our problems are increased. Seeking a way out of our dilemma, we From the Department Gynecology, Downstate Brooklyn-Cumberland

of Obstetrics and Medical Center, Medical Center.

have returned to chemotherapy, the “Cinderella of cancer research.“42e While the modern era of this approach is approximately 20 years, Pack and Arie132ehave described the use of arsenical ointment in Ebers Pupyrus, 1500 B.C., as the first recorded method of cancer therapy. Krakoff and Karnofsky254 cited the use by Lissaue?77 of potassium arsenite in 1865 as the first effective cancer chemotherapeutic agent. This drug was employed in the treatment of chronic leukemia. Between the Ebers Papyrus and World War II, a multiplicity of agents were tried. Wright 427 listed local caustics, vaccination therapy, heat therapy, cold therapy, lead, and vitamins. The forerunner of modern alkylating agents, sulfur mustard, was synthesized by Ritchie in 1854.428It was not until 1887 that its vesicant properties were described, and the compound was first used as a chemical warfare agent by the Germans against the British on the night of July 12, 1917, near Ypres.63 In 1919, Krumbhaar and Krumbhaar255observed that sulfur mustard caused leukopenia, dissolution of lyxnphoid tissue, bone marrow aplasia, and ulceration of the gastrointestinal tract. Adair and Bagg,3 in 1931, conducted experimental and clinical studies on the treatment of cancer by musta.rd gas.

488 Bloomfield

her.

One striking example of its effect was noted by S. F. Alexander,6 an alert United States medical officer. In 1943, he noted that the men surviving the initial shock of immersion and blast injury after the sinking of a Liberty Ship with a cargo of 100 tons of mustard gas were dying of a profound depressionof the leukocyte count. Rhoads, Goodman and a.ssociates,141 and Jacobson and associates202 reported in 1946 on the role of nitrogen mustards in the treatment of neoplastic disease. Subsequently, a host of other drugs were developed and clinical trials were instituted. Within less than two decadesof concerted and concentrated effort, this approach has in some areasbought time for us, in others comfort for our patients, and in one malignancy cure. A review of the current role of chemotherapy in our specialty will be presented. Molecular

biology

One of the current keys to understanding the effect of chemotherapy on cancer is to fathom what Karnofsky213 has called the “central dogma” of molecular biology, deoxy-

DNA

Transcription

I Replication

RNA

February 1, 1971 J. @beet. Gynec.

ribonucleic acid (DNA) to ribonucleic acid (RNA) to protein synthesis (Fig. 1). DNA, the genetic material of the cell, acts as the selective template for the pduction of the specific forms of transfer, ribosomal, and messenger RNA. DNA, in directing the formation of specific sequences of messenger RNA, determines which enzymes will be synthesized on the RNA templates. The enzymes, in turn, are responsiblefor the structure, metabolic activity, proliferative rate, and function of the cell. Furth126 stated that cancer is caused by changes upsetting those mechanisms which can control cell division or by environmental agents which irreversibly alter the cells genome (DNA) . Hitchingsl’s added, “that every cell type must have a characteristic biochemical pattern and, therefore, be susceptible to attack at some locus or loci critical for its survival and replication. The existence of cancer chemotherapeutic agents, however unsatisfactory, is evidence a priori that exploitable patterns of metabolism exist in various types of cancer cells” (Fig. 2). Emmelotg8 stated that cancer chemotherapy

Translation

Protein I Cell

I DNA

Strut

1

ture

enzyme Cell

function

Fig. 1. The role of DNA in the control of cell function.

Anti-Purines

--Steroids / / / RNA

Anti-Pyrimidines

Fig. 2. The sites of action of cancer chemotherapeutic agents. (Modified from Connors, T. A.: In Math& G., editor: Scientific Basis of Cancer Chemotherapy, New York, 1969, SpringerVerlag.7s

Volume Number

109 3

Current cancer chemotherapy

aims at the preferential destruction of a tumor growing in the host. In theory, the agent should possessselective toxicity by interfering solely with the biochemical activity of the cancer cell. While tumor cells may be more sensitive to drugs than normal resting cells, there are a number of normal dividing cells, such as the intestinal mucosa, bone marrow, and the reproductive organs, which act in several respects biochemically much like tumors and are damaged by the same agents which interfere with tumor growth. He feels the term “selective toxicity” applies, at best, to the selective destruction of certain tumors or a particular tumor by a given drug. Bruces3 and his group classified agents into three groups, based upon their suggested action at a cellular level. The agents of the first classwere gamma radiation and nitrogen mustard which kill cells in all portions of the generation cycle. The agents of the second classwere vinblastine and methotrexate which destroy cells only in one fraction of the cycle. (The alkaloids seemto act

in the G-2, premitotic phase, and the antimetabolites in the S, DNA synthesisphase.T1 The agents of the third class,54uorouraci1, cyclophosphamide, and actinomycin D, kill cells in all or most fractions of the cycle and sensitivity depends on the fraction in the proliferative state (Fig. 3). Classification

A workable classification of the relevant chemotherapeutic drugs would include : 1. Alkylating agents a. Nitrogen mustard (Mustargen) b. Chlorambucil (Leukeran) c. Cyclophosphamide (Cytoxan) d. TSPA (thio-tepa) e. L-phenylalanine mustard (Alkeran> 2. Metabolic antagonists a. Antifolics-amethopterin, methotrexate b. Antipurines-&mercaptopurine (Purinethol) c. Antipyrimidines-54luorouracil

Go

PHASE -s - DNA Synthesis

Activity Replication

- Cell is actively metabolizing C2 - Premitotic - Prophase, Metaphase Mitosis MAnaphase, Telophase G1

-

Postmitotic

489

- ( Cell’is energy

Go - Resting Phase Fig. 3. Phase of ceII cycIe. (Modified from Weinstein, Monogr. 30: 227, 1969.414)

actively building reservoirs )

up

G. D., and Frost, P.: Nat. Cancer Inst.

490

Bloomfield

Amer.

SN -2

SN -1 RBA CTION 9

-* RX,--R+X

February J. Obstet.

1, 1971 Gynec.

REACTION

RX tAe-+

RA +x*

1

Ae

RA Rate

= K 1(

Rate depends of RX.

only

RX = Alkylating R

= Alkyl

Rate=K&RX)(A*)

RX ) concentration

agent

Rate depends on concentration of RX and A. Bond making and bond breaking occur simultaneous1.y.

group

X = Entity attached on the character Rt= Charged

on

to alkyl group which becomes of the local reaction.

immonium

detached

depending

ion

Ae = Nucleophilic center Fig. 4. First-order and second-order nucleophilic substitution. (Modified from Osdene T. S.: In Clark, R. L., editot: Cancer Chemotherapy, Springfield, Illinois, 1961, Charles C Thomas, Publisher.sss)

3. Antibiotics a. Actinomycin D (dactinomycin) b. 6-Diazo-5-oxo-norleucine (DON) 4. Alkaloids a. Vinblastine (Velban) b. Vincristine (Oncovin ) 5. Hormones a. Synthetic progestins ( 1) 17cu-Hydroxyprogesterone caproate (Delalutin) (2) Medroxyprogesterone acetate (Prover-a, Depo-ProVera) Alkylating agents Mechanism of action. Alkylating agents are highly reactive compounds, which are capable of substituting an alkyl group, generally a short carbon chain (Cx H2x + 2), for a hydrogen ion on the reacting chemical structure.40BThe alkylating agents are electrophilic or electron-seeking reagents with nucleophilic or electron-rich centers to deactivate the functional groups in the biologic systems.41*These drugs can combine with water and most organic substances,the car-

boxyi, the mercapto, the amino, and the imidazole

groups

of proteins.261

There are two types of alkylating agentP”: the monofunctional and the polyfunctional. The monofunctional have one active alkyl group and are said to have less antitumor activity. The polyfunctional have two or more active alkyl groups and have more antitumor activity. Polyfunctional groups are said to be 50 to 100 times

more

active

than

monofunctional groups.160 Polyfunctional alkylating agents inhibit rapidly proliferating cells by cross-linking segmentsof DNA,4 DNA to proteiq3’j7 and protein to protein. s46In addition, they inhibit cellular enzyme systemsin the premitotic phase of cell division. This inhibition serves as the basis for their therapeutic application as well as for many of their toxic properties. Lethal toxicity may occur as a result of interphase and mitotic death.06 Two types of alkylation are described341: 1. Sn -1 reaction-First order nucleophi& substitution (Fig. 4).

Volume 109 Number

Current

3

0 II

CH2-CH2-N-CH I

NIc\ I

2 HN-C

\ I

5. The cross-linked N, position.

combination

C

/ II

\

/

R Fig.

NLc/c\N

CH3 C

491

0 II

I I

/N ;;’

\N/clN

2-C

cancer chemotherapy

I

N/C\NpNH2 A.

of nitrogen

2. Sn -2 reaction-Second order nucleophilic substitution (Fig. 4) . Sn -I reaction.‘1° The tertiary amines, such as nitrogen mustard, following the release of Cl ion, form a positively charged cyclic immonium ion. This intermediate ion reacts avidly with a large number of inorganic ions and organic radicals. The second chlorethyl group reacts with another nucleophilic group. In like fashion nitrogen mustard can combine with the guanine of DNA at the N, position260 (Fig. 5). The presence of an alkyl chain on DNA results in injury to the cell. Specifically from studies on bacteriophage and bacteriophage DNA, it has been deduced that alkylating agents react with guanine at the N, position.s0 The Sn -1 reactions of, gynecologic significance are with nitrogen mustard and chlorambucil.235 The rate of reaction in Sn -1 group is dependent on the concentration of the alkylating agent. Sn -2 reaction.64* 41o In the Sn -2 reaction no immonium ion is formed, transition complex involves both reactants. Thus the rate of reaction is a function of the concentration of both alkylating agent and the nucleophilic compound. The imine groups react with water or an organic molecule. A second imine group can act in the same way as the first. The Sn -2 reactant which has been most frequently employed for gynecologic malignancies is thio-tepa.235 Kaldorzos described the effects of alkylating agents on DNA. He noted that the alkylating drugs could cause rupture of the internucleotide phosphodiester linkages subsequent to the attack on the base rings. The

mustard with the guanine

of DNA at the

fission of intemucleotide linkages might be repaired improperly by the cell. The agents could rupture the covalent bonds within the nucIeotides by their attack on the N, position of guanine, the N, and N3 of adenine, and the N, of cytosine. Polyfunctional reagents may cross-link guanines using the N, atoms on the basesand result in the formation of new cross-linking covalent bonds. The formation of new covalent bonds between two chains of the DNA molecule or between different DNA molecules may inhibit the separation or proper recombination of the polynucleotide chains of the DNA molecule and therefore replication of such cells may be repressed. “Radiomimetic activity.” Dustinv3 and Phillips337 have pointed out the similarity between the biologic activity of alkylating agents and ionizing radiations. They noted that both have similar lethal syndromes, especially hematologic and intestinal. It was observed that each could suppressantibody formation and induce fetal anomalies in pregnant animals. Furthermore, certain neoplasms were found to have a common susceptibility to these two agents. Although the biologic effects of nitrogen mustard and xrays are similar in many respects, differences in their cytologic and mutagenic effects have been described.22 At doses producing approximately similar effects, the tissue damage caused by nitrogen

mustard

is more acute

and recovery more rapid than body irradiation.21e T&sue effects.66 Among the fected by the action of alkylating the hematologic, reproductive, and those of the nervous system.

after total tissues afagents are

neoplastic,

459

February 1.1971 Amer. J. Olmtet. Gynec.

Bloomfield

Hematologic. There is cessationof mitosis and disintegration of formed elements in the marrow and lymphoid tissues6 to 8 hours after a sublethal dose. Reproductive. The gonads are susceptible to the action of the alkylating agents. Subsequent to therapy the patient becomes amenorrheic for several months due to a transient maturation arrest of the Graafian follicles. NeojAzstic tissue. The action of these agents on malignant cells is nonspecific and merely reflects the susceptibility of rapidly proliferating cells to inhibition and damage. Nervous system. These agents stimulate the central nervous system to cause nausea and vomiting. The effect on the autonomic nervous system is cholinergic due to a structural relationship between acetylcholine and the transformation products of methyl-bis compounds. This explains the lacrimation, salivation, bronchorrhea, and bradycardia that can occur with their use. Finally, ShimkinsT3warned that one factor which should enter our consideration in using alkylating agents is the possibility of the iatrogenic induction of neoplasms.While he feels that this may be unimportant in a patient with a disseminated neoplasm, it cannot be ignored in the use of compounds in young patients with nonneoplastic diseaseof long prognosis. Ferguson,l”* however, studied five drugs, Cytoxan, 5-FU, 6-MP, DON, and MTX, and noted that they had little effect on host

CHZ-CH

z-C1

CH2-CH

2-a

resistance and did not foster the growth of tumor by suppressing host resistance. What effect there was occurred only with homografted tumors which do not correspond with human tumors. Two of the five drugs tested, 5-FU and Cytoxan, appeared to decrease host resistance to the homografted tumors. Nitrogen mustard (me&lore&amine, Mustargen, I-IN*). The formula for nitrogen mustard is shown in Fig. 6. Pharmacologic and cytotoxic effects. Nitrogen mustard rapidly undergoes destruction in water or body fluids.6s*s8o It is highly toxic to the bone marrow causing a fall in the leukocyte count and a decrease in the platelets.5BHN2 is a &cant and has caused venous thrombosis and sclerosiswhen given intravenously. The venous complication can be treated with isotonic sodium thiosulfate.38 The emesisthat occurs with this agent can be relieved by Compazine and barbiturates14*: dosage for nitrogen mustard is 0.4 mg. per kilogram of body weight.ls8 Therapeutic use. Intracavitary instillation for malignant effusions?16Intracavitary contrast media can be used to assure correct position of the needle or catheter and to confirm adequate distribution.33B Chlorambucil (Leukeran, CB-1348). The formula for chlorambucil is shown in Fig. 7. Synthesis was by Everett, Roberts, and Ross,~~in the British Isles in 1953, and clinical trials were done by Haddow, in 1954,155 and Galton and associates,in 1955.1zs Pharmacologic and cytotoxic eflects. These effects are similar to those of nitrogen mustard, but, at advised dosages,it is the slowest acting and least toxic alkylating agent in clinical use.62The depression of the bone marrow is gradual and usually reversible. The therapeutic effect is delayed until the

CH3-N < Fig.

6.

Nitrogen mustard.

c-c \\

COOH-CH2-CH2-CH2-d/ \ c=c Fig.

7. Chlorambucil.

/

CH2

C-N’ ’

-CH2-Cl

CH2-CH

2 -Cl

Volume 109 Number 3

Current

third week after starting the drug.6a The slower reaction of the drug with serum and cellular constituents allows the drug to be given orahy. It is said to have a wider margin of safety than melphalan, which can be given orally as well.236 With melphalan, a slight increase in dose may cause severe bone marrow damage and a slight decrease may diminish its therapeutic effectiveness. The dosage is 0.2 mg. per kilogram per day for 3 to 4 weeks.I** Initial maintenance is 0.1 mg. per kilogram per day. The therapeutic use is in carcinoma of the ovary. 231, 291,29%334, 424 It is part of the triple therapy for choriocarcinoma.43 Cyclophosphamide (Cytoxan, Endoxan) . The formula for cyclophosphamide is shown in Fig. 8. Synthesis was by Arnold and Bourseaux20in Germany in 1958, and clinical trials were done by Gross and Lambers152in 1958. Pharmacologic and cytotoxic effects. Cytoxan was designed as an inactive carrier for the alkylating moiety which was to be activated by the phosphamidesof the neoplasm.lD Cytoxan, however, is activated by serum and

H / 2HC \

CHrN,

CH2LCH

,-Cl

CH2-CH

+l

/

o=P-N

\

CHzO’

Fig. 8. Cyclophosphamide.

c-c \ COOH-

CH

-

CH2-

C;

,CH CH

c=c

l&H,

Fig. 9. Phenylalanine

2HC

2TCH

mustard.

-CH2

2Hi;)N-;=S 2HC 2HC ,% Fig. 10. Triethylene

CHtCl

,c -h’\

,-Hz

thiophosphoramide.

z-C1

cancer chemotherapy

493

liver.l12 In addition, this drug has shown more activity in the laboratory mouse and rat than in man. Cytoxan is essentially inactive as an antitumor agent when taken into the body. The resulting metabolites are the active antitumor compounds and the concentrations of these metabolites are high in the animalsbut low in patients.311 Cytoxan has less central nervous system manifestations of nitrogen mustard113 and lessplatelet depression,336 but alopecia73and hemorrhagic cystitis133t33*are problems. The alopecia is said to be temporary,21l 3*3 but the hemorrhagic cystitis has on rare occasions been severe enough to terminate fatally.20° This complication may be avoided by the administration of copious amounts of fluids 334, 353 The dosageis initially 15 mg. per kilogram per week intravenouslylE* with maintenance on 100 mg. per kilogram per day. The therapeutic use is in carcinoma of the ovary. 21,74,35, 351 Phenylalanine mustard ( L-sarcolysin, Alkeran, melphalan, PAM). The formula for phenylalanine mustard is shown in Fig. 9. Synthesis was by Bergel and Stock31 in 1954 in England and clinical trials were done by Holland and RegelsorP in 1958. Pharmacologic and cytotoxic efects. It has similar effects to the other alkylating agents but nausea and vomiting are infrequent.Y24 Dosage is 1 mg. per kilogram of body weight in 500 C.C. 5 per cent g/w over an 8 hour period, repeated in 3 weeks. An oral dose of 0.1 mg. per kilogram per day for 4 weekscan be given. Therapeutic use is in carcinoma of the ovary.58p3s2 Triethylene thiophosphoramide. The formula is shown in Fig. 10. It was synthesized by American Cyanamide Research Laboratories105 and clinical trials were done by Sykes and associates,s841953, and Farber and associates,lo21953. Pharmacologic and cytologic effects. In action thio-tepa is similar to the other alkylating agents, but oral thio-tepa has largely been supplanted by chlorambucil because it has wide discrepancies in toxicity due to its

494 Bloomfield

vagaries of absorption that occur when exposed to the acidic pH of the stomach.aOO Maximal bone marrow depression is usually not evident until 14 days after administration of the drug.so3 Thus, the effect of low doses of the drug should be carefully assessed before protracted courses are started. The dosage is 0.4 mg. per kilogram intravenously for 2 days.lss Then 2 weeks later 0.2 mg. per kilogram weekly for at least 4 weeks unless toxicity develops. Therapeutic use is in carcinoma of the ovary. 27, 147, 192, 208, 247 In expressing his hopes for alkylating agents Seligmax? states, “It appears that the greatest success with alkylating agents in the treatment of cancer will be achieved either when the drug deleteriously affects the tumor cells by virtue of their enzymatic peculiarity or when the drug can be brought to the tumor cells without reaching a significant portion of the bone marrow.” Antimetclbolites The molecular basis for the action of this group of chemotherapeutic agents is the design of synthetic analogues, which closely resembIe those of key naturally occurring biochemical substances (metabolites or cofactors) .3401ss6 These analogues, because of their similarity, are able to enter the cancer cell where they compete with the natural metabolite for its enzyme and thus block one or more specific biosynthetic pathways in the production of DNA. Amethopterin, Methotrexate, MTX. The interest in the antitumor effect of folic acid analogues began in 1944, with an observation by Leuchtenberger,2s4 Lewisohn,272 and their associates that fermentation of the Lactobacillus casei factor inhibited the growth of Sarcoma 180 transplanted in female Rockland mice and caused regression in spontaneousbreast tumors in three strains of mice. This led to the synthesis of folic acid antagonists by Hutchings and colIeagues100in 1947, and to the treatment of acute childhood leukemia by Farber and associateslo in 1948. The initial impetus for

February 1,1971 Amer. J. Obstet. Gynec.

the use of antifols in our specialty stemmed from the observations of Li, in 1953. He noted that a prompt fall in an elevated gonadotropin titer occurred folIowing a short course of methotrexate therapy in a patient who was undergoing treatment for a malignant melanoma and who had been previously submitted to a hypophysectomy. The serendipity of this paraneoplastic syndrome stimulated Li and Hertz274 to attempt to treat patients having chorionic gonadotropin-producing tumors with MTX. Fig. 11 shows a comparison of the structures of methotrexate, folic acid, and citrovorum factor. Mechanism of action. Folic acid is an essential growth factor from which is derived dihydrofolic (DHF ) , tetrahydrofolic (THF) acid, and related compounds concerned with the metabolic transfer of one carbon atoms.*8Folic reductasesare the necessary enzymes in the reduction of folic acid to its active coenzyme form (THF) .145,I62 Methotrexate (MTX) blocks the enzyme fohc reductase and diminishes the availabIe single carbon fragments for purine biosynthesis and the methylation of uracil to form thymine?70p382 The kinetics of inhibition are termed pseudoirreversible because MTX cannot be displaced significantly from the enzyme by any concentrations of folic acid attained physiologically.33 Thus, an overdose of MTX cannot be corrected by giving folic acid. Citrovorum factor (CF) , a derivative of THF, must be given.134p 360p 387 Knockz3? noted that it is ineffective if given after 4 hours, and CF does not displace MTX but provides a usable form of THF that cells can convert into essentialcoenzymes. Borsa and Whitmore observed, in the tissue culture system used, L cells in vitro, that the inhibitory effects of MTX could be compIetely reversed by the addition of thymidine and deoxyadenosine to the culture media. This indicated that all of the MTXinduced effects on cell proliferation and viability were due to the depletion of t+midylate and purines brought about by MTX disruption of the folic acid metabolism. Cells,

Volume 109 Number 3

Current cancer chemotherapy

H

CH2CH2COOH

folic

acid,

495

Methotrexate

Folic

Acid

N?cHC\ N ,yHp H OH

k, Y” 0

H

Citrovorum Fig.

11. Comparison

of the

structure

Factor of methotrexate,

whose proliferation was inhibited prior to exposure to MTX either by lack of essential amino acids or by having reached a stationary growth phase, were resistant to the cell-killing action of MTX. The authors felt that this study served to explain some of the MTX failures. Another problem with methotrexate is that it is poorly transported acrossthe bloodbrain barrier,l14*410 hence neoplastic cells that have entered the central nervous system are not affected by tolerated levels of the drug in plasma. Toxicity. The major lesions occur in the intestinal tract and the bone marrow.308*3*9 In the former, a hemorrhagic desquamatory enteritis can occur, and in the latter disturbance of the red cell maturation can result in an aplastic marrow. LipsetP noted hepatic fibrosis in patients with choriocarcinoma treated with MTX, and he found that patients with pre-existing hepatic diseasewere particularly susceptible to MTX-induced hepatic injury. Additional

and

citrovorum

factor,

forms of toxicity that he observed were pleuritic type chest pain, and localized peritonitis mimicking appendicitis, Condit, Chanes, and Joe117recently observed that MTX exerts a direct toxic effect on the kidney which cannot always be predicted. The toxic effect is idicated by microscopic evidence of damage to the tubular epithelium, increase in blood urea nitrogen, and decreases in the renal clearances of inulin and para-aminohippurate. The severity of these changes is usually directly related to the drug dosage.The authors stated that detailed studies of renal function before treatment had dubious predictive value, but they felt that an unexpected, severe response was unusual and that this problem was an acceptable risk considering the positive POtential effects of the drug. Of recent interest is the report of Clarysse and his associates” who stated that they could suggest but not prove that an allergic type of pneumonia was secondary to MTX therapy. The illness was characterized by fever, cough, dyspnea,

496

February 1.1971 Amer. J. Obstet. Gym.

Bloomfield

CH SH

OH

H

6-Mercaptopurine

OH

6-Mercaptopurine

Fig. 12. 6-Mercaptopurine

Ribonucleotide

and its ribonucleotide.

9 -F

HN/X I

i

04c\N/ HOH2q/*\1 ;;\:-:,

H 5-Fluorouracil Fig. 13. 5-Fluorouracil

7 OH

H

H

5-FUDR

and 5-fluoro-2 deoxyuridine.

cyanosis, and bilateral pulmonary infiltrates as we11as eosinophilia. Fate. Methotrexate is rapidly absorbed from the gastrointestinal tract and peak blood concentrations occur within an hour after oral ingestion.s6j11* Hall,15B however, maintains that the oral uptake of the drug is slow probably because the gastrointestinal tract is richly supplied with folic reductase which binds the methotrexate. Methotrexate is excreted rapidly in the urine and the concentration in blood has fallen to negligible levels 3 to 7 hours after the administration of the usual therapeutic dosasa50 The dosage is 10 to 30 mg. daily for 5 days,lss or 0.4 mg. per kilogram per day for 4 days and repeat course every 2 weeks.1*8 Therapeutic use is in trophoblastic disease.26, 48,17% 194252, 2749 285 &r eflom to conquer this previously devastating malignancy will be furthered when a Choriocarcinema Task Force can add its expertise to this problem.2e’

6-Mercaptopurine-( Purinethol, 6MP). Fig. 12 shows the formulas for 6mercaptopurine and its ribonucleotide. Synthesis was by Hitchings and co-workerslT6in 1950 and clinical trials were done by Burchenal and associates,551953. Mechanism of action. For its biologic action, 6-MP is converted to the corresponding ribonucleotide.45 This antimetabolite interferes with the utilization of hypoxanthine and adenine and this affects the synthesis of RNA and DNA.07 It is probable that 6MP ribonucleotide suppressesde novo biosynthesis of purines, “pseudo-feedback inhibition.“Z62~279 Pharmacologic and cytotoxic effects. The main toxic effect is a bone marrow depression afbzcting all of the elements.826Nausea, vomiting, and jaundice may occur.s08 The dosageis 2 mg. per kilogram per day orallyzX2 or 200 to 700 mg. per day @rally in combination with me-ate; currently the smaller doses are favored.24*8~

Volume 109 Number 3

Current

\

\

/

=3

ISI H-$.-C I

C-C-H I CHjN I SA RCOSINE I L-PROLINE

N CH3 I SA RCOSINE I L-PRdLINE

D-VA

D-VA

hE

o=c

I

I 0

&NE

I c=o

I CH I HN

H3CHC-

497

/

HC

CH

9

6

chemotherapy

GH3

3HC

3HC

cancer

HC

I

d

HCH3

NH

1 o=c

Fig. 14. Actinomycin

D.

Therapeutic use is in choriocarcinoma. Fluorouracil (5.FU). Fig. 13 shows the formulas for 5-Auorouracil and 5-Auoro2-deoxyuridine. In 1957 a collaboration of Heidelberger and associates162 resulted in the synthesisof 5-FU. Clinical trials were done by McIver and colleagues280 in 1957. Mechanism of action. 5-FU inhibits the thymidylate synthetase, thus blocking the conversion of deoxyuridylic acid to thymidylic acid therapy causing thymine deficiency and resulting in the inhibition of DNA synthesis.” Kessel and Hal12*0noted 5-FU via enzymic action is converted to mono-, di-, and txiphosphates of 5-fluorouridine and to a small extent to 5-Auoro-2-deoxyuridine (FUDRP) . This latter substance appears to be the most potent derivative and it strongly inhibits thymidylate synthetase leading to interference with DNA synthesisbut incorporation of 5-FU into RNA. Competition be-

tween 5-FU and uracil for enzymes involved in uracil metabolism are possible additional sitesof action. Pharmacologic and cytotoxic effects. 5-FU acts on the bone marrow and on the intestinal tract.14*loul3041 4s1The drug is halted if there is a severe drop in white blood count or if there is severe nausea, vomiting, or diarrhea.‘l The drug has a low therapeutic index.S26 Dosage is 15 mg. per kilogram per day for 5 days15-poor-risk patients require a lower dose, 10 mg. per kilogram per day.‘jl These are the elderly patients or those with bone marrow destruction by neoplasm, pelvic radiation, or alkylating agents. This group also includes patients with liver metastasis,complicating infection, marked protein loss, adrenalectomy, and hypophysectomy. AnsfieIdls has suggested a modified drug schedule of 12 mg. per kilogram per day for 4 to 5 days followed by 6 mg. per kilogram every other

498

day to the point of toxicity. The average course lasts 14 days. With this approach he noted a significant decrease in irreversible toxicity from 2.9 to 0.5 per cent. This was accomplished without a decrease in clinical effectiveness as compared to his original 15 mg. per kilogram schedule. Ovarian tumors unresponsive to alkylating agents have been treated with 5-FU.l”p 355 It has also been employed in patients with Krukenberg tumors.“’ Antibiotics

Actinomycin D- ( Cosmegen, dactinomytin). The formula for actinomycin D is shown in Fig. 14. Actinomycin D was isolated by Mar-raker and associateP in 1954. Actinomycin D is an unusual type of molecule in that it contains a chromophoric quinoid moiety as well as rings of amino acids.60This antibiotic, on a molar basis, is the most potent anticancer agent available.*Ol Clinical trial was done by Farber, Maddock and SwaffieldlO” in 1956. M&hanism of action. Actinomycin D forms a stable complex with DNA inhibiting the DNA-dependent synthesisof RNA.43o In cells in culture actinomycin D inhibits the synthesis of ribosomal RNA at low drug concentrations and both RNA and DNA at very high concentrations.430 The dosageis 0.5 mg. intravenously given daily for 5 days.lS8Lewis26ssuggesteda dose of 7 to 12 pg per kilogram intravenously for 5 days. Toxicity. One should check carefully for its toxic effects on the marrow, kidney, and liver.so51s36Thrombocytopenia frequently occurs before leukopenia, and with the appearance of the former the drug should be discontinued.lOs Therapeutic use is in choriocarcinoma.43* 270,

February I. 1971 Amer. J. Obstet. Gynec.

Bloomfield

273,

346,

343

DON (6-dim-5-oxo-L-norleucine) . Fig. 15 shows the formula for 6-d&o-5-oxo-Lnorleucine. It was initially isolated from the culture fluids of streptomycin by Diom and associatesaD in 1956 and clinical trials were done by Karnofsky and associates.218

N,CHCO-GH2-CH,-CH-COOH I NH2

Fig.

15.

6-Diazo-5-oxo-L-norleucine.

Mechanism of action. This glutamine antagonist inhibits purine biosynthesisby blocking the reaction of 5-phosphoribosyl-l-pyrophosphate with glutamine to form 5-phosphoribosylamine. 24DIt also blocks the conribotide version of formylglycineamide (FGAR) to formylglycineamidine ribotide (FGAM) , a processinvolving glutamine and phosphoribosylformylglycineamidine synthetase.24QIn addition, DON prevents the transfer of the amide nitrogen to glutamine to uridylic acid to form cytidylic acid and xanthylic acid to form guanylic acid.8 The toxic effects in man differ somewhat from those of alkylating agents. The oral mucosa is red and ulcerated. Abdominal pain and diarrhea may occur. Alopecia is common and is relative to the degree of damage to the digestive tract, bone marrow, depression is less severe than that following the alkylating agents.3g6J 412 Pharmacologic and cytotoxic eflects. A bright red tongue may appear 7 to 10 days after the onset of therapy.22s With this sign, it is advisable to decrease the dose by half for 2 days and the redness will subside. Treatment should then be continued at a lower dose titrating the dose against the tongue response.The ulceration of the oral cavity, vomiting, and diarrhea that can occur respond favorably to adenine.2*2 The dosageis 0.5 mg. per kilogram per day in three divided doses.223 Therapeutic use is in patients in good general condition with hydatidiform mole or chorioadenoma destruens.2*81 223 Alkaloids

The vinca alkaloids are derived from the periwinkle plant, a perennial, which is widely cultivated in gardens throughout the world and has been used in indigenous medicine in various parts of the world.26T In Brazil, it has been used to control

Volume 109 Number 3

Current cancer chemotherapy

459

3

O=i;-0-CH, Fig.

16. Vinblastine

and vincristine.

hemorrhage and scurvy, for toothaches, and cleaning chronic wounds.2o4In the British West Indies, it found favor in the treatment of diabetic u1ceTs,204 and in the Philippines it was reported to be an effective oral hypoglycemic agent.130 While they failed to verify this use, Noble, Beer, and Cutts318and Johnson, Wright, and Svabodazo5 became aware of its suppressive effect on the bone marrow. Vinblastine (Velban, VLB). Fig. 16 shows the formulas for vinblastine and vincristine. The vinca alkaloids are very similar chemically. They are asymmetric dimeric compounds with empiric formulas that approximate C,, Hs8 0, N,. The structures of vinblastine and vim&tine differ only in that VCR contains a formyl (R=CHO) group in the place of the methyl group attached to the nitrogen of the dihydroindole portion.67 There is no cross resistance between VLB and VCR.17 Synthesis was by Noble, Beer, and Cutts,318 Johnson, Wright, and Svoboda,205and their associatesin 1958 and 1959, and clinical trials were done by Hodes, Rohn, and Bond.lT7 Mechanism of action. The vinca alkaloids interfere with spindle formation, inducing metaphase arrest.263* s30 Wagner and Roizman406have shown that the vinca alkaloids inhibit both transfer and ribosomal RNA, but the inhibition is much greater for ribosomal than for transfer RNA. Pharmacologic and cytotoxic effects. Bone marrow depression, primarily leukopenia, is the most important cytotoxic action and this limits the dosage.lz5 With this drug, mental depression can occur, and this action resemblesthat of the other agents derived from indole, such as LSD and reserpine.23BSome

of the additional problems encountered are paresthesias, loss of deep tendon reflexes, convulsions, ileus, urinary retention, and phlebitis.68 The dosage is 0.1 mg. per kilogram body weight.140 Therapeutic use in choriocarcinoma refractory to MTX may respond to VLB.1?* Vincristine (VCR, Oncovin). Isolation was by Svoboda3goin 1961, and clinical trials were done by Armstrong, Dyke, and Fouts,l* and Karon, Freireich, and Frei.21e Mechanism of action. The mechanism of action is the sameasvinblastine. Pharmacologic and cytotoxic efects. Neurotoxicity is the limiting factor with this drug. 173 Paresthesias, loss of deep tendon reflexes, ataxia, and paralysis of extensor muscles and cranial nerves have been observed.6g Other side effects are alopecia, leukopenia, constipation, and hypertension. Vincristine is more active by weight than vinblastine and also causeslesssevere injury to the marrow in relation to its neurotoxic and gastrointestinal effects.253 The intravenous dosage is one-tenth the dose of VLB, 0.01 mg. per kilogram body weight.lso The dose is raised by weekly increments of 0.01 mg. per kilogram until toxicity occurs or the desired result is reached. Therapeutic use is in ovarian dysgerminoma and leiomyosarcoma.204~ 242 Hormones

The Nobel laureate, Charles Huggins,‘Q7 succinctly stated the case for hormonal control of hormone-dependent cancers when he wrote, “Hormones are dispensablefor life of normal cells. Hormones are obligatory for life of hormone-dependent neoplastic cells. Hor-

500

Bloomfield

mone-dependent cancer cells in man or animals die when their host is subjected to (a) hormone withdrawal or (b) hormone interference.” His pioneer work led to the inhibition of cancer of the prostate by the use of estrogens to neutralize the androgens which were felt to activate cancer of the prostate.lss *thetic progestins. In like manner, progesterone and later synthetic progestins were employed to relieve the prolonged unopposed excessivestimulation of the endometrium by estrogens which is thought by many to play a significant role in the development of cancer of the endome~rium.10,53, 9%13% 154, 167, 201g 287*288*204In 1953, Wellenbach and Rakoff41edemonstrated that in oophorectomized hamsters induced endometrial hyperplasia would undergo rapid regression when progesterone was given. Kistner,232 in 1959 and 1962 noted that synthetic progestins produced profound gland atrophy and decidual conversion of the stroma in 9 patients with adenomatous hyperplasia or carcinoma in situ of the endometrium. Kelley and BakerZZ6~ 226in 1960 reported objective remission of metastatic endometrial cancer in 7 of 22 patients treated with 17 a-hydroxyprogesterone caproate. The patients demonstrating the most impressive response were characterized by: ( 1) A long hiatus between the original treatment and the appearance of recurrence of the endometrial cancer. (2) A well-differentiated adenocarcinoma or adenoacanthoma. (3) Pulmonary metastasis with or without local recurrence in the pelvis. Kelleyzz7 cites a recent review by Reifenstein of 247 patients with adenocarcinoma of the endometrium with metastases treated with 17a-hydroxyprogesterone caproate in which a 34.4 per cent objective remission rate was recorded. Other progestinsthat have been used with success include medroxyprogesterone’*306and medrogestone.411 Kelleyzz4 has described total regression of pulmonary metastases,marked regression of hepatic metastases, recalcification of bone lesions,and shrinkage of intra-abdominal and pelvic masses.In some patients these changes have been maintained for years. She observed

Amer.

February J. obatet.

1, 1971 Gym.

that pelvic lesionswhich have been subjected to heavy irradiation are unlikely to respond or react in a transient fashion. Fig. 17 shows the formulas for progesterone, cu-hydroxyprogesterone, medroxyprogesterone, and medrogestone. Mechanism of action. Despite the fact that steroids have been used extensively, the exact mechanism of action remains unknown. It is known that hormones stimulate RNA and protein synthesis and influence cell nuclei function. Thus, they may act by modifying gene activity. The specific action of each hormone on tissue metabolism and its regulation of gene function, according to Koide246may be dependent on its interaction at a particular locus of DNA transcription. The hormones may interact with nuclear membranes, DNA, histones, RNA, acidic proteins, phospholipids or influence acetylation, methylation, and phosphorylation of nuclear proteins. Side effects rarely occur. Dosage for DelalutinG 7%12%22% 2% 23x9 3Top 3g1*s02*4o2is 1,000 to 2,000 mg. weekly for pulmonary and primary lesions, and dosesof 2 to 3 Gm. weekly may be necessary to induce regression in osseous,pelvic, and intra-abdominal recurrences,228particularly if the latter has been subjected to prior radiation. Provera can be given orally in doses of 100 to 200 mg. daily or intramuscularly twice a week in dosesof 200 to 600 mg. Added to our clinical data will be the knowledge gained from molecular endocrinology as to the interaction between hormonesand receptor sites.Some of the current approaches that are being pursued include: 1. The selective binding of systemically administered estradioLgH by the uterus and vagina of the rat, and the decreased uptake of this estradiol by the uterus when Scr-fluoro1l-hydroxyprogesterone is systemically administered.203 2. The inhibition in the mouse uterine and vaginal uptake of estradioVH is by 17a-ethyl19-nortestosterone and by l-( P-2-diethylaminoethoxyphenyl) - 1- phenyl-2-p..methoxyphenyl ethanol (MER-25) .384

Volume 109 Number 3

Current cancer chemotherapy

3

o&

3

o&mocolcH2

Progesterone

Alpha

)4CH3

Hydroxyprogesterone

CH3 I c=o ;&--OAc

cH3 I c=o O&--CH3

I

1 f CH3

6H 3 Medroxyprogesterone Fig. 17. Progesterone,

a-hydroxyprogesterone,

3. The blocking of the effects of estradiol on the uterus and the vagina by actinomycin without an effect on the uptake and retention of estradS3H by these organs.g86 Tumor

501

resistance

HreshchyshyP2 described the two types of resistance that can occur, namely, natural and acquired. In natural resistance,he noted that from the onset the tumor growth was not affected by a particular drug. The toxicity required to affect the tumor is prohibitive in view of the damage to normal tissues such as the bone and gastrointestinal mucosa. Other causesof natural resistanceare: 1. The absence of an agent necessary to activate the drug at the tissue level. 2. Tumor vascularity-which determines the transport of the agent to the cell. 3. Altered cell permeability which affects transport of the drug into the cell. 4. Increased production of an essential metabolic product, which overcomes or bypassesthe deficiency caused by the drug.

Medrogestone medroxyprogesterone,

5. Utilization

and medrogestone.

of

an

alternate

metabolic

pathway to bypass an inherited metabolic step. 6. The tumor cell capacity to deactivate the drug by enzymatic breakdown. 7. Immunologic deactivation. 8. Combination of the drug with nonessentialproducts in the cell. In acquired resistance the alterations and biologic mutations may occur during treatment. Acquired resistance may also be the expression of a selective effect on a sensitive cell type in the tumor population with the resultant overgrowth of a naturally resistant type. Limburg and HeckmarP5 write of primary resistance in which a drug is completely ineffective from the beginning of therapy and secondary resistance in which there is an initial responsefollowed by subsequent generation of tumor cells that are completely resistant to the chemotherapeutic agent or patients in whom the primary tumor responds and the metastasisresiststhe same agent,

502

Bloomfield

Problems

of mass

Amer.

screening

An expansion of this previous theme has been explored by Berenblum and Cotton,30 who pointed out the problems of mass screening. This empirical approach which worked well with antibiotics against bacteria was less successful with cancer therapy because the two problems are not comparable. They explained that, since bacteria differ markedly in their behavior and properties from the human cell, there would be many substances in nature capable of destroying bacteria and leaving the body cells unharmed. In cancer cells, however, which are similar to normal cells, the number of natural or synthetic substances which would destroy one and leave the other unharmed are few. In addition, the body’s defense against bacteria is greater than that against cancer. The body destroys bacteria unless the invasion is overwhelming, the bacterial virulence is excessive, or the body’s defenses are subpar. Contrary to this, our defenses against cancer appear to be quite limited. Finally, the tumor may change from dependence to autonomy and the drug may destroy 99 per cent of the cancer cells, but the remaining 1 per cent, the last surviving cancer cells, will continue to multiply and eventually will fail to respond to the drug. The last surviving cancer cell The pursuit of the last surviving cancer cell has commanded the attention of chemotherapists for some time. A most promising approach has been that of Skipper, Schabel, and Wilcox,37*, 37T the modern proponents of Furth’P theory that one viable leukemic cell could reproduce steadily and quickly proliferate to a number that would kill the host. Thus, they feel that the minimal requirement for cure is the elimination of the last cancer cell. Wilcox421 noted that a given dose of a drug killed the same percentage of cells in leukemia or lymphoma, regardless of the size of the population. The same dose of a drug killed 99 per cent of 100,000 leukemic cells or 99 per cent of l,OOO,OOO leukemic cells, depending on the number present in the host. While the num-

February J. Obstet.

1, 1971 Gym.

ber of cancer cells destroyed is larger if the population is l,OOO,OOO cells than if it is 100,000, the fraction destroyed, 99 per cent, remains the same. The technical term they use to describe the constant per cent reduction in a population, regardless of its size, is First-Order Kinetics, in biologic terms, the logarithmic order of death. The characteristics of a first-order reaction are: The reaction of a constant percentage of the population, regardless of its size, and the reaction of an equal per cent in equal units of time. This reaction is likely to occur when there is only one reactant and that agent is present in excessive amounts such as in drug-treated leukemias. In leukemic mice, they felt cures could be produced if the drug was administered on an intermittent schedule to allow for normal cell recovery and if the dose was large enough so that the percentage of tumor cell population killed outpaced the muitiplication of the surviving leukemic cells. In theory, a number of periods of treatment and recovery would consecutively reduce the number of cancer cells until they were essentially eliminated. Success depended on early treatment or prior treatment with other modalities to reduce the number of cells. Wilcox and colleagues believed that the failure to kill all the susceptible cells immediately was due to the fact that the chance of a reaction in any particular encounter is small. Only a few molecules have enough energy to react and the molecules are of complicated shapes so that even those with enough energy to react must at the same time be oriented properly. Most of the drug is lost because of decomposition in the presence of body fluids and/or excretion before the drug has a chance to react with the cells. When the population becomes very small, the fraction reacting is variable, but there is a calculable chance, states Wilcox, that in any given interval, the last survivor will be eliminated. He feels that a treatment that kills 99 per cent of a large number of cells has a 99 per cent chance of killing one cell. The theoretical rate of tumor cell growth, assuming the cells are identical and non-

Volume Number

109 3

differentiating, is exponential. Each tumor cell divides into two cells each generation time or complete division. The cycle is approximately the same for all cells in the population so that by ten generations, a single cell proliferates into 1,000 cells of 103.295 Further estimations have resulted in the knowledge that to be detected, a tumor must have a volume of at least 1 C.C. and consist of approximately log cellsZg6 The critical kill volume for a patient is 1012, a separation in time representing ten generations in growth, 103.2g6 In leukemia, which is often the forerunner of work done in our specialty, the best therapy reduces the tumor population from lOI to 106.sog At the latter level, the disease is undetectable and the patient is in complete remission. Cure resides in the ability to destroy IO6 cells, since a single leukemic cell implanted in a mouse could multiply and eventually destroy the host. Our dilemma is that we cannot measure below the log level, and this level can only be determined indirectly by the duration of the unmaintained remission.278 Furthermore, diameter, volume, or weight fail as means of measuring the response of a solid tumor to treatment, since tumor size seems to be related to the number of viable and dividing, dead, and dying cells.3og One striking fact is that even after exposure to a lethal dose of drug, tumor cells may go through an increase in volume before decreasing in volume. Moreover, during therapy some tumor cells may act differently and may enter a prolonged resting phase and be less susceptible to drug attack. The National Advisory Cancer Council31o noted that the problem is apparently more complex with solid tumors in which lesions such as choriocarcinoma and Hodgkin’s disease are rapidly growing and respond well to chemotherapeutic agents while malignancies of the breast, lung, and colon are slow growing and are less susceptible to drugs. It was shown that as a tumor grows larger, the doubling time, or time required for the viable tumor cells or tumor volume to double, becomes longer. This increased doubling time may be due to the fact that, as a tumor gets

Current

cancer

chemotherapy

503

older, a certain percentage of its cells may crowd together and enter a nonproliferative phase due to diminished availability of nutrients, oxygen, blood, or increased waste products. They commented that laboratory studies have demonstrated that if you transplant the tumor cells of a population with a prolonged doubling time into a new animal, the transplanted tumor develops a very short doubling time. One means of exploiting this sequence would be to treat the tumor with antimetabolites to destroy a high percentage of actively growing tumor cells, rest the patient, and allow the bone marrow to recover. Then, employ an alkylating agent which attacks the tumor in all phases of the cycle. Wilcox and associates422 pursued the earlier concepts in studying the kinetics of solid tumors using Cytoxan. He assumed that the mass of tumor was in direct proportion to the number of cells in it and that the cells killed by the drug become nonviable promptly, though they divide a few times after treatment. The cells remaining viable despite therapy begin to grow again, after a relatively short lag period, at approximately the same rate as the untreated cells. The previously described approach caused BerenbaumZg to comment that, when the relationship between the dose of a destructive agent and the surviving fraction of a proliferating population is an exponential one, elimination of the last survivor is more likely to be achieved by concentrating the amount of agent that can be given into one or a few massive doses rather than by dividing as it has been advocated by Skipper and associates. He further stated that with antimetabolites logarithmic decreases in cell survival required logarithmic increases in drug dose not linear increases as with radiation and alkylating agents. He viewed the dose response curve for antimetabolites as hyperbolic and not exponential. He felt that cancer cell populations should not be considered apart from their host and that the aim of chemotherapy is not simply to eliminate the last surviving cancer cell, but to do so without critically endangering the host. Berenbaum may well

504

Bloomfield

have been considering Shakespeare’s367 admonition to cancer chemotherapists : “Come, vial, . . . What if this mixture do not work at all? What if it be a poison.” To which Skipper and associates might have replied with Hamlet’s366 remark, “diseases desparate grown by desparate appearance are relieved or not at all.” Various approaches to therapy have been pursued, such as pulsing therapy, combination therapy, and other techniques. With pulsing therapy, an intermittent schedule of drug is used to achieve selective toxicity and to provide a rest period for recovery of the normal cells. The Li, Hertz, and SpencerzT4 use of methotrexate in choriocarcinoma is one such example. In combination therapy, chlorambucil, actinomycin D, and methotrexate have been used against single therapy resistant choriocarcinoma.43 Rall and Homan have suggested the use of a combination of alkylating agents and/or radiation therapy combined with the typical cycle active antimetabolites as sequential therapy for tumor cells in the Go, resting (nonproliferative), phase or the viable tumor cell in the middle of a seminecrotic solid tumor. Indications

February J. Obstet.

Amer.

for

chemotherapy

Karnofsky 210 has suggested a list of indications for chemotherapy and has mentioned the factors that must be considered. He listed three major groups: determination of patient status, principles of therapy, and indications for the use of anticancer drugs. Referable to the determination of patient status was a confirmed diagnosis, the extent of disease, the degree of specific organ dysfunction, the performance status of the patient, and the patient’s attitude toward his disease and treatment. The principles of therapy included a careful plan adjusted to the patient’s requirements, treatment in adequate dosage, careful follow-up for toxicity and disease status, and the use of supportive measures, such as surgery, radiation, nutrition, antibiotics, and blood. Finally, he lists two types of indications for the use of anticancer drugs, namely, estab-

1, 1971 Gynec.

lished indications and experimental indications. The established indications were a disease known to respond, alternative or adjuvant treatment by radiation or surgery, supportive therapy for psychological and situational reasons. His guidelines for experimental indications consisted of a disease that does not respond satisfactorily to conventional measures, a patient who presents objective criteria for evaluation, and a patient who is willing to accept a new agent or procedure. Shimkin has divided drugs and procedures in cancer chemotherapy into three categories of effect: curative, arrestive, and palliative. He considers MTX and actinomycin D as curative in a high per cent of women with choriocarcinoma. Chlorambucil, in approximately one third of patients with cystadenocarcinoma of the ovary, is considered an example of arrestive therapy in which regression of disease and prolongation of life can be recorded. Unfortunately, as he points out, most of the drugs presently available for the majority of neoplastic diseases fall into the palliative group. These are agents that produce clinical improvements without demonstrating an effect on survival. Hreshchyshyn Is7 favors the use of chemotherapy in the following situations: (1) patients who are not suitable for radiation or surgery; (2) for all patients with previous surgery or radiation suffering from endometrial or ovarian carcinoma; (3) to eradicate lesions predisposing to cancer (when clinical circumstances mitigate against radiation or surgery) ; (4) for malignant trophoblastic disease; (5) in combination with radiation, or as an adjunct to surgery. Prevention complications

and

treatment

of

Hreshchyshynla5 states that patients with white blood counts of 5,000 per cubic millimeter and platelet counts of 100,000 per cubic millimeter can be given myelosuppressive drugs in full doses. The dose is decreased by half if the white count falls between 3,000 and 5,000 and the platelets fall to between 75,000 and l,OOO,OOO. The drug is stopped if the counts fall below these limits. If the

Volume Number

109 3

white count is below 1,000 or the platelets are less than 50,000, he places the patients on tetracyclines. Patients who are bleeding secondary to thrombocytopenia are transfused with platelets. With patients on MTX or 5-FU, the diarrhea, stomatitis, and pharyngitis provide a warning of marrow depression and the need to temporarily discontinue the drug. Often the major toxic effect that limits further use of chemotherapeutic agents is bone marrow suppression. Frei115 listed three experimental approaches used to control the side effects of this suppression. He cited platelet transfusions,lf7 white blood cell transfusionslls to control drug-induced leukopenia, and in leukopenic patients prophylactic antibiotics and reverse isolation363r s64 to decrease the risk of infection. (The initial idea of plastic isolators57 led to the development of laminar air flow, LAF,36* 37 units in which the patient is protected from infections by a controlled flow of recirculating filtered air. The contaminated air brought in by visitors is blown into filters and rendered germ-free before it is recirculated to her.) Brodsky and his co-workers46~ 47* 51 have employed a fourth technique, pharmacologic doses of testosterone enanthate in an attempt to modify the marrow suppressive effects of chemotherapeutic drugs. Their data suggest that testosterone could do this and thus permit the administration of larger doses of chemotherapy. The effect of testosterone on erythropoiesis was also evaluated and in 9 out of 11 patients there were significant increases in the hemoglobin concentration, packed cell volume, and red blood cell mass50 Of concern to our specialty is the dose of testosterone employed, namely, 600 mg. per week for 6 weeks.49 One major side effect of this dose was the masculinization in females associated with hirsutism and deepening of the voice. In place of testosterone, Nelson31” had advocated the short-term use of cortisone to reverse bone marrow depression. One means of evaluating the marrow granulocyte reserve was the use of the pyrogen stimulation test4*v llol 248 in which Piromen,

Current

cancer

chemotherapy

505

a Pseudomonas lipopolysaccharide endotoxin, was injected intravenously in a dose of 25 mg. Normal subjects challenged by the endotoxin characteristically show a fall in leukocyte count at 1 to 1.5 hours. Then within 3 to 5 hours there is a 2,500 per cubic millimeter or greater rise in the absolute granulocyte count as compared to the control level before injection. A depressed response indicates a decrease in the marrow granulocyte reserve. This is usually associated with increased sensitivity to chemotherapeutic drugs from the standpoint of the early development of severe leukopenia. Methods

of evaluation

The language of therapy. A current

and most laudable attempt to audit the bewildering maze of data that have been accumulated, and to make it meaningful, is the work of Feinstein, Pritchett, and Schimpff.lo7 They note that, at any moment, the clinical course of a cancer can be identified according to the variation in five different types of data: ( 1) demographic, which describes the patients’ personal and environmental attributes; (2) clinical, which describes the patients’ symptoms and signs; (3) paraclinical which describe roentgenographic, gross anatomic, endoscopic, microscopic, and laboratory details; (4) comorbid which described agents and procedures of treatment. The clinical course can be affected statistically or therapeutically by the decision of the doctor and the patient. The physician must decide about criteria for diagnosis of cancer, adequate classification of patients’ symptoms, choices of therapeutic procedures, evaluation of therapeutic accomplishments, and appraisal of the clinical mode of death. The decisions made by the patient include a choice of circumstances in which to seek medical attention and an acceptance or rejection of the proposed clinical management. These differences must be analyzed to ascertain comparability in groups of treated patients. The time sequence of the clinical course of cancer can be labeled by the prezero

506

Bloomfield

interval, the zero interval, and the postzero interval. The prezero interval refers to the events between the last negative examination and the pretherapeutic detection of cancer. The zero interval is the first neoplastic treatment and the postzero interval includes the subsequent course, treatment, and, when pertinent, the terminal events. Fre? feels that short of cure the duration of unmaintained remission (DUR) is the best parameter to evaluate the number of malignant cells present, and since this work in antileukemic therapy has often preceded that of gynecologic chemotherapy, his thoughts on the subject are most relevant. He defines the DUR as the time from the cessation of treatment which has yielded complete remission to relapse. He states that the time from the cessation of treatment to death is a precise measurement of the number of persisting leukemic cells at the end of therapy or the reduction of the number of leukemic cells by treatment. The fewer the persisting cells, the longer the time to relapse. To Hreshchyshyn,lss an index of symptomatic improvement and prolongation of life was a decrease in the size of the mass by greater than 50 per cent by palpation or 25 per cent by direct measurement, in one diameter for at least 3 months in the absence of prohibitive toxicity and without signs of progression of the disease elsewhere in the body. One problem, however, is that Gurland and Johnson 153 have stated that the discrepancy between measurements of tumors made independently by different physicians or the same physician on different occasions can be substantial. This problem was also noted in measuring tumors seen on x-ray film. Despite the hue and cry for more objective measures for evaluating the progress of a cancer patient. Schneidermar? makes a strong plea for the sensitive physician who, he feels, has at his command far keener and potentially far more useful measures of evaluation. He states that objective measures are merely substitutes for the better (when properly made) subjective measures. Objective measures, however, do have a place in the

Amer.

February .I. Obstet.

1, 1971 Gynec.

early stages of drug development in the drugoriented studies, such as the measurement of tumor shrinkage. In the more advanced studies the purpose is not only to find “What does the treatment do,” but also is more to find “How does the patient respond, in total, to the treatment.” The objective measures have to be supplemented if not supplanted by whole patient (subjective measures), if we are to avoid “Getting the correct answer to the wrong question.” Here, he declares the artistry of the physician in determining what is really the proper question may be much more important than the “objectivity” of the measure. A most effective approach is the criteria of Performance Status of KarnofskyZ17 in which the patient is given a grade from 100 per cent to 0 per cent with an increment of decrement of 10 per cent. A grade of 100 per cent means that she is normal, asymptomatic, and has no evidence of disease. At 80 per cent she can accomplish normal activity with effort and has some signs or symptoms of disease. At 60 per cent she requires occasional assistance, but is able to care for most of her needs. At 40 per cent she is disabled and she requires special care and assistance. At 20 per cent hospitalization is necessary. She is very sick, and active supportive treatment is necessary. At 0 per cent she is dead. In addition, he classified the response to therapy. He listed three “Categories of Response” and their subdivisions.214 Category 0 was one in which there was no clinically useful effect on the course of the disease. In Category I, a clinical benefit with favorable objective changes in all measurable criteria of the disease was noted. Category III was characterized by interruption or slowing in the progression of the disease without evidence of subjective or objective improvement. Currently, Greenberg and Grizzle144 have the last word when they declare that the best and most useful statisticians in clinical studies are those who can learn to get along with doctors. They describe the physicians’ view of the statistician as a meddler and the statistician who has a closed mind to the

Volume Number

109 3

suggestions of the physician. The statistician may view his role as one of rescuing the experiment from the “stupid doctors.” The authors stress the importance of a senior person of prominence who actively participates during the planning stage and acts as an amicus curiae for the neophytes. Considerable emphasis is placed on the importance of the collaboration between the statistician and the physician. It is important that the statistician become acquainted with the disease, the personnel, and the problems that arise in carrying out the protocol. Sensitivity testing. Von Muraltto4 Danielli,84 and Knock241 have observed the wide range of clinical response of patients treated with the same drug for the same kind of tumor. Thus, they have directed their efforts at drug sensitivity tests. These include the use of agar plate assays,gl~ 302 Schrek tests,362 and biochemical tests of drug activity.32, 34p178, 425 With specific reference to our specialty have been the efforts of Kohorn and Tchao,245 as well as Limburg and Heckman.275 Kohorn and Tchao have studied a system of tissue culture to predict which cases of endometrial cancer are sensitive to progesterone. They used survival organ cultures, since they felt that the cell behavior under these conditions would better reflect conditions in vivo. Medroxyprogesterone, 10 mg. per milliliter, caused necrosis in one case and enhanced the culture in the other. In the tissue culture of 10 patients with endometrial cancer progesterone in low concentration, 10 mg. per milliliter, yielded enhancement in eight cultures while progesterone in large concentrations, 50 mg. per milliliter, caused necrosis. Kohorn and Tchao cited the work at Nordqvist,31g who observed that progesterone in concentrations of 50 to 80 mg. per milliliter is not only toxic to endometrial carcinoma, but also to the normal endometrial cell. In six cultures, the cancer was studied by Kohorn and Tchao in the presence of serum from the patient. Inhibition was observed in 4 cases and in 2 cases the serum had no significant effect. They stated that the effect of the serum of the patient on the cancer is of great im-

Current

cancer

chemotherapy

507

portance and they referred to the paper by Rubin,s50 who found that in 12 patients with endometrial carcinoma there was a correlation of the prognosis with the ability of the patients’ own serum to inhibit the growth of cancer in tissue cultures. Limburg and HeckmarP5 used freshly cultivated tumor cells before the cells could lose their original character by adaptation to the nutrient medium during a long cultivation, The dosage of the cytostatic drugs in vitro was adjusted to the conditions of clinical therapy. The single therapeutic dose was correlated in vivo to the median body weight of a patient of 60 kilograms with a median blood volume of 5,000 ml. In addition to in vitro testing the authors used two more tests for resistance in tumor cells. They employed a quantitative method to determine the effect of cytostatic drugs on tumor cells from the amount of lactate dehydrogenase activity passing from the cell into the nutrient media. They also transplanted human cancer tissue into a chamber with a Millipore filter in the peritoneal cavity of a rat. After the administration of a carcinostatic drug to the rat the cytostatic effect was assessed by the reduction of tumor growth. The investigators then computed the mean survival time of 140 cases of advanced cancer of the female genitals using the TNM classification. Their results were as shown in Table I. Another method of predetermining the effect of a chemotherapeutic drug on ovarian carcinoma has been the technique described by Nelson.314 He noted that the spindle poisons, vincristine, vinblastine, colchine, and podophyllin, when injected into patients produced arrest of mitosis in the metaphase. This picture was referred to as an exploded metaphase. This fact was used to determine the mitotic index of all new cases of ovarian carcinoma prior to the institution of chemotherapy. Of the 31 cases studied a sharp dividing line was observed between those with a low mitotic index and those with a high mitotic index. Nelson remarked that in no instance had a case with a low mitotic

508

Bloomfield

/her.

Table I. Mean survival time in patients with advanced cancer of the female genital tract

Therapy

apfilied

Untreatedpatientswithout chemotherapy Cytostatic drugswithout sensitivity tests Cytostatic drugsafter

sensitivitv tests CombinaGon of operation or radiation and cytcstatic drugs without sensitivity tests Comdmation of operation or radiation with cyto-

static drugsafter sensitivity tests

Mean survival I No. of I time 1 Patients 1 (days)

14

79

23

168.8

12

373.8

18

411.9

19

640.8

Advanced anaplastic ovarian carcinoma 14 No chemotherapy 15 Without sensitivitvtests After sensitivity t&s 25

2:: 527

index responded to chemotherapy, whereas all patients with a high mitotic index have had good objective remissionsin their disease for at least 6 months. One of the major drawbacks of the chemotherapeutic approach to cancer is the narrow range between the therapeutic effect and systemic toxicity, the therapeutic/toxicity ratio. Since the metabolic action of several agents seemedto interfere primarily with the synthesis of nucleic acids, Valenti, Adams, and Breed401attempted to enhance the cytostatic effect of 5-FU by its application to a population of synchronized cells in vitro. In this manner the cell population is brought to a point in ifs cycle which is metabolically most sensitive to the agent so that a significant reduction in both dosage and duration of cell exposure to the drug might be achieved. The authors are using this technique to test the sensitivity of individual tumors to antimetabolites in vitro. One intriguing facet of the search for additional markers of trophoblastic activity has been the work of Nelson and Hall.sle~317 They demonstrated the absenceof germinal centers in lymph nodes during pregnancy, a

February J. Obstet.

1, 1971 Gym.

change which lasted for 6 weeks. They also stated that if we accept the germinal centers as sites of lymphocytic production then the lymphopenia in pregnancy is understandable. Subsequently, Nelson313examined the lymph nodes of 2 patients with choriocarcinoma who had not received chemotherapy. These nodes showed the samechangesas those seen in the nodes of patients with normal pregnancy. He suggested that there was an apparent inverse relationship between the absolute lymphocyte count and chorionic gonadotropin titers in casesof choriocarcinoma. In view of this finding, he felt that the use of the absolute lymphocyte count would be a far simpler method of following response to chemotherapy than the use of chorionic gonadotropin levels. Lewis and his associates26sl 271 studied heterotransplantation of human choriocarcinoma in the hamster cheek pouch (an approach pioneered by HertP* to use as model system for screening drugs for clinical trials in the treatment of metastatic gestational choriocarcinoma). They were abIe to suppressthe immune rejection of the tumor with heterologous antilymphocytic serum. Thus, they were able to assess more accurately the responseof the tumor to MTX. Serial measuring of plasma gonadotropin by radioimmunoassay was employed as a measure of growth. Five days after tumor implantation, plasma HCG concentration and tumor size bore a closecorrelation. Errors

in therapy

Larionov259 states that the most important errors in clinical cancer chemotherapy are as follows. Delayed treatment. The application of chemotherapy only in the advanced stages of the disease. Undertreatment. Discontinuing therapy because of a reduction in the size of the mass. It is important to use the maximum tolerated dose, despite side effects. Overtreatment. Excessive therapy producing a profound drop in the white count with a decline in the immunobiologic properties of the body.

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Infatuation

Current

with

new drugs. The

delayed treatment coupled with undertreatment are the cause of a drive for a new drug. One should learn to master what we have before rushing to the new. The response to a treatment often depends not only on the drug used but the correctness of the indications for its use and the technique of treatment. Chemotherapy in specific sites Cervix.215* 344 Hreshchyshynls7 noted that the mortality in New York State from cancer of the cervix had declined from 14 per 100,000 to 6.5 per 100,000. Cutlers1 observed that more cases of cervical carcinoma were being diagnosed early. Data from the State of Connecticut and from Almeda County indicate that approximately two thirds of all neoplasms of the uterine cervix are now discovered in the situ stage. He noted a marked improvement in patient survival among both surgically and radiologically treated patients. For the treated patients, the 5 year relative survival rate increased from 75 per cent in the 1940’s to 89 per cent in 1955-1959. The corresponding increase among radiologically treated patients was from 45 to. 55 per cent. He commented that the difference in survival rates was largely due to the proportion of localized tumors in each group. Among the surgically treated patients in 1960-1964,80 per cent were classified as having localized disease. Among the radiologically treated patients 47 per cent were so classified. Kaufman and KarnofskyZZo noted that despite the decline we still had a country-wide mortality figure of 10,000 per year. Chemotherapy has not been effective here. Intra-arterial nitrogen mustard has been palliative in patients with intractable pelvic pain.lB7 The effect is a dampening of the sensory nerve ending rather than tumor destruction. There are current trials with methotrexate,306y 331 but one must keep in mind that MTX is hazardous in patients with impaired renal function, and obstructive uropathy is a common complication in recurrent cervical cancer.lll$ 307s327 5-FU has also been tried, with slight success, by Malkasian and associates283 and Chan, Ho, and

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WOO.~O SmithBT8 commented on 91 patients who had received Cytoxan as palliative treatment for carcinoma of the cervix. He found that Cytoxan was the easiest to administer. Of the patients treated, 20 per cent had 50 per cent or more shrinkage of the tumor volume for three months or longer, and about 50 per cent of the patients with pain had excellent control for at least 3 months with Cytoxan. Pain, however, as an end point has its problems. As early as 1915, Wei1413 wrote about the therapeutic claims made for pain relief in cancer patients and felt that in the great majority of these cases the result was in no small measure psychic. Corpus. CutlerB2 noted that in a large proportion of patients, cancer of the endometrium was being diagnosed in a localized stage. The proportion of tumors limited to the corpus had increased from 64 per cent in 1940-1949, to 74 per cent in 1960-1964. The proportion of patients treated by surgery alone or in combination with radiation had also increased from 54 per cent in 1940-1949 to 64 per cent in 1960-1964. These changes have been accompanied by a marked increase in patient survival. The 5 year survival in cases diagnosed in 1955-1959 is 72 per cent compared to 60 per cent in cases diagnosed in the 1940’s. Sykessg3 stated that there are approximately 40,000 new cases of cancer of the uterus in the United States each year; of these, 29,000 are cervical and 11,000 are endometrial. She commented that carcinoma limited to endometrium with no pronounced involvement of the myometrium was associated with a 5 year survival which may be as high as 80 per cent. With extrauterine spread, the prognosis is poor. I have previously mentioned the studies of Kistner231 with atypical adenomatous hyperplasia and carcinoma in situ and the work of Kelly and Baker225l 226 with metastatic disease. Hreshchyshyn1a8 noted that 80 patients with recurrent endometrial cancer had a 19 per cent marked or complete tumor regression. The alkylating agents, 5-FU and mitomycin C were tried by Parker, Newton, and Peete.333 A significant objective response was described

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as infrequent. Clomiphene citrate caused tumor regression in a patient unresponsive to progestin therapy. 407 The ability to produce regression of a far advanced endometrial carcinoma by hormonal manipulation has added immeasurably to our management of this gynecologic malignancy. The collaborative study by LewiP5 in investigating the roles of surgery, radiation, and chemotherapy should bring us much closer to the most effective approach to endometrial carcinoma. Uterine sarcoma. In uterine sarcoma, if the lesion is resectable, surgery has been the treatment of choice.80* 371 Hreshchyshynlao~ Is4 considers the use of actinomycin D alone or in combination with radiation for mixed mesodermal tumors. For patients with nonresectable lesions who have not had radiation a combination of radiation and this drug can be employed. However, he advises great caution in the combined use of these two methods since one of his patients died from toxicity. The median survival in 7 patients treated by surgery and radiation was 3 months. The median survival in nine patients given the agent alone was 4 months. The median survival for 9 patients to whom a combination of radiation and actinomycin D was administered was 6 months. Hreshchyshyn commented that neither the quality of objective response and its duration nor the prolongation of survival was as good as that observed in ovarian cancer. Malkasian and associates2s4 treated 26 patients with advanced gynecologic sarcoma with various chemotherapeutic drugs. Of the 9 patients treated with actinomycin D and radiation, 4 (3 leiomyosarcoma and 1 fibrosarcoma) obtained an objective response for 3 to 10 months. Two were later treated with 5-FU when recurrences appeared and both demonstrated an objective response. There were 10 patients treated with 5-FU and 5 had objective responses to therapy for 3 to 8 months. These 5 tumors represented 4 1eiomyosarcoma.s and 1 carcinosarcoma. The only death related to drug administration in the series was that of a patient treated with 5-FU.

Amer.

February J. Obstet.

1, 1971 Gynec.

Their experience with other drugs was unrewarding. Finally, the authors felt that while the responses that they obtained were dramatic they were also brief and they did not believe that the survival of patients with these tumors was increased significantly. stated that only 28 per Ovary. Cutlers3 cent of ovarian tumors are diagnosed in a localized stage and there has been no significant change during the past 25 years. In recent years, 1960-1964 he observed that chemotherapy alone or as adjuvant therapy has been used much more frequently. In 1960-1964, 27 per cent of patients with ovarian carcinoma were so treated, compared with 9 per cent in 1955-1959 and only 4 per cent in 1950-1954. While the prognosis remains poor, he commented that a slow but continuous increase in patient survival rates had occurred during the past 25 years. The 3 year relative survival rate increased from 30 per cent in 1940-1949 to 38 per cent in 1960-1964. The 5 year relative survival rate increased from 24 per cent in the 1940’s to 30 per cent in 1955-1959. In the latter period the 5 year survival rate for surgically treated patients with localized disease was 73 per cent. Cancer of the ovary has become the fourth leading cause of death from neoplastic disease in American women stated Griffith.151 He noted that in contrast to the declining death rate from carcinoma of the cervix the death rate has more than doubled since 1930 (from 3.2 to 8.9 per 100,000) and that if the 1962-1964 death rates prevail more than one out of every 100 women in the United States between the ages of 30 and 45 will eventually die from ovarian cancer. Kaufman and Karnofsky2*l state that the present 5 year figures for Stages I and II of ovarian cancer are approximately 50 to 60 per cent. For Stage III it is somewhat less than 30 per cent and for Stage IV less than 10 per cent. They also noted that in 75 per cent of the patients with ovarian carcinoma the tumor is not resectable at the time of the diagnosis. Adequate radiation is rarely possible because in the majority of the cases the tumor has spread beyond the pelvis and 50 per cent

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of the patients die within 6 months. At present 9,000 women die of ovarian cancer each year in the United States, and Pomerance, Maltz, and Ha1P40 noted that, at the time of their report in 1966, the leading cause of death from gynecologic malignancy in the City of New York had been ovarian carcinoma. Julian and Woodruff207 listed the chemotherapeutic drugs used for the systemic approach to this disease, An alkylating agent is tried initially. If it fails, a 5-FU or a combination of actinomycin D, 5-FU, and chlorambucil may be considered; nitrogen mustard is reserved for those effusions that fail to regress with systemic chemotherapy. who has studied thioHreshchyshynlsg tepa extensively suggests the following scheme of management: 1. If at 6 weeks after the start of treatment there is no response or whenever, following induction of a remission, reactivation of the growth occurs further treatment with alkylating agents is terminated and the patient is started on 5-FU or VLB. He feels that the chances are poor with these two drugs. Ansfield, I5 however, observed a 20 per cent remission rate with 5-FU. 2. One may retreat with alkylating agents if the initial drug treatment was discontinued following a response and in all patients in whom the initial treatment with the drug is judged inadequate. Hreshchyshynlg3 who analyzed 130 patients with ovarian carcinoma treated with chemotherapy alone found that: ( 1) 17 per cent of the patients had a good response (50 per cent decrease in size of the mass by palpation or 25 per cent decrease by actual measurement for a period of 3 months) ; (2) 21 per cent had some response; (3) In 50 patients with ascites and/or pleural effusion 26 per cent had complete suppression of the fluid and 38 per cent had partial suppression. (4) Chemotherapy was a contributor to the death of 11 patients. (5) Patients with a good response to chemotherapy survived three times as long as patients with a lesser or no response (13 months as compared to 4 months) .lg6 (6) Forty-five patients with

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primary combined radiation and chemotherapy had a median survival of 12 months. Masterson and Nelson2g2 reviewed the results of chlorambucil 0.2 mg. per kilogram per day given for 4 to 6 weeks to 280 of 289 patients with advanced ovarian carcinoma. Objective remission lasted for at least 6 months in half of the patients and another 15 per cent showed arrest of the tumor for at least 6 months. Some 40 patients given repeated courses for 2 to 4 weeks at intervals of 1 to 3 weeks have been kept in remissions for 2 years or longer. The white cell count fell below 5,000 per cubic millimeter in 60 per cent of patients, including 85 per cent of those with objective remissions during and after the initial course of therapy. Usually a level of 2,500 to 4,000 cells per cubic millimeter was maintained. Two of the 3 patients with Krukenberg tumors were given 5-FU and had dramatic remissions. Serous and mutinous cystadenocarcinoma were more sensitive to chlorambucil than malignant teratomas. Poor prognostic indices according to a recent statement by MastersonzgO are a white blood count that remains above 5,000 cells per cubic millimeter and herpes zoster. Jolleszo6 and Varga and Henriksen403 administered progestational agents to a total of 16 patients with ovarian carcinoma and 3 responded well. Wider and his associates420 administered combined methotrexate, actinomycin D, and chlorambucil to 4 patients with ovarian carcinoma containing choriocarcinoma. They obtained a sustained remission lasting from 14 months to 4yz years in 3 of the 4 patients. Decker and colleagues reported that 36.5 per cent of their 104 patients with recurrent ovarian carcinoma and 48.2 per cent of their 139 patients with untreated advanced cases showed some response to Cytoxan. Rutledge554 reviewed the M. D. Anderson experience with phenylalanine mustard (PAM) given to 239 patients and 49.4 per cent of the patients so treated were benefited objectively. If the patients who received inadequate therapy, less than three courses, are

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excluded the number of patients helped rose to 62.7 per cent. The objective responses’of papillary serous and mutinous carcinomas were 53 and 55 per cent, respectively. When the patients with the papillary serous and mucinous carcinomas who received incomplete therapy are removed from the series the per cent of positive responders become 61.2 and 68.7 per cent. The patients with adenocarcinoma with adequate therapy responded in 44 per cent of the cases, and with the separation of those who received insufficient theatment the number of positive responders rose to 61.2 per cent. In the failures to PAM, 5-FU has been employed but has proved to be disappointing. The current management of ovarian cancer by the M. D. Anderson groups5” consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy, if surgically feasible, plus omentectomy when gross tumor is present. In Stage I disease posthysterectomy, irradiation using the total abdominal strip technique is given. (In the strip technique as described by Delclos and Fletcher,86 cobalt60 is employed. The entire treatment time to cover an area from the pelvic floor to the diaphragm extends from 30 to 40 days. A tumor dose of 2,500 to 2,700 rads measured at the midline of the patient along a sagittal plane can be delivered safely. The authors feel that the moving strip technique allows for greater biologic efficiency and better tissue tolerance than the static field technique. The anterior and posterior surfaces of the abdomen from the pubis to the xiphoid and divided into contiguous transverse strips 2.5 cm. wide. Alternating daily between the anterior and posterior positions, strips are irradiated beginning at the pubis with the first strip. Thereafter, one strip is added daily until four strips have been irradiated front and back. Then the 10 cm. strip is moved 2.5 cm. up every day by alternating front and back until the last strip is reached. The field is then reduced by one strip daily. In the last 2 days a single strip is irradiated. The kidneys are shielded from the back with two half-value layers of lead which reduces the dose to the kidneys

February 1, 1971 Amer. .I. Obstet. Gynec.

by 50 per cent. The right side of the liver front and back is shielded with three halfvalue layers of lead.) In Stages II and III when all the tumor is excised or when no tumor masses over 3 cm. remain, strip abdominal radiation plus an additional 2,000 r to the pelvis is given. When tumor masses over 3 cm. and/or ascites exist PAM is administered. If the tumor masses decrease to less than 3 cm, and ascites disappears, chemotherapy is discontinued and strip irradiation and the previously noted additional pelvic irradiation is given. Failure to respond after 5 courses of PAM or return of tumor after initial response requires changing the noted that after receiving drug. ( Gallager’2R phenylalanine mustard the presence of histologically demonstrated neoplasm with or without degeneration was an unfavorable sign.) Since the results with 5-FU have been disappointing Rutledge355 has been using a combination of actinomycin D, 5-FU, and Cytoxan in smaller doses. Frick and colleagues124 reported 15 per cent objective remission in 104 patients with disseminated ovarian carcinoma previously treated by surgery. In most of their cases external x-ray to the pelvis or pelvis and abdomen had been administered before chemotherapy was started, these patients were generally treated by a single course of chemotherapy. Their current proposallZZ is as follows : Stage I-Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy (surgery) . Stage II-Surgery plus external x-ray to the pelvis (4,500-5,000 rads) over 4 to 5 weeks following the completion and recovery from external therapy, the administration of an alkylating agent, prophylactically is seriously considered. Stage III-Surgery plus total abdominal irradiation by external x-ray (3,000 rads) in 4 weeks with shielding of one kidney after total abdominal therapy is completed. Therapy with an alkylating agent is strongly recommended. Stage IV-Surgery plus an alkylating agent as primary therapy, the surgery is per-

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Current

formed whenever possible. The main exception is in case of young woman with a unilateral, borderline tumor. BurchenaP4 believes that chemotherapy and radiotherapy can be partners and cites the use of radiation to reduce bulky tumors followed by chemotherapy to destroy the few surviving cells. VillaSanta and Bloedorn405 have gone one step further and advocate a combination of surgical removal of as much tumor as possible, external abdominopelvic irradiation and protracted chemotherapy in ovarian cancer extending beyond one ovary. Critical assessment of the effect of chemotherapeutic drugs on ovarian carcinoma has often been hampered by the different criteria used to judge an objective response, the dissimilarity in staging, the varying combinations with surgery and or radiation, and at times incomplete data as to the histolo
tumors

The fundamental contributions of Nov&32% 321 and H&g166 166 and other++ 2, 10% 2891*g3, 378;432 in interpreting the pathology and clinical course of trophoblastic tumors have been outstanding. Hertigls4 cited the incidence of a hydatidiform mole at Boston Lying-in Hospital as 1 per 2,000 pregnancies and choriocarcinoma was preceded by a mole in 50 per cent of the cases. Novak and Leahsz2 and Park332 noted that approximately 85 per cent of the patients with molar pregnancy will undergo complete remission after uterine evacuation. In the prechemotherapy era, Delfss7 studied 119 patients with moles and 9 per cent developed a malignant invasive phase. Schiffer,359 in the same period, followed 63 patients and 19 per cent

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developed a malignant counterpart. It is estimated that the incidence of invasive mole including choriocarcinoma is one in 15,000 to one in 20,000 pregnancies or about 200 to 265 new cases a year in the United States with approximately two thirds of these cases being choriocarcinoma.“22 While the time-honored classification has been hydatidiform mole, chorioadenoma destruens, and choriocarcinoma,94 a partial listing of the current classification adopted by the International Union Against Cancerl” is: I. Classification A. Gestational B. Nongestational C. Clinical diagnosis 1. Nonmetastatic 2. Metastatic a. Local (pelvic) b. Extrapelvic (specify location) 3. Other required information (evidence, antecedent pregnancy, previous treatment) II. Morphologic diagnosis 1. Hydatidiform mole a. Noninvasive b. Invasive 2. Choriocarcinoma 3. Uncertain 4. Other required information (diagnostic-basis date of diagnosis, subsequent change in morphologic diagnosis).

Hydatidiform

mole.

Diagnosis. In the clinical history of a patient with a mole there is often a history of uterine bleeding, anemia, a uterine size in excess of her dates, uterine infection, hyperemesis, and toxemia, but the diagnosis is often made only after the passage of vesicles or the expulsion of the specimen.g6 Goldstein and ReidlS7 considered the following procedures helpful: a fetal ECG36g to verify the absence of a fetal heart; the use of ultrasound281; and, most important, an increased urinary or serum human gothey mentioned nadotropin I37 level. While the absence of a fetal skeleton they were more impressed with the intrauterine dye in-

514

Bloomfield

jection techniquezsi which showed a motheaten or honeycombed appearance when a mole was present. Satisfactory radiographs were obtained in 18 women with suspected molar pregnancy. Of these, 15 had the condition. Two of the remaining 3 had multiple gestations and one had a benign cystic teratoma with a coexisting normal pregnancy. Using ultrasound, Gottesfeld and associates14? studied 61 patients with suspected hydatidiform mole. Molar pregnancies were diagnosed correctly in 17 patients. One patient who initially was thought to have a missed abortion was later thought to have had a mole. Management. Eastman and HellmanQG have advised the use of oxytocin stimulation followed by a careful curettage, abdominal hysterotomy in uteri over 12 to 14 weeks, and abdominal hysterectomy in patients over 40 years of age. Brandes, Grunstein, and Peretz41 have also mentioned the use of suction curettage. In a pilot study of prophylactic chemotherapy by Goldstein and Reid,13s MTX has been employed to prevent the dissemination of tumor by manipulation and to counter the innate tendency for invasion and deportation of trophoblastic tissue. The dose of MTX used is 15 to 20 mg. daily for 5 consecutive days given intramuscularly or actinomycin D 7 to 12 rg per kilogram daily for 5 consecutive days given intravenously. The drug is started 2 days before surgery at the time of spontaneous delivery of a mole. The patients are followed with white blood cell counts, platelet counts, and serum transaminase levels. In their series there were 49 women who served as controls and 39 treated patients. Of the control group 64 per cent were well after evacuation and in the treated group 90 per cent. There was nonmetastatic disease in 22 per cent of the controls and 10 per cent of the treated patients. No cases of metastatic disease had been noted, in the treated group whereas 14 per cent of the controls had metastatic disease. The major toxic problems in the treated women included stomatitis in 60 per cent, leukopenia

February 1, 1971 Amer. 3. obstet. oynec.

in 45 per cent, granulocytopenia in 25 per cent, and hepatic function test impairment in 25 per cent. There were no observed differences with respect to the rapidity of urinary gonadotropin titer fall in either group. Chun, Lu, and ChungT2 observed the prophylactic use of chemotherapy in 14 consecutive cases following termination of a molar pregnancy. One patient developed metastatic choriocarcinoma under therapy but went into complete remission after two further courses of MTX and 6-MP. They preferred giving prophylactic chemotherapy only when the chorionic gonadotropin titer persisted in the urine for 4 weeks after termination of the molar pregnancy since, in their if the chorionic gonadotropin experience, titer was positive at 4 weeks over 62 per cent of the patients would develop choriocarcinoma if left untreated. Koga and Maeda244 gave systemic chemotherapy to 92 patients within 3 weeks after the removal of a mole. Of the 53 patients treated with MTX, 10 of whom received intrauterine and systemic MTX, none developed choriocarcinoma. There were 37 patients in the control group and 3 developed choriocarcinoma. With the 39 patients treated with other drugs, HN,, N,O, thiotepa, Cytoxan, Mitomycin C, and Chromomycin A-3, choriocarcinoma developed in 3. Follow-up. Goldstein13B views Gravindex, a quantitative immunologic test, as adequate for follow-up when the measured human chorionic gonadotropins (HCG) are over 5,000 I.U. per 24 hours. For gonadotropin levels below 5,000 I.U. per 24 hours, urinary gonadotropin excretion must be assayed by the mouse uterine weight test which measures total gonadotropins including FSH, LH, and HCG and is expressed in mouse uterine units per 24 hours ( 1.0 mouse uterine unit = 0.1 of an International Unit of HCG) . This test has the advantage of being able to detect as little as 0.5 I.U. per 24 hours. This level of gonadotropin excretion is consistent with endogenous pituitary values and indicates total absence of HCG. According to Goldstein, normal values are less than 200 mouse uterine units per 24 hours in women

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with functioning ovaries and less than 2,000 mouse uterine units in castrated or postmenopausal women. He feels that urinary gonadotropin excretion should be normal 6 weeks after evacuation. After that bioassays, at monthly intervals for 6 months, and bimonthly intervals for 6 months, are performed. Hammond and Parkerls8 note that HCG and pituitary LH cross react and the only distinguishing feature between them is quantification (Midgley and JaffeZDp have described a method of distinguishing between HCG and LH by techniques of gel filtration and radioimmunoassay). In the laboratory of Hammond and Parker the normal pituitary will produce up to 4 I.U. per 24 hours of LH-HCG if the gonad is functional and up to 20 I.U. per 24 hours if the gonad in nonfunctional (castrated or postmenopausal female). The procedure employed is that of bioassaying the concentrate by the mause uterine weight technique of Klinefelter, Albright, and Griswold.233 Hammond and Parker also stres that the routine immunologic and biologic tests require approximately 1,000 I.U. per 24 hours or more of HCG to give a positive response. The danger of relying on these tests if negative is appreciated when one realizes that 25 to 30 per cent of patients with trophoblastic disease will have HCG titers below the 1,000 I.U. required to give a positive pregnancy test. They state that if the pregnancy test is positive it is of use, but if it is negative the full pituitary test must be done to exclude persistent trophoblastic disease. Once monitoring of the patient is begun it must be continued until all the HCG has been removed. Goldstein’35 added that when dealing with a castrated or postmenopausal female, it was wise to carry out an estrogen suppression test using stilbestrol 5 mg. daily for one week prior to the urine collection before assuming the gonadotropin titer to be normal for this patient. BagshaweZs and other+ 288 have advocated the use of radioimmunoassay for the measurement of HCG, Yen, Pearson, and Rankir? have stated that a quantitative immunologic assay is satisfactory when the titer is at a low level.

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In those cases a sensitive bioassay means of measuring urinary gonadotropin is needed. He contends that radioimmunoassay for quantitative analysis of serum HCG has provided a reliable and sensitive index for the activity of trophoblastic tumors. In addition, this type of assay is less time-consuming and less expensive than bioassay and circumvents the 24 hour urine collection. UCG titers have afforded a rapid and satisfactory means for the diagnosis and initial therapeutic monitoring since HCG levels are usually high and the absolute value relatively unimportant to the clinical management at this state of disease. UCG titers should be used initially. Immunoassays or bioassays should be employed when the UCG titer becomes negative, for assurance that the disease has been eradicated. Goldstein and Reidl’O advise a follow-up of weekly gonadotropin titers until normal, chest x-rays every 2 weeks until gonadotropin excretion is normal, repeat gonadotropin assays at monthly intervals for 6 months (then bimonthly for 6 months), and avoidance of pregnancy for one year. Eastman and Hellmans contended that pregnancy could be safely undertaken if: the chorionic gonadotropin titer remains negative for 6 months; recurrent ovulation is indicated by regular normal menses biphasic temperature curves and ovulatory vaginal smears. Goldstein and Reid stated that if, at any time following the evacuation of a mole, urinary gonadotropin excretion reaches a plateau or begins to rise the presence of viable trophoblastic tissue is more than a possibility. The chances of nonmetastatic disease or metastatic disease following molar pregnancy increase in proportion to the duration of time it takes for gonadotropin titers to reach normal levels. If it takes 4 weeks following evaluation, the patient has a 20 per cent chance of developing choriocarcinoma. If a level is still elevated at 6 to 8 weeks, the patient has a 40 to 60 per cent chance of developing this complication. Hammond and Parker*50 list as their criteria for institution of therapy a tissue diagnosis of hydatidiform mole, an HCG titer

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that remains elevated 6 weeks after evacuation; a titer that shows a tenfold rise during the 6 week interval or if metastases appear during the 6 week interval. If the patient has chorioadenoma destruens or choriocarcinoma, an assay is done and the patient is treated immediately. Single intermittent therapy with either methotrexate or actinomycin D can be employed. Treatment is stopped when the HCG titer becomes normal. The agent is changed if the HCG titer plateaus with two courses or rises tenfold or new metastases appear. The oncolytic agent is monitored by the use of weekly HCG titers, chest x-rays, physical, and pelvic examinations. A remission is considered to be three consecutive weekly normal gonadotropin titers. Follow-up consists of gonadotropin titers monthly for 6 months thereafter. They advise that there be no pregnancy for one year. They also submit the patient to routine evaluation every 3 months during the first year. Hreshchyshynlg5 advises that subsequent to the evaluation of a mole the patient should be followed for at least one year, preferably 2, with chorionic gonadotropin titers. Curettage should be repeated if 4 to 6 weeks after evaluation there is bleeding or the uterus is subinvoluting. If no molar tissue is found at curettage and there is a persistent elevation of chorionic gonadotropin one must suspect extrauterine trophoblastic growth. If the titers are falling one may wait. He feels that, if abnormal titers of chorionic gonadotropin persist unchanged for 2 weeks or rise, chemotherapy is the treatment of choice. Hendrickse and colleakgues163 favored the use of pelvic angiography3Dv 131* l’** 423 in the management of malignant trophoblastic disease and performed 100 such procedures between 1961 and 1964. They felt that a dilatation and curettage was contraindicated because the procedure carried the risk of disseminating the tumor with resulting tumor emboli going to the lung, and the operation could be associated with severe hemorrhage requiring an emergency hysterectomy. A negative histologic report might only mean

February J. Obstet.

1, 1971 Gynec.

that the tumor does not communicate with the uterine cavity or was missed with the curette. They cite the fact that 5 patients with malignant trophoblastic disease had histologically normal curettages. On angiographic appearance, one noted dilation of the vessels supplying the uterus and adnexa. In the initial films, the uterine artery or arteries were enlarged to greater than 1 mm. in diameter. Increased vessel redundancy and coiling may also be present. The contrast media, in the later phase enters irregular vascular spaces. In most cases of malignant trophoblastic disease, a functional arteriovenous shunt develops through the tumor deposits. Another of our dilemmas is distinguishing between a normal pregnancy following trophoblastic disease and the advancement or recurrence of tumor. Samaan and colleagues358 have studied human placental lactogen, HPL, by radioimmunoassay of HPL throughout pregnancy. They demonstrated an early and marked rise that continues up to term. In contrast, HPL assay of mole and choriocarcinoma revealed very low levels which remained low during the course of the disease. Yen, Pearson, and Rankin,42D however, in a subsequent paper noted that the HPL production by the trophoblastic neoplasms was limited and did not necessarily reflect the total function of these tumors. They felt that HPL levels are a less satisfactory index of neoplastic activity than HCG levels in these patients. Another approach is the use of ultrasound. Kobayashi243 has observed that, with this technique, pregnancy can be accurately diagnosed in approximately 98 per cent of the patients at 6 weeks after the last normal period. Chorioadenoma destruens and choriocarcinema. Management. In the past the treatment would have been hysterectomy and radiation or an attempted excision of a metastatic growth. The recent Albert Mathieu Chorionepithelioma Registry44 figures published in 1963 for the 5 year survival following hysterectomy was 41.4 per cent. The 5 year survival for 70 patients without known me-

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tastases at the time of surgery was 41.4 per cent, and the 5 year survival of 52 patients with known metastases at the time of surgery was 19.2 per cent. In 1956, Li, Hertz, and Spencer,2’4 reported that MTX produced remission in three patients with metastatic trophoblastic tumor using 15 to 25 mg. once daily for 5 consecutive days. In 1961, Hertz16Q reported on 111 patients with metastatic trophoblastic disease, 98 of whom were initially treated with MTX. They noted that 46 per cent obtained a complete remission without relapse for from one to 7 years. Ross and associates346 in 1965, writing on the same group, summarized the status of 50 patients treated with either MTX alone during 1961-1964 or followed by actinomycin D in resistant cases and found complete remission in 76 per cent with choriocarcinoma and 73 per cent with invasive mole. Toxic responses to treatment were followed with daily blood counts, tests of hepatic function (SGOT, SGPT, and alkaline phosphatase) , renal function evaluation (BUN, serum creatinine) at least every other day during active therapy. 347 Treatment was rarely initiated, continued or resumed if any one of the following was observed: ( 1) white blood count less than 3,000 per cubic millimeter; (2) platelet count less than 100,000 per cubic millimeter; (3) polymorphonuclear leukocyte count less than 1,500 per cubic millimeter; (4) abnormal hepatic function tests; (5) abnormal renal function tests. Treatment was continued until the urinary gonadotropin was normal or there was a lack of response. After three consecutive normal titers the patient was discharged from the hospital and followed with serial titers. Ross, Hammond, and Odell347 noted their results in 44 patients with nonmetastatic gestational trophoblastic disease. Complete remissions were obtained after chemotherapy in 33 of the 34 patients with antecedent molar pregnancies, 3 of the 5 patients with antecedent term pregnancies, and all 5 of the patients with pregnancies ending in abortion. Two of the 3 chemotherapy failures responded to hysterectomy

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and the chemotherapeutically induced remission group had no recurrences for more than 5 years in some cases. Among those patients with complete remission 18 had one or more pregnancies with 14 term infants with no obvious defects, 3 spontaneous abortions, one stillbirth cause unknown, and one death following surgery for correction of a tetralogy of Fallot. At no time was there exacerbation of disease or subsequent new trophoblastic growth. Lewi? commented on the factors affecting prognosis in patients with metastatic gestationa trophoblastic dise&se. He observed that the most favorable criteria for a good response to chemotherapy were effective treatment early in the course of the patient’s disease and a chorionic gonadotropin titer of less than one million mouse uterine units per 24 hours. The site of metastases was important. Patients with lesions of the liver and brain responded poorly to chemotherapy unlike those with pulmonary metastases who do very well. Hreshchyshynlg” favors MTX as the initial drug of choice. His suggested dosage is 0.4 mg. per kilogram of body weight intramuscularly for 4 days. Once the condition is stabilized he may give the treatment by mouth. Repeat 4 day courses are given approximately 2 weeks apart. If the BUN rises to 25 mg. the dose is decreased by half. Before the response to the drug is evaluated, the patient receives at least three courses over a 6 week period. If there is a decrease in the chorionic gonadotropin titer and a decrease in the size of detectable lesions one continues to treat as long as there is evidence of disease and the patient continues to respond. He states that patients with no response at 6 weeks after at least three courses and those who become refractory or develop reactivation following an initial response to MTX should be treated with actinomycin D. Those patients who fail to respond to methotrexate and actinomycin D can be considered for surgery if the tumor is resectable. Goldsteir? pointed out that since there can be a 5 to 10 per cent incidence

518

February Amer. J. Obrtet.

Bloomfield

of relapse during the first 3 to 6 months a full therapeutic course of the last drug given should be administered after the first normal titer is obtained. When relapse does occur, chemotherapy should be reinstituted immediately. Sung, Wu, and Ho3s8 have employed 6-MP effectively and this may also be considered. Bagshawezs used MTX and 6-MP and has achieved a total regression in over 85 per cent of his patients. Vinblastine has also been helpful in methotrexate failures.lTO As mentioned above, Li’s273 triple therapy, of methotrexate, chlorambucil, and actinomycin D, has been used in patients whose tumor proved resistant to both methotrexate and actinomycin D. Hammond and Parkerleo have attempted to improve the results in selected patients with poor prognosis. These are the patients who before initial therapy have HCG titers above 100,000 I.U. per 24 hours, a duration of disease in excess of 4 months, cerebral or hepatic metastases, or are patients with metastatic disease who have developed resistance to all forms of conventional single agent therapy. They have employed intensive combination therapy with methotrexate, actinomycin D, and chlorambucil. With this form of therapy, the authors noted severe marrow depression and a mortality rate of 10 to 15 per cent. When cerebral or hepatic metastases are discovered simultaneous radiotherapy is given. The dose delivered is 2,000 rads during 5 to 10 days as either whole cerebral irradiation or whole hepatic irradiation. They contend that this frequently allows completion of chemotherapy without major hemorrhage from metastatic foci. They have evaluated further the place of surgical treatment and adjunctive chemotherapy in patients with nonmetastatic disease who do not desire additional children, those with persistent uterine disease who developed resistance to single agent chemotherapy, and those with metastases controlled by chemotherapy but who have persistent uterine disease. A standard course of methotrexate or actinomycin D is begun and the patient is operated on the third day of the 5 day course. She, is monitored in the usual

1, 1971 Gynec.

fashion. In addition, these investigators have employed pelvic arteriography to diagnose trophoblastic disease and regional chemotherapy infusion to treat patients with persistent pelvic disease. Therapy is given by infusion pumps which deliver methotrexate or actinomycin D daily. The only problem has been thrombophlebitis during infusion. Our efforts to conquer this previously devastating malignancy will be furthered when a choriocarcinoma task force can add its expertise to this problem.2B7 Teratogenic

effect

Karnofsky*‘l remarked that reviewing drugs as teratogenic agents was a complicated and frustrating assignment. He asserted that the problem was even more difficult with cancer chemotherapeutic agents since they are used therapeutically at near toxic doses. The critical embryonic periods are implantation and organogenesis during the first trimester and the drug must be present in relation to these specific events to result in a significant effect by causing either fetal destruction or developmental defects if the embryo survives. The results of studies in laboratory animals are of uncertain relevance to man. Karnofsky remarked that each species has its characteristic placental functions, maternal endocrine status, embryonic biochemical differentiation, and organogenesis and operates on its own time schedule in terms of changing interrelationships. Also the drug dose on a body weight basis is often greater than the therapeutic dose recommended in man. He maintained that the mechanics of action of a drug on a subcellular, cellular, and organ level would have to be related to detailed information on maternal physiology, placental function, and embryologic development. The studies on the teratogenic effects of chemotherapeutic agents on humans are rela3% 3751 381Tu&m~-Duplestively sparse. 14% sis400 commented that the teratogenic action of the anticancer compounds on the human fetus had been proved only for Myleran, chlorambucil, cyclophosphamide, and amino-

Volume Number

109 3

pterin. He presumed that this was due to the fact that the teratogenic effect of a compound was difficult to detect. Most notable are the works of ThierschSDr in which aminopterin, an antifol, was given to 12 women during the third to the eighth week of gestation causing spontaneous delivery within 5 to 17 days and the inquiries of Warkany4”* on the teratogenic effects of the antifols. Stutzman and Soka1388 reviewed 86 cases of anticancer drugs administered during pregnancy. Of 58 cases in the first trimester 26 resulted in abortions and there were 9 malformations. Six patients received MTX during pregnancy and no abnormalities or abortions were noted. Three patients received it during the first trimester. Twenty-one patients were given 6-MP, 6 patients each in the first and second trimester, 2 in the third trimester, with insufficient data in the remaining cases. No malformations were noted in these patients. The drug was used in patients with acute leukemia who would not have survived without it. VLB was employed in 4 patients of whom 2 were in the first trimester and no fetal damage was observed. Cytoxan given in the first trimester to one patient was associated with multiple congenital anomalies. There was also a single case report in which multiple congenital anomalies followed the administration of chlorambucil given in the first trimester. A recent case of interest is that described by Milunsky and Graef.sol In an infant born after unsuccessful abortifacient use of MTX 2.5 mg. daily for 5 days, between the eighth and tenth weeks of gestation, there were multiple congenital anomalies, including absence of the frontal bone, synostosis of the lambdoid and coronal sutures, multiple anomalous ribs, partial bilateral syndactyly of the third and fourth fingers, no digits on the right foot, and one digit on the left foot. Despite the reported safety in many cases, Stutzman and Soka1388 contend that cancer chemotherapeutic agents should be avoided during pregnancy unless they are lifesaving, as in patients with fulminating leukemia and

Current cancer chemotherapy

519

lymphomas. If such situations occur, decreased dosages or intermittent therapy during the first trimester should be planned whenever possible. Ethical problems of cancer therapy. The ethical problems of human experimentation have received increasing attention.28l lzlf 114* 261, 374 When one is giving potentially lethal drugs to the patient this is particularly true. Many aspects of the problems have been surveyed. Freund119, lZo has stressed the importance of voluntary consent and of hospital committees to consider all protocols for research involving human subjects. Blumgart3” noted the difference between the doctorpatient relationship which is a therapeutic alliance and the experimenter-subject relationship which is a scientific alliance. He felt that in the clinical management of a patient the expected benefits must outweigh the estimated risk. The investigator-subject relationship must be guided by the concept of an informed consent and the precepts of the Nurembergz40 and Helsinki9 codes. The Nuremberg code demands the highest degree of skill and care in all steps of human experimentation and repeatedly warns the physician to prevent needless injury to his patient. The Declaration of Helsinki reinforces the admonition of the Nuremberg code. Knock23D has succinctly reminded us, Primum non nocere-First do not injure. Final

comments

Lute, Bodey, and Frei2’8 remarked that to the clinician the size of the tumor is one measure of effectiveness, since a 90 per cent reduction in the number of neoplastic cells frequently results in the clinical disappearance of the tumor. However, there are lOlo to 1O’l number of tumor cells in the average patient with metastatic cancer and, since it is the fractional reduction in tumor cells rather than the absolute number of cells that remains constant for a given course of treatment, a complete regression due to 90 per cent tumor cell destruction marks just the beginning and not the end of effective treatment. The production of chorionic gonadotropin

520

by

February

Bloomfield

a very

plastic

small cells

highly

Amer.

subclinical

affords

number

the

important

of

neo-

chemotherapist

guide

to

continued

a treat-

ment. This course is pursued until the hormonal titer is normal. This presumably is when all the neoplastic cells are destroyed. Such an approach is largely responsible for the success in curing choriocarcinoma. Unfortunately,

this

plastic

with

disease

is the a

only

known

quantitative

neomarker

for a subclinical number of malignant cells. Lute, Bodey, and Freis7* viewed our efforts for the last three decades. They recalled the past when morphine was all we had, commented on the present where we can treat with certain drugs and stand a good chance of achieving long-term control, and voiced future hopes for cure. Saluting the work of those involved they declared that with

the

advent

of

cures

these

efforts

Acosta-Sison, H.: 58: 125, 1949. Acosta-Sison, H.,

AMER.

J. OBSTET.

5. 6. 7. 8. 9.

10. 11.

12.

13. 14.

OBSTET.

represent the most splendid achievement of the era. One must, however, be aware that no form of therapy whether it be surgical, radiotherapeutic, cytotoxic, or whatever the future holds in store will do well unless we, as physicians, are empathic and sensitive to the total needs of our patients. As stated so eloquently by Graham,143 as a senior medical student, “If a physician is to heal, then as a man he must care.” I wish Louis M.

to express my Hellman, James

Masterson,

J. E. HalI,

appreciation H. Nelson,

MyrosIav

this direction

and

Tricomi and this review.

Richard

especially Calame

to Drs. John G.

Hreshchyshyn,

and Manuel Ochoa, Jr., who over answered my questions and guided

15.

GYNEC.

1, 1971 Gynec.

the years have my efforts in

to Drs. for

their

Vincent help

with

will

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J.

J. Obstet.

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16. and

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Bloomfield

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Volume 109 Number 3

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142.

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149.

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352. 353. 354. 355. 356.

357.

358.

359.

360. 361.

362. 363. 364.

365.

366. 367. 368. 369. 370. 371.

372.

373.

374. 375. 376.

377.

cancer

chemotherapy

527

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381. 382.

383. 384. 385. 386. 387. 388.

389. 390. 391.

392. 393. 394.

395. 396. 397. 398.

399.

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Amer.

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405. 406. 407.

408. 409. 410. 41 I. 412.

413. 414. 415. 416. 417. 418.

419.

420.

421. 422.

423. 424. 425. 426. 427. 428. 429. 430. 431.

432.

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