Advances in the Chemotherapy of Solid Tumors*

Advances in the Chemotherapy of Solid Tumors* ROBERT D. SULLIVAN, M.D. ELTON WATKINS, JR., M.D. S. PETER GIBB, M.D.

AN ENORMOUS UNDERTAKING of cancer research is currently in progress to develop anticancer drugs for use in the management of neoplastic disease in man. Increasing numbers of chemotherapeutic agents are filtering through the preclinical animal tumor and animal pharmacologic screening programs and are available for clinical use by the physician. The federal government's chemotherapy program has greatly accelerated the 'search for chemical agents for the control of cancer. In 1960, over 21 millions of dollars was appropriated for the various programs of the Cancer Chemotherapy National Service Center (CCNSC).21 These funds support vast programs which embrace the synthesis of new drugs, animal tumor screening, pharmacologic investigation and clinical trial of selected compounds. Despite the prodigious efforts of these preclinical and clinical programs, progress has been slow and no chemical agents have been developed that are capable of inducing a general curative effect on disseminated forms of cancer. Nevertheless, definite advances have been made in recent years in the introduction of new chemical compounds, and special techniques of administration of these chemicals in the control of advanced cancer have been described. This report is concerned with these developments and will review the chemotherapy of solid tumors, exclusive of the lymphomas and leukemias, the hormonal management of breast and prostate cancer and the use of radioactive isotopes.

END RESULTS OF CANCER THERAPY

Notwithstanding the many advances that have been made in the surgical management of neoplastic disease and in the use of different forms of radiation therapy, cancer continues to be the second most * Supported by research grants from the Lahey Foundation. 807

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Table 1.

RESULTS

Over-all End Results of Cancer Therapy 5 YEAR SURVIVALS, (per cent)

Favorable (20 to 50 per cent) Buccal cavity and pharynx ..... . Larynx ................... . Breast ................................. . Cervix uteri ............................ . Corpus uteri. . . . . . . . . .. . ............... . Colon and rectum ....................... . Unfavorable (5 to 20 per cent) Stomach... . . . .................... . Prostate ............................... . Lung .................................. . Kidney and bladder ..................... . Very Unfavorable (less than 5 per cent) Esophagus ............................. . Biliary passages and liver ................ . Pancreas ............................... . Brain and nervous system ................ .

25 35-40

28 20-40 40 25-30

5 8-27 5-10 20-35

0-5 0-5 0-5

*

* Difficult to evaluate because of problems of classification common cause of death in the Western world,22 and represents the third leading cause of annual hospital admissions (middle aged group) in the United States. ss The examination of the mortality figures for cancer arising in different sites provides a perspective for evaluating the magnitude of the problem posed by patients with nonresectable or recurrent cancer. Table 1 has been compiled from a review of the results of treatment of cancer reported by Cameron. s Even in the most favorable types, the over-all five year survival rate is between 20 and 50 per cent and in many common forms of cancer this figure is less than 5 per cent. There exists, then, a large group of patients with incurable cancer who are beyond conventional control with surgery or radiation therapy, many of whom may be susceptible to treatment with chemical agents.

SYSTEMIC CHEMOTHERAPY

Selection of Patients and Indications for Therapy

Certainly every patient in whom the presence of recurrent or disseminated disease has been established is not a candidate for chemotherapy. Only a small percentage of such patients may obtain benefit, and hence, careful patient selection is mandatory to prevent the serious harm which could result from the indiscriminate use of these drugs. Many

Advances in the Chemotherapy of Solid Tumors

809

factors must ·be evaluated before instituting the use of a drug in an individual case. These include the type of cancer, the stage of the disease and the particular clinical problem presented by the patient, the extent of disability, response to previous treatment, social and psychologic make-up of the patient and his family, and the knowledge and experience of the physician in the use of the compound to be administered.!· Since the available drugs produce only occasional benefit for a relatively short period of time, usually at the expense of moderate toxicity, their use should be restricted to situations in which definite palliation is needed. In general, patients considered suitable for therapy are those with certain types of cancer for which known agents have been shown to be of some practical value, whose disease is not preterminal, and in whom progression of disease is apparent and is associated with symptoms and increasing disability that are not controlled by purely supportive measures. There is no justification for the casual use of chemotherapy in an asymptomatic patient on the ground that such therapy may delay the onset of symptoms, retard the growth of the tumor, and hence prolong life. However, controlled investigative programs to evaluate the adjuvant use of these agents in delaying or preventing recurrence in patients undergoing curative surgery are clearly justified. These studies are in the area of clinical investigation and do not represent conventional cancer chemotherapy. Classes of Compounds

Several classes of drugs are available that have been shown to be of practical therapeutic interest. The major categories of useful drugs are: (1) alkylating agents, (2) antimetabolites, (3) antibiotics, and (4) miscellaneous compounds. The chemistry, mechanism of action and pharmacology will not be reviewed except when pertinent to their clinical use. In Table 2, the various compounds of each category which are currently in use are listed and the types of neoplasm in which favorable responses have been reported are tabulated. Many compounds of all classes which are in the process of clinical trials have not been included in the table or in this report. ALKYLATING AGENTS. Ever increasing numbers of compounds of this group have been synthesized and introduced into clinical chemotherapy. Although the chemical structure of these compounds may differ considerably, the mechanism of action appears to be similar; namely, in vivo inactivation of deoxyribonucleic acid. Various analogues may have special properties in relation to dosage, route of administration, and acute toxicity, but there is no convincing evidence that a difference in the spectrum of therapeutic activity or toxicity exists among the various members of this group.!6 Nitrogen mustard is useful for hospitalized patients, while thio-TEPA or Cytoxan can be conveniently administered to ambulatory outpatients.

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Table 2.

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SULLIVAN, ELTON WATKINS, JR., S. PETER GIBB

Chemotherapeutic Agents in Clinical Use--Diseases Showing Favorable Response DRUG DOSE AND ROUTE

Alkylating Agents Nitrogen 1. V. 0.4 mg./kg. mustard (HN,) Triethylene mel- 1. V. 0.04 mg./kg. X 3 amine (TEM) Triethylene thio- 1. V. 0.2 mg./kg. X 5 phosphoramide P.O. 5-10 mg./day (TSPA) 1. V. 3.5-5.0 mg./kg./day Cyclophosphamide X 10 (40-50 mg./kg. total dose) P. O. 100(Cytoxan) 200 mg./day Antimetabolites Methotrexate (MTX) 5-Fluorouracil (5-FU)

5-Fluoro-2' -deoxyuridine (5-FUDR)

Antibiotics Actinomycin D

15-25 mg./day X 5 1. V. 15 mg./kg./day X

3-5; then Yz dose every other day X 2-4

TOXICITY

Cancer of lung, breast, ovary and testis; melanoma; miscellaneous sarcomas

Nausea and vomiting (HN2 ), bone marrow depression, alopecia, skin rash (rare)

Choriocarcinoma in female Cancer of large bowel, pancreas, stomach, biliary passages, breast, ovary, lung, bladder, head and neck

1. V. 30 mg./kg./day X

3-5; then Yz dose every other day X 2-4 or 1. V. 0.5-1.5 mg./kg./day (24 hour infusion)

1. V. 15 gamma/kg. X 5

Miscellaneous Compounds Hydroxyproges- 1. M. 500 mg. 3 times terone caproweekly ate (Delalutin) 0, p, 'DDD P. O. 2-10 gm./day

Vinblastine (Velban)

TYPE OF TUMOR

1. V. O. 15 mg./kg. twice

weekly

Combination Chemotherapy Actinomycin D 1. V. 0.5 mg. X 5; repeat in 2 weeks Methotrexate P. O. 5 mg./day X 16-25 Chlorambucil P. O. 10 mg./day X 16(Leukeran) 25

Oral ulceration, diarrhea, bone marrow depression, alopecia (rare), photosensitivity

Wilms tumor; mis- Oral ulceration, cellaneous diarrhea, bone sarcomas marrow depression, photosensitivity Cancer of corpus uteri

None

Cancer of adrenal cortex (functional)

Anorexia, nausea and vomiting, skin rash, adrenal insufficiency' somnolence Bone marrow depression, nausea and vomiting, alopecia

Various carcinomas

Choriocarcinoma, seminoma and embryonal carcinoma of testis

Combined toxicity of each compound

811

Advances in the Chemotherapy of Solid Tumors

These agents block or modify the formation of purines and pyrimidines, compounds essential for nucleic acid biosynthesis. Methotrexate, a folic acid antagonist, has been shown to be of value in the treatment of choriocarcinoma in the female as well as in other limited situations. In 1956, Li, Hertz and Spencer18 reported that relatively intensive and repeated courses of this agent produced substantial and striking tumor regression associated with decrease in chorionic hormone titer, clinical benefit and prolongation of life. Seventy to 80 per cent of patients have responded to Methotrexate therapy and in one-half of these there has been no evidence of recurrence. The 5-fluorinated pyrimidines were synthesized by Heidelberger et al. 14 and extensive clinical trials have been reported. 2 , 6, 7,27 Objective evidence of tumor regression and clinical benefit following the m:e of 5-fluorouracil (FU) and 5-fluoro-2'-deoxyuridine (FUDR) have been reported for an impressive number of tumors (Table 2). The incidence of remissions has varied from 15 to 40 per cent and is of short duration (four to 16 weeks). Repeated courses of therapy have increased the duration of benefit to four to eight months in some cases. Response, in most cases, has been associated with varying degrees of toxicity which, at times, has been fatal. The therapeutic range and rate of responsiveness of FU and FUDR have been essentially similar when the compounds were administered by single daily intravenous injection. 9 Studies of the effects of 24 hour intravenous administration of these compounds conducted in our laboratory have shown the toxicity of FU is decreased while that of FUDR is greatly increased. 30 Prolonging the duration of administration of FU may result in less toxicity for equivalent therapeutic effect, as suggested by Lemon. 17 Our studies of the clinical effects of the 24 hour intravenous infusion of FUDR suggests that the metabolic fate of the compound is altered 20 and that the therapeutic index is extended. 26 Of 67 patients with advanced cancer who were evaluated for therapeutic effect, objective tumor regression was noted in 29 (Table 3). It is our impression that continuous intravenous infusion of FUDR is a more feasible method of its administration. ANTIMETABOLITES.

Table 3.

Objective Tumor Regression with Continuous Intravenous FUDR

SITE OF DISEASE

TOTAL NUMBER OF PATIENTS

OBJECTIVE TUMOR

NUMBER WITH

EVALUATED

REGRESSION

Lung....................................... 8 Breast. . . . . . . . . . . . . . . . . . . .......... 13 Colon and rectum. . . . . . . . . . . . . . . . . . . . . . . . . . .. 13 Stomach........................... 8 Mycosis fungoides. . . . . . . . . . . . . . . . . . . . . . . . . .. 3 Miscellaneous carcinoma and sarcoma. . . . . . . . .. 22

3 3 6

67

29

TOTAL . . . . '"

...........................

4 6

7

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Fig. 1. Epidermoid Ca1'cinoma of the Nasopharynx. a, Before FU therapy. Note the intracutaneous lesions which have extended onto the anterior chest wall. b, After therapy. Note the striking decrease in facial edema and the regression of the intracutaneous lesions that have occurred.

F.L.c. cf36 Yr.

",000

___/,\ ___P_LA_:r_E_LE_~_S.!::....._~

~:Lt

_ _........!""","-

100

40

20 O~----------------------

____________

15~EXP.RED wec 10

Xl,OOO

5

OL-----________________ G.I. TOXICITY

750 mil ( 15mll/kg)

1+ 0 2+ 5- FLUOROURACIL X91.V. X4

X8

X9

II I II

1958 MAY

JUNE

0

• JULY

~

_________ 1+

0 X4

I

AUG.

X8

I

0

i SEPT.

Fig. 2 (Case 1). FU therapy in epidermoid carcinoma of the nasopharynx.

Advances in the Chemotherapy of Solid Tumors

813

t!63Yr; ADENa CA STOMACH METASTATIC LESION OF SHOULDER PERFORMANCE STATUS

wac (1,000")

~.,

l.,\.

30% 75

50

70

60

60

15 10 5

25 2

BIURUBIN (MG."')

15 10 5

3 30 25

ALKAUNE PHOSPHATASE 20 (BU) 15 10

o o

TOXICITY

0

0

15mg./kg.

THERAPY

x

I.V. FU

SEPT. OCT. 1961

NOV.

DEC.

Fig. 3 (Case 2). Continuous intravenous FUDR and conventional FU therapy in adenocarcinoma of the stomach.

The following case reports illustrate the occasional benefit observed with the use of the fluorinated pyrimidines in solid tumors. CASE 1. Epidermoid Carcinoma of the Nasopharynx. The patient was a 36 year old Chinese male with advanced cancer of the nasopharynx. He had had extensive radiation therapy as well as bilateral radical neck dissections. At the time of initiating FU therapy, there was extensive edema of the face and bilateral neck lesions (Fig. 1, a). FU was given by single daily intravenous injection in the dose of 15 mg. per kilogram per day for four to nine days. Seven courses of therapy were given over a five month period (Fig. 2). Temporary improvement was sustained over a four month period (Fig. 1, b), but progression of disease eventually resulted in the patient's death. CASE 2. Adenocarcinoma of the Stomach. The patient was a 63 year old white male with recurrent cancer of the stomach. During the month before FUDR therapy, symptoms of intestinal oestruction progressed and icterus increased because of an enlarging liver. An intracutaneous metastatic lesion of the shoulder

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contained, on biopsy, adenocarcinoma. FUDR was given by continuous intravenous infusion in the dose of 1.5 mg. per kilogram per 24 hours for six days. All symptoms gradually abated, the metastatic lesion of the shoulder progressively decreased and the abnormal liver function tests returned toward normal (Fig. 3). The patient subsequently received several courses of FU by single daily injection as an outpatient. He is alive and free of symptoms at present, seven months after initiating fluorinated pyrimidine therapy.

ANTIBIOTICS. Several substances have been isolated from antibiotic beers and have reached clinical trials. Actinomycin D is the only compound in this category that has proved to be of any clinical benefit.!2 This compound has shown activity against several solid tumors of infants and children and is used in the triple combination chemotherapy of testicular tumors. Dosage regulation of this compound is difficult and extreme toxicity may develop. It should be used with great caution. MISCELLANEOUS COMPOUNDS. The prolonged administration of progestational agents has been shown to produce regression of metastatic adenocarcinoma of the uterus in 30 per cent of patients.!6 Seven of 21 patients had objective tumor regressions lasting from nine months to four and a half years. The hormone most commonly used is Delalutin (17-alpha-hydroxyprogesterone caproate) and it is given in the dose of 500 mg. three times a week by the intramuscular route. It has recently been shown that o,p'DDD (2, 2-bis [4-chlorophenyl, 2-chlorophenyl] -1, 1-dichloroethane) will produce a favorable effect on the rare functional tumor of the adrenal cortex.! The manifestations of excessive adrenal corticosteroid production are relieved and occasional tumor regression is effected with the oral use of this compound. A new plant alkaloid, prepared from Vinca rose a Linn. (periwinkle), vinblastine, has shown antitumor effects in patients with cancer of the large bowel, choriocarcinoma and other solid tumors.!3 Reported results to date have been variable and inconsistent. Combined Chemotherapy and Radiation It has been reported that a number of compounds including actinomycin D, FU and FUDR will potentiate the effects of radiation by sensitizing cancer cells to its effects. While it has been adequately documented that these agents will increase the skin sensitivity to radiation,!!' 24 there is no satisfactory evidence that they will potentiate the effects of radiotherapy on human neoplasms. Adjuvant Chemotherapy

A number of procedures have been utilized at the time of definitive surgery in an attempt to reduce the incidence of recurrent and metastatic disease. These techniques are based upon the theses that tumor implants may be a consequence of accidental spilling of tumor cells in the operative field, or that during surgical manipulation, cells may be thrust into

Advances in the Chemotherapy of Solid Tumors

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lymphatic and blood vessels and result in metastatic implants. The methods employed consist of the instillation of various agents into the operative field and the administration of alkylating agents (HN2, thioTEPA) during and after the operation. 23 Several well controlled clinical studies are currently being investigated by cooperative groups in the United States, but to date no conclusions have been drawn that would warrant the conventional use of these procedures. REGIONAL CANCER CHEMOTHERAPY

Several methods of regional cancer chemotherapy have been developed in an attempt to enhance the antitumor effects of compounds in patients with advanced, but locally confined cancer. Many types of cancer remain localized throughout their clinical evolution and produce disability and eventually death, due to the relatively localized, but uncontrolled growths. Head and neck cancer, primary brain tumors, cancer of the cervix and bladder are fairly common forms of neoplastic disease that fall into this category. These forms of cancer may be susceptible of control by regional chemotherapy. The methods of regional chemotherapy that are undergoing clinical trials are: regional perfusion through an extracorporeal circuit, and arterial infusion. Regional Perfusion

Extracorporeal isolated perfusion as described by Creech et al. 5 involves the exclusion of the tumor-bearing area from the general circulation for periods of 30 to 60 minutes, during which time high concentrations of a drug are perfused in the isolated part. OtherIess complicated techniques have been described34 utilizing Dotter-Lukas balloon catheters which are introduced through accessible vessels of the extremities and pass antegrade or retrograde to the desired site. This method, when applicable, minimizes the operative procedures. In general, the best results have been obtained with the use of various alkylating agents in patients with tumors of the extremities. Clinical benefit has been noted in patients with melanoma and soft tissue sarcomas, while adenocarcinomas have generally failed to respond. 4 Continuous Arterial Infusion

Several reports have been published which describe the rationale for arterial infusion therapy, techniques of catheter insertion and maintenance of infusion assembly, drug dose schedules, selection of patients, complications and results of therapy. 8. 25.28. 29 Elsewhere in the current issue of this journal (Watkins et al.) is an article which describes techniques employed in continuous arterial infusion therapy. Briefly, the method of therapy involves the continuous 24 hour in-

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In.,

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fusion of cancer chemotherapeutic agents through polyethylene catheters inserted into a known site in the arterial blood supply of tumors. The compounds are infused for periods of one to four weeks or more, alone in doses which the entire body can tolerate, or they are given in supralethal doses and the specific antidote is administered systemically by a different route. Most arterial infusions have been performed using antimetabolites, but certain antibiotics are under current preliminary investigation. 24 The largest clinical experience to date has been with the antifolic acid compound, Methotrexate, and with the fluorinated pyrimidines, FU and FUDR. Drug Dose Schedules

ARTERIAL METHOTREXATE-INTRAMUSCULAR LEUCOVORIN THERAPY. The usual dose schedule for unilateral catheterization is: Methotrexate, 50 mg. per 24 hours infused in 1000 to 1500 cc. of glucose and water or saline solution per 24 hours. For bilateral catheterization, the dose used is: Methotrexate, 25 mg. per side per 24 hours infused in 1000 to 1500 cc. of glucose and water or saline solution per side per 24 hours. Leucovorin (C.F.) is given intramuscularly in the dose of 6 mg. every six hours. ARTERIAL METHOTREXATE THERAPY. Arterial Methotrexate therapy without the concomitant use of intramuscular C.F. has been given in the dose of 3 to 5 mg. of Methotrexate per 24 hours, infused in 1000 to 1500 cc. of solution per 24 hours. FLUORINATED PYRIMIDINE THERAPY. 5-FU in the dose of 7.5 to 15 mg. per kilogram per 24 hours or 5-FUDR in the dose of 0.15 to 0.5 mg. per kilogram per 24 hours has produced satisfactory local antitumor effects and associated tumor regression without the development of systemic toxicity. An adequate course of therapy is defined as that amount of therapy that results in moderate local toxicity within the area of infusion (diffuse unilateral or bilateral skin erythema, superficial mucosal ulceration, or both) with or without the development of mild systemic toxicity (hematologic depression, gastrointestinal side effects). An adequate course of therapy takes one to six weeks using Methotrexate combined with C.F., four to 12 days using arterial Methotrexate alone, and five to ten days using the fluorinated pyrimidines. The dosage schedule should be "tailored" to the individual patient and his disease process. In patients with relatively slow growing tumors, it is desirable to prolong the period of therapy in order to affect the slowly metabolizing cells. In this instance, the aim is a two to four week period of infusion therapy. Using the antimetabolite-metabolite combination of Methotrexate = C.F., this may often be achieved by adjusting the dose of either compound in order to develop the maximum effect (for example, local toxicity) within the desired interval of treatment.

t

Advances in the Chemotherapy of Solid Tumors

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Fig. 4 (Case 3). Epidermoid Carcinoma of the Maxillary Sinus. a, Before intraarterial infusion therap~'. Note the extension of the tumor to the soft tissues of the face. b, Mter therapy. Note the complete apparent tumor regression that ~s occurred.

Results of Arterial Infusion Therapy

Evaluation of clinical results to date are limited to studies using arterial Methotrexate and intramuscular C.F.,4, 10,25,28,32,35 Methotrexate alone,25 and to a lesser extent with the use of the fluorinated pyrimidines. 25 , 31 In general, when the disease has been limited to the area of infusion, results have been good in terms of objective tumor regression and clinical benefit. When there was contiguous disease outside the actual area of infusion, although definite evidence of objective tumor regression has been noted in the treated areas, the disease outside the treated area was unaffected by therapy and little clinical benefit was appreciated by the patient. Several cases are presented to illustrate drug dose schedules, local antimetabolic effects produced and antitumor effects that have been noted. CASE 3. Epidermoid Carcinoma of the Maxillary Sinus. The patient was a 55 year old Negro woman in whom a diagnosis of carcinoma of the right maxillary antrum was made in January 1960. The tumor had extended into the soft tissues of the face as well as to the hard palate bilaterally (Fig. 4, a). Biopsy revealed an anaplastic epidermoid carcinoma. She received bilateral Methotrexate therapy in a dose of 15 to 30 mg. per side per 24 hours. Therapy was given in courses lasting four to six days of continuous drug administration over a cumulative period of 14 days of therapy. C.F. was given in a dose of 6 mg. every six hours by the intramuscular route. Visible tumor progressively decreased and complete apparent tumor regression had occurred by the thirty-seventh day (Fig. 4, b). The disease did not recur over a follow-up period of six months. CASE 4. Epidermoid Carcinoma of the Cervix. The patient was a 35 year old Negro woman in whom a diagnosis of cancer of the cervix was made by biopsy in January 1960. The cervix was replaced by a fungating mass and the tumor extended to the vaginal walls (Fig. 5, a). The uterus was fixed by masses ex-

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Fig. 5 (Case 4). Epidermoid Carcinoma of the Cervix. a, Before arterial infusion therapy. The cervix is virtually replaced by a fungating tumor which extends to the vaginal walls. b, After therapy. Note the complete apparent tumor regression that has occurred.

tending to the pelvic walls. Bilateral internal iliac catheters were inserted and the patient received arterial Methotrexate in the dose of 25 mg. per side per 24 hours and intramuscular C.F. in the dose of 6 mg. every six hours. Over a 25 day period, the patient was given 12 days of therapy. Progressive decrease in visible tumor was observed and by the twenty-ninth day after treatment was begun, there was no clinical evidence of residual cancer in the cervix, vagina or pelvis (Fig. 5, b). Biopsy specimens after treatment were free of tumor. The patient has remained clinically well with apparently normal menstrual periods for 23 months to date. CASE 5. Epidermoid Carcinoma of the Bladder. The patient was a 56 year old white man in whom the diagnosis of inoperable epidermoid carcinoma of the bladder was made in October 1960. Several transurethral fulguration procedures were performed. For several months prior to intra-arterial chemotherapy, he noted constant hematuria and dysuria. Cystoscopy* showed a bladder of reduced capacity and a papillary, broad -based neoplasm was visible on the left lateral wall and floor, completely obscuring the left ureteral orifice. Mild, diffuse cystitis was present and the prostatic, bulbous, and anterior urethrae were involved by neoplasm. Biopsy revealed epidermoid carcinoma, grade II. Intravenous pyelogram showed nonvisualization of the left kidney and a small bladder with a filling defect on the left side (Fig. 6, a). An 11 day course of Methotrexate, infused into both internal iliac arteries, was given in the dose of 25 mg. per side per 24 hours. C.F. was given in the dose of 6 mg. every six hours by the intramuscular route. A second course of therapy was refused by the patient. Hematuria ceased by the sixth day of therapy and the patient was asymptomatic. Cystoscopy following treatment showed that the bladder tumor had

* Performed by Dr. Vernon S. Dick of this

clinic,

Advances in the Chemotherapy of Solid Tumors

819

Fig. 6 (Case 5). Epidermoid Carcinoma of the Bladder. a, Before intra-arterial infusion thera.py. Intravenous pyelogram showing nonfunction of the left kidney and a filling defect of the left side of the bladder. b, After therapy. Note the good concentration of dye by the left kidney and improvement in the filling defect of the bladder.

regressed by an estimated 90 per cent and the urethral lesions were not visible. Intravenous pyelogram showed good concentration of the dye on the left side with a moderate degree of hydronephrosis. There was considerable improvement in the filling defect on the left side of the bladder (Fig. 6, b). The patient was asymptomatic for three months when hematuria recurred. Further therapy was refused.

Response was noted as early as the fourth day of infusion therapy. Resistance to drug therapy was not noted on repeated courses of therapy and prior radiation therapy did not appear to be a factor affecting response to treatment. Complications of technique of catheter insertion and maintenance of infusion assembly were frequent and often serious. They consisted of inaccurate catheter placement, premature catheter displacement, infection and bleeding, or both, around the tract of the catheter and leakage of infusate. These complications may be minimized by careful attention to techniques of catheter insertion (Watkins, et al., this issue) and accurate determination of the area of infusion by using the fluorescent dye visualization method. The increased local biologic effects noted with arterial infusion chemotherapy and the marked antitumor effects that have been observed are attributed to (1) the arterial route of administration producing a higher local drug concentration 19 and (2) the continuous 24 hour administration of the antitumor drug resulting in a continuous antimetabolic effect so

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that slowly metabolizing cells may be affected by the continuous exposure of the antimetabolite as they enter an active metabolic phase. Because of the frequency of complications relating to technique, this form of therapy must be considered to be in the realm of clinical investigation. There are many problems inherent in regional chemotherapy that will require much future work before they are solved. Foremost of these problems relate to the functional blood supply of tumors in various areas. Techniques to elucidate more accurately the blood supply of tumors in various sites and in a given patient to determine the exact distribution of arterial infusate in relation to the extent of tumor must be developed. Studies pertinent to duration of action of many compounds currently under clinical investigation have not been carried out in animal or human systems. These and many more preclinical and clinical studies are necessary in order to utilize fully the possible practical benefits of regional chemotherapy. SUMMARY

A huge undertaking of cancer research is currently in progress to develop anticancer drugs for use in the management of neoplastic disease in man and an increasing number of compounds are becoming available for clinical use by the physician. Despite the prodigious efforts of these preclinical and clinical programs, progress has been slow and no chemical agents have been developed that are capable of inducing a general curative effect on disseminated forms of cancer. Nevertheless, over the past several years definite advances have been made in the introduction of new chemical compounds and special techniques and procedures of their administration for the chemical control of advanced cancer. The many factors that must be evaluated before instituting chemotherapy in an individual patient are reviewed. The several classes of compounds that are available for systemic chemotherapy and their indications for use are assessed. Certain methods of regional chemotherapy have been developed to enhance the antitumor effects of compounds in patients who have relatively localized, but uncontrolled, cancer. These techniques of drug administration have occasionally produced complete apparent tumor regression associated with sustained clinical benefit. Because of a high incidence of complications, however, these techniques should not be considered for general use. REFERENCES 1. Bergenstal, D. M., Lipsett, M. B., Moy, R. H. and Hertz, R.: Regression of

adrenal cancer and suppression of adrenal function in man by o,p'-DDD. In: Pincus, G. and Vollmer, E. P., editors: Biological Activities of Steroids in Relation to Cancer. New York, Academic Press, 1960, pp. 463-473. 2. Brennan, M. J. and Vaitkevicius, V. K.: 5-Fluorouracil in clinical cancer experience with 155 patients. Cancer Chemotherapy Rep. 6:8-12 (Feb.) 1960.

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