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Medical Management of Advanced Lung Cancer
Medical Management of Advanced Lung Cancer* ROBERT B. GOLBEY, M.D.
Lung cancer is a problem that concerns every physician, because of the high and increasing frequency of the disease. Pulmonary carcinoma is not often curable, but there are several procedures of proved value in alleviating distressing symptoms and in prolonging useful life. Dr. Golbey has analyzed the course of advanced lung cancer and described the methods available for managing certain clinical problems. EVERY physician must be aware that ultimately one in four of his patients may be expected to develop cancer in some form. In approximately 8 per cent of those who do develop cancer, the tumor will originate in the lungs, and among those of his patients who die of their cancer, lung cancer will have been responsible for about 13 per cent of the deaths. In males this figure will be 21.5 per cent and in females 4 per cent. In its simplest terms this means that more than 2 per cent of his patients will die of lung cancer even if the incidence of lung cancer does not continue to rise at a rate which has resulted in a sixfold increase in this disease since 1920. 1 A physician must be prepared to attack the problem at three distinctly different levels. He must attempt to prevent cancer. Failing that he must act promptly to provide potentially curative therapy and failing in that he must be prepared to provide palliation. As can be seen in Figure 1 ill which these three aspects of therapeutic activity are shown on different horizontal levels, it is important that the patient should be treated at the highest level consistent with his situation, since the outcome of treatment at the palliative level is not nearly so satisfactory to the patient as it may be at a higher level. Since this figure is as applicable to other forms of cancer as it is to lung carcinoma, it is important to note that level reading "to cure" may be satisfactory in some forms of cancer only in a relative sense. The relativity depends on one's definition of cure. In lung cancer, however, the definition of cure can be fairly precise. In most series 50 per cent of the patients who are going to die of their disease will have died * This investigation was supported in part by research grant CY-3215 from the
National Cancer Institute, Public Health Service, and in part by a grant from the Damon Runyon Memorial Fund for Cancer Research.
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within nine months of the onset of symptoms. Ninety per cent will have died within a few months more. Patients who have survived three years after treatment with no evidence of disease usually are safe from a recurrence of lung cancer. As the number of cancers in which etiological factors have been found increases and as the awareness of the significance of these factors grows, the increase in potential of preventive medicine in cancer has become apparent,2 but we are not concerned with this problem here. We also will not concern ourselves here with the problems presented by the patient with localized disease, in whom there is an apparent chance to completely excise the areas of malignancy. Our concern is with those patients who present themselves with disease which is clearly beyond the possibility of complete surgical excision, whether this be at the time of the initial diagnosis or at the time after surgery that a recurrence is found. These, for our purposes, will be considered to be the patients with advanced lung cancer. In this definition you will note that there is no implication of a time scale. A lung cancer may be advanced even at a time when the patient is completely without signs or symptoms and, in fact, even when by all our available techniques there is no detectable disease in the lungs. On the other hand, it may not be advanced even though it can be demonstrated retrospectively that the lung tumor has been quietly growing in place for years. Metastatic spread is also not implicit in the definition. A patient may be in the advanced stage of the disease by virtue of local extension to vital areas where its total removal is not possible, even though no distant spread has occurred. 3 In considering what can be done for a patient with advanced carcinoma of the lung, one must first take great pains to determine whether the case in question is truly advanced and is no longer potentially curable by
M edical Management of
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G29
surgical treatment. Each surgeon will have his own criteria of inoperability. All important criterion is the involvement of a distant viscus with cancer. Frequently the implicated organ is the liver. Even in patients with known cancer present elsewhere in the body, this diagnosis of metastatic involvement is difficult to make. In the absence of a positive liver biopsy, which is the only way that an absolutely certain diagnosis can be made, one must insist that there be an enlarged, nodular liver with abnormal liver function tests including at least an abnormal bromsulphalein retention or an elevated alkaline phosphatase. If one of these criteria is ignored, the accuracy of the diagnosis of metastatic involvement of the liver will fall off markedly. Similarly, all other criteria of inoperability must be critically reviewed in the light of the individual patient's situation. It is preferable to err on the side of more surgery which is ultimately only exploratory or palliative. Palliative surgery can often significantly improve a patient's comfort, and sometimes even his period of surviva1. 4 PATTERNS OF LUNG CANCER
Once advanced disease is shown to be present, it can progress in any one of several ways. Patterns of advanced lung cancer have been described previously by our group." It was found that most cases fall into one of three major patterns of clinical behavior and that many will clearly fit into one of the well-defined subgroups. These elinical patterns are determined by many parameters but chiefly by an anlyasis of (1) the mode of onset, (2) rate of growth, (3) site of metastases, (4) rate of metastasis, (5) rate of growth of metastases, (6) complications and (7) cause of death. Local Pattern
This study has shown that about 20 per cent of patients with primary carcinoma of the lung who die of their carcinoma will have either no distant metastases or a few small and clinically asymptomatic metastases, usually detectable only in those who have a postmortem examination. Budinger,6 in a series of 250 autopsied cases of untreated bronchogenic cases, found 16 cases in which the tumor was confined entirely to the lung. This local pattern is different from the other patterns below, but not in that it is less malignant. The median survival time is no greater, probably because the tumor is locally more aggressive and invasive, frequently with involvement of unusually large segments of lung and adjacent tissues. The pleura, mediastinum, ribs, spine, skin, pericardium and myocardium may all be extensively involved by local growth in continuity. Discontinuous growth is sometimes seen in the other lung. Pulmonary hemorrhage and respiratory failure, secondary to tumor
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growth, atelectasis and infection, will be common causes of death. All example of this "local pattern" is seen in Figure 2. As will be discussed later, this group raises several interesting considerations when the appropriate therapy is being sought. Organ-Specific Metastases Pattern
A second major pattern is seen in patients who develop clinically significant distant metastases in only one organ. This organ may be the liver, brain or bones. When these organs are to be exclusively involved by metastatic lung cancer, the metastatic involvement may appear before, simultaneously with, or shortly after the primary site in the lung is detected. The clinical involvement of a single organ does not mean that there is only a single metastasis. This is particularly apparent in the bones where multiple widely scattered areas of involvement restricted to that one organ system can be easily detected. There seem to be factors governing the localization of metastases other than blood vessel invasion and pure chance. Among these factors are very likely obscure biochemical differences in the tumor cells which control its ability to grow on "foreign soil." The one site for which most pulmonary carcinomas appear to share a common affinity is the adrenal gland. About 60 per cent of all of our autopsied cases had adrenal metastases and if the local pattern is excluded, although even some of these had small adrenal metastases, the percentage rises to about 90 per cent. Generalized Pattern
The third major pattern is of generalized disease, in which any and every organ in the body may be involved. This pattern can be subdivided on a temporal basis, depending on when and at what rate the metastases appear. In one group all of the metastases will become clinically apparent within a span of a few days or a few weeks. This may occur in a patient who was previously well with no known malignant disease. A diagnosis of the primary site of the tumor may be very difficult to establish, since a similar pattern is seen in several other malignant diseases and the histology is frequently not sufficiently distinctive to permit any certainty of diagnosis. Among other primary tumors which exhibit this phenomenon are melanoma, breast carcinoma and gastric carcinoma. Recognition of this pattern when it is due to lung cancer is primarily of prognostic significance in that most of these patients will be dead within three months of the onset and almost all will be dead within six months. When this pattern is seen as the presenting complaint, it can aptly be described and classified as acute carcinomatosis. The last subpattern of generalized disease is one in which different organs become clinically involved gradually, with intervals of many weeks or months occurring between the involvement of one organ and another. An example of this pattern is seen in Figure 3.
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Fig. 3. This chart illustrates the progressive course of a patient with a generalized pattern of lung cancer. Temporary improvement in symptoms and in performance status with the decrease in the bulk of the tumor as a result of treatment are demonstrated.
The importance of an appreciation of the natural history of lung cancer in the optimal management of these patients cannot be overemphasized. The histology of the tumor does not seem to be as prognostically significant, once dissemination has occurred, as it is in the apparently operable case, but other factors, some of which have been mentioned, do assume great importance. The ability to anticipate the ultimate consequences and the complications of a tumor deposit in a particular site, a facility which comes only with knowledge of the natural history of the process, is basic to effective management. TREATMENT
The management of patients with advanced lung cancer involves two major areas of therapeutic endeavor. The first of these is in the use of
Medical Management of Advanced Lung Cancer TERMINAL EVENTS: RESPIRATORY FAILURE
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antitumor agents whose use is intended to halt or to slow the progression of the disease. The second area is a less specific one in which all of the medical disciplines are called upon to provide relief from the problems presented by the anatomical, functional or metabolic alterations produced by progressively growing cancer. This latter area is only indirectly related to the site of origin of the tumor, and it represents a problem common to the management of all forms of cancer. 7 Its scope is such as to preclude discussion here, but its importance has been well emphasized by Karnofsky,8 who said: "Until more satisfactory specific therapy (... of metastatic cancer ... ) is discovered, the physician must employ all the knowledge and therapeutic techniques available in an attempt to relieve distress and to prolong life. Steady therapeutic progress (the epoch-making empirical discoveries are excepted) stems mostly from an understanding of the physiopathology of disease." Careful analysis of each patient's problem, in terms of what factors are specifically responsible for each facet of his disability, and what can be done about these factors, is the single most important principle in this sphere of management of the cancer patient. We will confine ourselves here to a discussion of those methods'Cof treatment which are used because they may directly damage cancer cells.
Radiation Therapy
Patients with lung cancer can be benefited by treatment with ionizing radiation and with a variety of chemotherapeutic agents. Some of the considerations entering into some frequently encountered clinical situations will be briefly reviewed. Southam has stated, in discussing the management of the patient with disseminated cancer,9 that cancer that is not producing signs or symptoms is not important. In certain instances, however, it is sometimes possible to anticipate the development of symptoms and, with judicious treatment, to prevent them. Localized lung cancer, even if not curable by resection, does not fit Southam's concept, which applies only to dissemina'ted cancer. Many cases of lung cancer in which distant metastases
634
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are not apparent can be helped by radiation therapy. Most papers which discuss the usefulness of radiation in lung cancer do not present any useful statistics on which a prognosis for a given case can be based. The authors will content themselves with the statement that results are poor in so far as three or five year survival with no evidence of disease is concerned, but they will also go on to describe one, two or three cases in which the survival exceeded all expectations, and some that might merit the cautious use of the description "cured."9a Much of the despair over the usefulness of this method of treatment comes from the fact that these patients, despite prolonged suppression of the disease in the treated areas, go on to die of their distant metastases. As was noted earlier in the brief discussion of the natural history of advanced lung cancer, at least some of the patients who present with localized tumor will not have significant, distant metastases even at the time of death. It is certainly from this group with the localized pattern that the few long survivors come, and from which more will be derived when the utilization of the newer radiation techniques and equipment becomes more widely practiced. Smart and Hilton 10 have reported on the primary treatment with radiation of a small group of patients who would have been candidates for total surgical extirpation by the usual criteria applied preoperatively. Twelve of these patients had been followed for five years or more. Four (33 per cent) are alive and well, one survived three years, two survived more than two years, and five died within two years. Whether this response rate, which is similar to the surgical response rate, will continue to hold up as the series expands, is not pertinent to our discussion here since these are early cases, but these figures do lend support to the belief that in selected situations radiation therapy can be of great value. Large numbers of patients cannot be expected to be salvaged by radiation, but it would not require many to significantly improve the salvage obtained from surgical therapy alone. Of the 36,000 persons the American Cancer Society predicts will develop lung cancer in 1961, fewer than 1800 will be cured by operation. As many as 7000 of them, however, may die with localized nonresectable disease which could have been significantly benefited by radiation therapy. Whether cure is achieved or not, radiation therapy is worth using purely for its ability to palliate symptoms and to prevent complications. Timely treatment call prevent or ameliorate cough, hemoptysis, dyspnea, pain, atelectasis, infection and other manifestations of the growing local lesions, thereby achieving the goal of palliation-as comfortable and as normal a Jiff as is possible, for whatever time is left. A limiting factor in radiation to the lung is the possibility of producing fibrosis and'"respiratory insufficiency. This consideration limits the dose and the size of the field that can be treated. The radiologist must take this, and other factors such as respiratory reserve, progress of disease in
Medical Management of Advanced Lung Cancer
635
other areas and skin changes, as well as the facilities available, into consideration in planning the optimal treatment. In addition to being specifically indicated in the treatment of localized, nonresectable disease, x-ray is useful in the palliative treatment of many metastatic foci. In brain metastases particularly, the results may be gratifying in duration, degree and frequency. Chu and Hilarisll have reported on the treatment of brain metastases in 74 patients with carcinoma of the lung. Of these, 54 survived long enough to complete the prescribed course of treatment. Forty-five had clinical improvement in their intracranial disease for more than one month. The average remission of symptoms lasted 4.5 months while the average survival was 6.4 months. The nonresponders survived only an average of 2 months. These authon: also show that some long responses can be obtained. Some of the failures and short responses resulted not because the intracranial lesion did not respond, but because the tumor in the liver or els8where progressed~~o a fatal degree. They also report a ,distinct dose-response correlation. Patients treated with less than 2750 rads showed a 29.4 per cent failure rate and there were no five-month remissions, while those receiving more than 2750 rads had only a 9.6 per cent failure rate and 38.5 per cent had a remission for five months or more. Additionally, seven out of ten patients had a useful response to a second course of therapy, and one of two had a response to a third course. When it is considered that most of these patients had generalized metastases, it is apparent that, should one encounter a patient with only brain metastases, as discussed earlier under organ-specific metastases, this form of treatment is not only indicated but almost mandatory. Similarly bone metastases which are painful, or threaten to result in collapse or fracture, can be benefited sufficiently often by radiation therapy to justify its use whenever these lesions present a problem in clinical management. The results of treatment of hepatic metastases with x-ray are less satisfactory, but there are situations in which it should be tried. If a patient was symptomatic due to liver involvement and a localized lesion in the porta hepatis were suspected, or the absence or minimal nature of other metastases indicated that shrinkage of the liver and/or improvement in li vel' function could make a vast difference in the patient's status, x-ray therapy should be tried. In Memorial Hospital supervoltage therapy is strongly preferred for treatment to the liver. The use of radiation therapy must be considered whenever one is confronted by a localized tumor mass which is, or soon will be, producing symptoms. Occasionally radon seeds can be implanted into an accessible tumor mass, such as a superior sulcus tumor, with beneficial results. External radiation is specifically indicated in the treatment of situations such as a superior vena caval syndrome or spinal cord compression, but the discussion of this use is deferred until the later section on alkylating
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agents since it is our practice to use x-ray in conj unction with chemotherapy in these situations unless the chemotherapy is specifically contraindicated. Discussion of the use of radioactive colloid suspensions in the treatment of malignant effusions is similarly deferred since we prefer chemotherapeutic agents as the treatment of choice in most of these eases. Chemotherapy
Almost every drug that is introduced into clinical trial is tested against bronchogenic carcinoma. Many of them have demonstrated an ability to affect the growth of the tumor in an occasional case, but with only one class of compounds, the alkylating agents, have the results been sufficiently useful in frequency, in degree, in duration and in being accompanied by an acceptable toxicity risk, to merit mention in a clinical paper. The alkylating agents are a group of chemical compounds which are diverse in structure but similar in their mode of action, their major toxic manifestations and their therapeutic effects. They are as a class called "radiomimetic" because their biological effects, although mediated through different chemical reactions, resemble those of ionizing radiations. The effects of these drugs, like those of radiation, are most profound on rapidly dividing cells, so that the greatest antitumor effect can be expected against the more anaplastic cells, and the major toxicity at therapeutic doses is seen in their effects on the rapidly growing cells of the bone marrow, gastrointestinal mucosa and germinal epithelium. Some authors 12. 13 have described what they believe to be evidence of a specificity of one or another of these drugs in its action against a particular cell type, while others have indicated that these differences represent, at most, quantitative variations rather than qualitative specificity.14 It is the latter view which is subscribed to here and for this reason we would suggest that every doctor treating malignant disease become thoroughly familiar with one standard intravenous and one standard oral alkylating agent, before becoming concerned with the minor refinements of dose form, stability and side effects which distinguish one alkylating agent from another, in their use against human tumors. The first reports on the usefulness of nitrogen mustard in lung cancer appeared in 1948. 16 This drug is the prototype of all alkylating agents and is the standard against which claims of unique activity for other alkylating agents should be measured. In our current usage we administer nitrogen mustard (HN2; Mustargen) intravenously in a dose of 0.4 mg./kg. This dose will regularly produce a tolerable degree of bone marrow depression beginning in about one week, becoming maximal at about two weeks, and returning to normal in about three weeks. Other manifestations of systemic toxicity are not usually seen although nausea
Medical Management of Advanced Lung Cancer
637
and vomiting may be troublesome for some hours after the HN2 is administered, unless controlled by antiemetics and sedation. Some observers have reported that patients having lung cancer but with normal bone marrows will tolerate up to twice this dose. This does not appear to offer any advantage over the practice of giving 0.4 mg./kg. and then repeating this dose or some fraction of it if a fall in white blood cells or platelets have not occurred in seven to ten days. Using essentially this dosage regimen, Karnofsky reported: "Nitrogen mustard was used in the treatment of 35 patients with inoperable carcinoma of the lung. In 74 per cent of the patients some clinical improvement occurred. This was evidenced by an alleviation in symptoms such as cough, dyspnea, hemoptysis, pain, weakness, and the syndrome associated with obstruction to the superior vena cava; and such objective changes as regression of pulmonary and metastatic lesions and absorption of pleural effusions. The improvement usually lasted from two weeks to two months and further courses of HN2 were usually not as effective as the first." Continued experience with this drug for the past 12 years has made the series larger, but has not changed the basic conclusions quoted. Similar results can be obtained with triethylene melamine, Thio-TEPA and Cytoxan given intravenously, or Leukeran, Myleran, Cytoxan, triethylene melamine and Thio-TEPA orally. The alkylating agents are of particular usefulness in three frequently occurring situations. The first is that in which symptoms are produced by the pressure of the growing tumor on a vital structure such as a nerve, bronchus or vein. Relatively minor reductions in the size of the tumor may be sufficient to relieve the pressure or the obstruction, and thereby provide major symptomatic relief of pain or of bronchial, biliary or other obstruction. An example of this effect is the way in which relief of the superior vena caval syndrome can frequently be obtained. Since this condition frequently is, or can easily become, a medical emergency, we initiate treatment with a full course (0.4 mg./kg.) of nitrogen mustard. The onset of relief is generally within 24 hours. The duration of benefit after HN2 alone is short. We therefore follow the drug with a course of radiation therapy to the superior mediastinum. This prolongs the effect so that this particular complication frequently does not recur during the period of survival of the patient. Even where rapidity of onset of effect is not essential, but where the edema that frequently accompanies the first doses of radiation could cause an initial worsening of symptoms, it is useful to pretreat the patient with an alkylating agent intravenously, since at the doses used it does not cause a reactive edema as does x-ray. The x-ray dosage can be increased more rapidly after such pretreatment. This effect of alkylating agents is also of great importance when multiple sites of involvement require treatment at the same time. The systemic action of these agents is then preferable to the localized effect of x-rays. The second area of specific usefulness of these drugs is in the treatment
638
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of malignant effusions. Systemic administration of the drug will be sufficient to clear some effusions, but if it is not, it is possible to inject the drug in the same dosage that would be used intravenously, directly into the pleural or pericardial cavities after first removing most of the fluid. The absorption of the drug from the body cavity is unpredictable, so that doses no higher than those that would be used systemically are recommended. Whatever part of the dose is absorbed, the initial concentration in the cavity is higher than could possibly be achieved by systemic therapy. Our experience with this form of treatment parallels that of Weisbergcr,16 who reported that 55 per cent of patients with lung cancer were improved after intracavitary treatment with HN2. In the same paper, he reports that 64 per cent of all malignant effusions treated with HN2 had benefit and that 60 per cent of similar patients treated with intracavitary AU 198 were comparably benefited. Because of the greater availability and simplicity and the lower cost of treating with an alkylating agent it is recommended as the treatment of choice in this situation. Cyclophosphamide (Cytoxan) is not, on the basis of current knowledge, recommended for intracavitary use since it is injected in an inactive form and is dependent on intracellular enzymatic action for its conversion to an active form. This activation may not occur in the pleural or pericardial spaces. If the initial treatment is partially or totally ineffective, a second course may produce a better result. In patients in whom bone marrow depreRsion secondary to previous treatment or to marrow invasion by turn or is a problem, the use of colloidal AU198 or colloidal radioactive chromic phosphate would be preferable to the use of an alkylating agent. The third situation in which the alkylating'agents can be specifically useful is in those patients with pulmonary metastases who require treatment and in whom previous x-ray therapy has made pulmonary fibrosis an existing or a potential problem. Again, if the chest x-ray cannot distinguish between radiation fibrosis and lymphangitic metastases the administration of an alkylating agent would be the treatment of choice. Status of Various Experimental Approaches in the Treatment of Lung Cancer
Considerable time and effort have been expended in recent years in an attempt to define the usefulness of alkylating agents when administered prophylactically at the time of, or shortly after, surgical intervention. A nationwide cooperative program was set up to provide an answer to this problem. The study is not yet completed, but to date no useful effects have been proved with the prophylactic use of HN2 and Thio-TEPA in lung cancer. In a preliminary report on this study Moore17 states: "We do not think these chemotherapeutic compounds should be used
M edical Management of Advanced Lung Cancer
639
by the practicing surgeon until we have some evidence that their beneficial effects outweigh their adverse effects." A number of other drugs, not members of the group of alkylating agents, and not in themselves capable of producing a significant or a consistent effect against lung carcinoma, are being tested for their ability to enhance the effect of x-ray therapy. Among them are actinomycin D and 5-fluorouracil. It may well be that one or~both of these will prove useful in this regard. Proof of this effect is not yet at hand, but a group using x-ray plus fluorouracil are currently obtaining hopeful results. 18 Combinations of two or more chemotherapeutic agents, in which drugs with different mechanisms of action are administered simultaneously, arc also under study. The potential effectiveness of one form of combinatioJl therapy in other forms of cancer has already been demonstrated. 19 , 20 Preliminary studies ha vc shown that some cases of bronchogenic carcinoma can be benefited by various drug combinations but much more work is needed to determine whether this will be a reproducible and useful effect, and to determine which, if any, of the combinations tried so far will have clinical usefulness. The final area of experimental therapy to be mentioned here is the study of the administration of various standard agents by means of more or less complicated and unusual techniques in an attempt to enhance the local effectiveness of the drug while reducing the systemic toxicity. The techniques of isolated perfusion and direct intra-arterial infusion which are currently under investigation 21 do not appear to have any applicability to lung cancer. A technique recently described by Miller et al.,22 however, has promise in the treatment of tumor in the lungs. This is a procedure whereby a catheter with a balloon tip is introduced into the aorta, via the femoral artery. When it is advanced to the level of the diaphragm, the balloon is inflated, cutting off the flow of blood to the lower half of the body. At the same time, the venous return and the collateral circulation are interrupted by the inflation of a pneumatic cuff around the upper abdomen. A dose of nitrogen mustard can then be administered through the normal intravenous route in the arm. Since HN2 is rapidly fixed ill the tissues, the circulation need only be interrupted for ten to fifteen minutes. A dose somewhat higher than the standard intravenous dose is thereby delivered to the upper half of the body, while the bone marrow and the intestinal tract in the lower half of the body are protected from the toxic effects of the drug. Once the details of the optimal dose and the optimal drug have been worked out, this technique may enhance the value of the alkylating agents in the treatment of advanced lung cancer when the symptomatic disease is in the upper one-half of the body. Other tumors in the lungs, mediastinum and neck have already been seen to respond to this technique, to a greater degree than could have been achieved by conventional systemic administration.
640
ROBERT
B.
GOLBEY
Ineffective Therapy
The list of agents that are without effect on lung cancer is a long one and will not be recorded here, but two of these failures are worthy of specific mention because they are so readily available and the temptation to use them is frequently so great. The agents in question are estrogens and adrenal steroids. The possible value of estrogens was suggested by the 8:1 male:female incidence of epidermoid carcinoma; however, estrogens have had no beneficial effects on the symptoms or on the progression of lung cancer. Parenthetically, androgens have also been tested, with a similar lack of effect. 23 Adrenocortical steroids are even more tempting to employ in this disease than are the sex hormones, because of their general supportive effect and because of the high incidence of adrenal metastases. We cannot confirm or deny from our personal observations the report that adrenal steroids actually have a detrimental effect on the course of bronchogenic carcinoma,23 but we can agree that we have seen no tumor regression with their use. Even in those very rare patients who do develop overt signs of adrenal insufficiency, the benefit derived from their administration is so brief as to be almost without significance. This is not to say that adrenal steroids do not have a role in the symptomatic management of patients with lung cancer. In patients with bronchospasm, hypercalcemia, shock secondary to septicemia and a variety of other conditions, adrenal steroids may well be indicated and may be of considerable supportive usefulness. CONCLUSION
The incidence of lung cancer is increasing, and the available forms of treatment are not very good. A major hope for the future must be that lung cancer can be prevented, and that better therapy will become available for those cases that cannot be avoided. Even now, however, a nihilistic approach to the treatment of this disease'is not justified. If we cannot prolong life, we can at least try to prolong useful and comfortable life. If we diligently attempt to understand the cause and the significance of each sign and symptom, and then apply the appropriate currently available form of treatment, we will help our patients, occasionally far beyond our expectations, provided our expectations at the start were realistic. REFERENCES 1. American Cancer Society: Cancer Facts and Figures, 1960.
2. Wynder, E. L.: Environmental Causes of Cancer in Man. M. CLIN. NORTH AMERICA 40: 629-645 (May) H)56. 3. Karnofsky, D. A., Golbey, R. B. and Pool, J. L.: Preliminary Studies on the Natural History of Lung Cancer. Radiology 69: 477-488 (Oct.) 1957.
M edical Management of Advanced Lung Cancer
641
4. Ochsner, A., Ray, C. J. and Acree, P. W.: Cancer of Lung. Am. Rev. Tuberc. 70: 763-783 (Nov.) 1954. 5. Golbey, R. B., Streeter, B. and Karnofsky, D. A.: Clinical Observations on Patterns of Cancer. Acta Internat. Union Against Cancer 16: 1469-1472, 1960. 6. Budinger, J. M.: Untreated Bronchogenic Carcinoma. Cancer 11: 106-116 (Jan.Feb.) 1958. 7. Karnofsky, D. A. Myers, W. P. L. and Phillips, R.: Treatment of Inoperable Pulmonary Cancer, Primary and Metastatic. Am. J. Surg. 89: 526-537 (Feb.) 1955. 8. Karnofsky, D. A.: Panel Meeting. Management of Disseminated Neoplastie Disease. Bull. New York Acad. Med. 33: 681-734 (Oct.) 1957. 9. Southam, C. M.: Panel Meeting. Management of Disseminated Neoplastie Disease. Direct Effects of Cancer. Bull. New York Acad. Med. 33: 720-734 (Oct.) 1957. 9a. Phillips, R: Radiotherapy in Thoracic Neoplasms. Dis. Chest 3.9: 50-55 (Jan.) 1961. 10. Smart, J. and Hilton, G.: Radiotherapy of Cancer of Lung. Lancet 270: 880-881 (June 9) 1956. 11. Chu, F. C. H. and Hilaris, B. B.: Value of Radiation Therapy in Management of Intracranial Metastases. Cancer, May-June, 1961. 12. Rundles, W. and others: Comparison of Chlorambucil and Myleran in Chronic Lymphocytic and Granulocytic Leukemia. Am. J. Med. 27: 424-432 (Sept.) 1959. 13. Zubrod, G. C.: Useful Drugs in Treatment of Cancer. Arch. Internal Med. 106: 663-678 (Nov.) 1960. 14. Gellhorn, A.: Status of Alkylating Agents in Clinical Cancer Chemotherapy. Comparative Clinical and Biological Effects of Alkylating Agents. Ann. New York Acad. Sc. 68: 1254-1257 (April) 1958. 15. Karnofsky, D. A., Abelman, W. H., Craver, L. F. and Burchenal, J. H.: Use of Nitrogen Mustards in Palliative Treatment of Carcinoma. Cancer 1,' 634656 (Nov.) 1948. 16. Weisberger, A. S.: Direct Instillation of Nitrogen Mustard in Management of Malignant Effusions. Comparative Clinical and Biological Effects of Alkylating Agents. Ann. New York Acad. Sc. 68: 1091-1096 (April) 1958. 17. Moore, G.: Present Status of Investigation in Surgical Adjuvant Therapy. COI1ference on Experimental Clinical Cancer Chemotherapy. National Cancer Institute Monograph No. 3, 107-126, August 1960. 18. Willett, F. N., Foye, L. V. Jr., Roth, M. and Hall, B. E.: Combined Therapy of Inoperable Lung Carcinoma with 5-Fluoracil and Irradiation. Dis. Chest 39: 38-41 (Jan.) 1961. Hl. Li, M. C., Whitmore, W. F. Jr., Golbey, R. B. and Grabstald, H.: Effects of Combined Drug Therapy on Metastatic Cancer of Testis. ,LA.M.A. 17-'r: 1291-1299 (Nov. 5) 1960. 20. Golbey, R R, Li, M. C. and Levick, S.: Results of Treatment with Actinomycin D, Methotrexate, and an Alkylating Agent; A Progress Report. Proc. Am. A. Cancer Res., 1961. 21. Pierpont, H.: Techniques of Lung Perfusion with Cancer Chemotherapeutic Agents. Cancer Chemotherapy Reports No. ID (Perfusion ConfereIwe), 15-19, (Dec.) 1960. 22. Miller, D. G. and Lawrence, W.: Successful Bone Marrow Protection by Vascular Occlusion Following Large Doses of Nitrogen Mustard Therapy. Proc. Am. A. Cancer Res., 1961. 2:~. Wolf, J., Spear, P., Yesner, It. and Patno, M. E.: Sex Hormones and Cortisone in Treatment of Inoperable Bronchogenic Carcinoma. In: Biological Activities of Steroids in Relation to Cancer, G. Pincus, and E. P. Vollmer, Eds. New York, Academic Press, 1960, pp. 413-423. 24. Karnofsky, D. A. and Burchenal, J. H.: Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: Evaluation of Chemotherapeutic Agents, C. M. McLeod, Ed. New York, Columbia University Press, 1949, pp. 191-205.
Lung cancer is a problem that concerns every physician, because of the high and increasing frequency of the disease. Pulmonary carcinoma is not often curable, but there are several procedures of proved value in alleviating distressing symptoms and in prolonging useful life. Dr. Golbey has analyzed the course of advanced lung cancer and described the methods available for managing certain clinical problems. EVERY physician must be aware that ultimately one in four of his patients may be expected to develop cancer in some form. In approximately 8 per cent of those who do develop cancer, the tumor will originate in the lungs, and among those of his patients who die of their cancer, lung cancer will have been responsible for about 13 per cent of the deaths. In males this figure will be 21.5 per cent and in females 4 per cent. In its simplest terms this means that more than 2 per cent of his patients will die of lung cancer even if the incidence of lung cancer does not continue to rise at a rate which has resulted in a sixfold increase in this disease since 1920. 1 A physician must be prepared to attack the problem at three distinctly different levels. He must attempt to prevent cancer. Failing that he must act promptly to provide potentially curative therapy and failing in that he must be prepared to provide palliation. As can be seen in Figure 1 ill which these three aspects of therapeutic activity are shown on different horizontal levels, it is important that the patient should be treated at the highest level consistent with his situation, since the outcome of treatment at the palliative level is not nearly so satisfactory to the patient as it may be at a higher level. Since this figure is as applicable to other forms of cancer as it is to lung carcinoma, it is important to note that level reading "to cure" may be satisfactory in some forms of cancer only in a relative sense. The relativity depends on one's definition of cure. In lung cancer, however, the definition of cure can be fairly precise. In most series 50 per cent of the patients who are going to die of their disease will have died * This investigation was supported in part by research grant CY-3215 from the
National Cancer Institute, Public Health Service, and in part by a grant from the Damon Runyon Memorial Fund for Cancer Research.
627
628
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GOLBEY
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within nine months of the onset of symptoms. Ninety per cent will have died within a few months more. Patients who have survived three years after treatment with no evidence of disease usually are safe from a recurrence of lung cancer. As the number of cancers in which etiological factors have been found increases and as the awareness of the significance of these factors grows, the increase in potential of preventive medicine in cancer has become apparent,2 but we are not concerned with this problem here. We also will not concern ourselves here with the problems presented by the patient with localized disease, in whom there is an apparent chance to completely excise the areas of malignancy. Our concern is with those patients who present themselves with disease which is clearly beyond the possibility of complete surgical excision, whether this be at the time of the initial diagnosis or at the time after surgery that a recurrence is found. These, for our purposes, will be considered to be the patients with advanced lung cancer. In this definition you will note that there is no implication of a time scale. A lung cancer may be advanced even at a time when the patient is completely without signs or symptoms and, in fact, even when by all our available techniques there is no detectable disease in the lungs. On the other hand, it may not be advanced even though it can be demonstrated retrospectively that the lung tumor has been quietly growing in place for years. Metastatic spread is also not implicit in the definition. A patient may be in the advanced stage of the disease by virtue of local extension to vital areas where its total removal is not possible, even though no distant spread has occurred. 3 In considering what can be done for a patient with advanced carcinoma of the lung, one must first take great pains to determine whether the case in question is truly advanced and is no longer potentially curable by
M edical Management of
A~dvanced
Lung Cancer
G29
surgical treatment. Each surgeon will have his own criteria of inoperability. All important criterion is the involvement of a distant viscus with cancer. Frequently the implicated organ is the liver. Even in patients with known cancer present elsewhere in the body, this diagnosis of metastatic involvement is difficult to make. In the absence of a positive liver biopsy, which is the only way that an absolutely certain diagnosis can be made, one must insist that there be an enlarged, nodular liver with abnormal liver function tests including at least an abnormal bromsulphalein retention or an elevated alkaline phosphatase. If one of these criteria is ignored, the accuracy of the diagnosis of metastatic involvement of the liver will fall off markedly. Similarly, all other criteria of inoperability must be critically reviewed in the light of the individual patient's situation. It is preferable to err on the side of more surgery which is ultimately only exploratory or palliative. Palliative surgery can often significantly improve a patient's comfort, and sometimes even his period of surviva1. 4 PATTERNS OF LUNG CANCER
Once advanced disease is shown to be present, it can progress in any one of several ways. Patterns of advanced lung cancer have been described previously by our group." It was found that most cases fall into one of three major patterns of clinical behavior and that many will clearly fit into one of the well-defined subgroups. These elinical patterns are determined by many parameters but chiefly by an anlyasis of (1) the mode of onset, (2) rate of growth, (3) site of metastases, (4) rate of metastasis, (5) rate of growth of metastases, (6) complications and (7) cause of death. Local Pattern
This study has shown that about 20 per cent of patients with primary carcinoma of the lung who die of their carcinoma will have either no distant metastases or a few small and clinically asymptomatic metastases, usually detectable only in those who have a postmortem examination. Budinger,6 in a series of 250 autopsied cases of untreated bronchogenic cases, found 16 cases in which the tumor was confined entirely to the lung. This local pattern is different from the other patterns below, but not in that it is less malignant. The median survival time is no greater, probably because the tumor is locally more aggressive and invasive, frequently with involvement of unusually large segments of lung and adjacent tissues. The pleura, mediastinum, ribs, spine, skin, pericardium and myocardium may all be extensively involved by local growth in continuity. Discontinuous growth is sometimes seen in the other lung. Pulmonary hemorrhage and respiratory failure, secondary to tumor
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Fig. 2. This chart portrays the course of an essentially untreated patient with a localized pattern of lung cancer. The period uf survival from the onset of symptoms is median for our entire series and for the local pattern. The period of hospitalization is indicated by the cross-hatched area on the time scale. The abrupt change in the gradually falling performance status" should be noted.
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M edical M anagernent of Advanced L1wg Cancer
631
growth, atelectasis and infection, will be common causes of death. All example of this "local pattern" is seen in Figure 2. As will be discussed later, this group raises several interesting considerations when the appropriate therapy is being sought. Organ-Specific Metastases Pattern
A second major pattern is seen in patients who develop clinically significant distant metastases in only one organ. This organ may be the liver, brain or bones. When these organs are to be exclusively involved by metastatic lung cancer, the metastatic involvement may appear before, simultaneously with, or shortly after the primary site in the lung is detected. The clinical involvement of a single organ does not mean that there is only a single metastasis. This is particularly apparent in the bones where multiple widely scattered areas of involvement restricted to that one organ system can be easily detected. There seem to be factors governing the localization of metastases other than blood vessel invasion and pure chance. Among these factors are very likely obscure biochemical differences in the tumor cells which control its ability to grow on "foreign soil." The one site for which most pulmonary carcinomas appear to share a common affinity is the adrenal gland. About 60 per cent of all of our autopsied cases had adrenal metastases and if the local pattern is excluded, although even some of these had small adrenal metastases, the percentage rises to about 90 per cent. Generalized Pattern
The third major pattern is of generalized disease, in which any and every organ in the body may be involved. This pattern can be subdivided on a temporal basis, depending on when and at what rate the metastases appear. In one group all of the metastases will become clinically apparent within a span of a few days or a few weeks. This may occur in a patient who was previously well with no known malignant disease. A diagnosis of the primary site of the tumor may be very difficult to establish, since a similar pattern is seen in several other malignant diseases and the histology is frequently not sufficiently distinctive to permit any certainty of diagnosis. Among other primary tumors which exhibit this phenomenon are melanoma, breast carcinoma and gastric carcinoma. Recognition of this pattern when it is due to lung cancer is primarily of prognostic significance in that most of these patients will be dead within three months of the onset and almost all will be dead within six months. When this pattern is seen as the presenting complaint, it can aptly be described and classified as acute carcinomatosis. The last subpattern of generalized disease is one in which different organs become clinically involved gradually, with intervals of many weeks or months occurring between the involvement of one organ and another. An example of this pattern is seen in Figure 3.
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The importance of an appreciation of the natural history of lung cancer in the optimal management of these patients cannot be overemphasized. The histology of the tumor does not seem to be as prognostically significant, once dissemination has occurred, as it is in the apparently operable case, but other factors, some of which have been mentioned, do assume great importance. The ability to anticipate the ultimate consequences and the complications of a tumor deposit in a particular site, a facility which comes only with knowledge of the natural history of the process, is basic to effective management. TREATMENT
The management of patients with advanced lung cancer involves two major areas of therapeutic endeavor. The first of these is in the use of
Medical Management of Advanced Lung Cancer TERMINAL EVENTS: RESPIRATORY FAILURE
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Fig. 3 (cont'd)
633
antitumor agents whose use is intended to halt or to slow the progression of the disease. The second area is a less specific one in which all of the medical disciplines are called upon to provide relief from the problems presented by the anatomical, functional or metabolic alterations produced by progressively growing cancer. This latter area is only indirectly related to the site of origin of the tumor, and it represents a problem common to the management of all forms of cancer. 7 Its scope is such as to preclude discussion here, but its importance has been well emphasized by Karnofsky,8 who said: "Until more satisfactory specific therapy (... of metastatic cancer ... ) is discovered, the physician must employ all the knowledge and therapeutic techniques available in an attempt to relieve distress and to prolong life. Steady therapeutic progress (the epoch-making empirical discoveries are excepted) stems mostly from an understanding of the physiopathology of disease." Careful analysis of each patient's problem, in terms of what factors are specifically responsible for each facet of his disability, and what can be done about these factors, is the single most important principle in this sphere of management of the cancer patient. We will confine ourselves here to a discussion of those methods'Cof treatment which are used because they may directly damage cancer cells.
Radiation Therapy
Patients with lung cancer can be benefited by treatment with ionizing radiation and with a variety of chemotherapeutic agents. Some of the considerations entering into some frequently encountered clinical situations will be briefly reviewed. Southam has stated, in discussing the management of the patient with disseminated cancer,9 that cancer that is not producing signs or symptoms is not important. In certain instances, however, it is sometimes possible to anticipate the development of symptoms and, with judicious treatment, to prevent them. Localized lung cancer, even if not curable by resection, does not fit Southam's concept, which applies only to dissemina'ted cancer. Many cases of lung cancer in which distant metastases
634
ROBERT
B.
GOLBEY
are not apparent can be helped by radiation therapy. Most papers which discuss the usefulness of radiation in lung cancer do not present any useful statistics on which a prognosis for a given case can be based. The authors will content themselves with the statement that results are poor in so far as three or five year survival with no evidence of disease is concerned, but they will also go on to describe one, two or three cases in which the survival exceeded all expectations, and some that might merit the cautious use of the description "cured."9a Much of the despair over the usefulness of this method of treatment comes from the fact that these patients, despite prolonged suppression of the disease in the treated areas, go on to die of their distant metastases. As was noted earlier in the brief discussion of the natural history of advanced lung cancer, at least some of the patients who present with localized tumor will not have significant, distant metastases even at the time of death. It is certainly from this group with the localized pattern that the few long survivors come, and from which more will be derived when the utilization of the newer radiation techniques and equipment becomes more widely practiced. Smart and Hilton 10 have reported on the primary treatment with radiation of a small group of patients who would have been candidates for total surgical extirpation by the usual criteria applied preoperatively. Twelve of these patients had been followed for five years or more. Four (33 per cent) are alive and well, one survived three years, two survived more than two years, and five died within two years. Whether this response rate, which is similar to the surgical response rate, will continue to hold up as the series expands, is not pertinent to our discussion here since these are early cases, but these figures do lend support to the belief that in selected situations radiation therapy can be of great value. Large numbers of patients cannot be expected to be salvaged by radiation, but it would not require many to significantly improve the salvage obtained from surgical therapy alone. Of the 36,000 persons the American Cancer Society predicts will develop lung cancer in 1961, fewer than 1800 will be cured by operation. As many as 7000 of them, however, may die with localized nonresectable disease which could have been significantly benefited by radiation therapy. Whether cure is achieved or not, radiation therapy is worth using purely for its ability to palliate symptoms and to prevent complications. Timely treatment call prevent or ameliorate cough, hemoptysis, dyspnea, pain, atelectasis, infection and other manifestations of the growing local lesions, thereby achieving the goal of palliation-as comfortable and as normal a Jiff as is possible, for whatever time is left. A limiting factor in radiation to the lung is the possibility of producing fibrosis and'"respiratory insufficiency. This consideration limits the dose and the size of the field that can be treated. The radiologist must take this, and other factors such as respiratory reserve, progress of disease in
Medical Management of Advanced Lung Cancer
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other areas and skin changes, as well as the facilities available, into consideration in planning the optimal treatment. In addition to being specifically indicated in the treatment of localized, nonresectable disease, x-ray is useful in the palliative treatment of many metastatic foci. In brain metastases particularly, the results may be gratifying in duration, degree and frequency. Chu and Hilarisll have reported on the treatment of brain metastases in 74 patients with carcinoma of the lung. Of these, 54 survived long enough to complete the prescribed course of treatment. Forty-five had clinical improvement in their intracranial disease for more than one month. The average remission of symptoms lasted 4.5 months while the average survival was 6.4 months. The nonresponders survived only an average of 2 months. These authon: also show that some long responses can be obtained. Some of the failures and short responses resulted not because the intracranial lesion did not respond, but because the tumor in the liver or els8where progressed~~o a fatal degree. They also report a ,distinct dose-response correlation. Patients treated with less than 2750 rads showed a 29.4 per cent failure rate and there were no five-month remissions, while those receiving more than 2750 rads had only a 9.6 per cent failure rate and 38.5 per cent had a remission for five months or more. Additionally, seven out of ten patients had a useful response to a second course of therapy, and one of two had a response to a third course. When it is considered that most of these patients had generalized metastases, it is apparent that, should one encounter a patient with only brain metastases, as discussed earlier under organ-specific metastases, this form of treatment is not only indicated but almost mandatory. Similarly bone metastases which are painful, or threaten to result in collapse or fracture, can be benefited sufficiently often by radiation therapy to justify its use whenever these lesions present a problem in clinical management. The results of treatment of hepatic metastases with x-ray are less satisfactory, but there are situations in which it should be tried. If a patient was symptomatic due to liver involvement and a localized lesion in the porta hepatis were suspected, or the absence or minimal nature of other metastases indicated that shrinkage of the liver and/or improvement in li vel' function could make a vast difference in the patient's status, x-ray therapy should be tried. In Memorial Hospital supervoltage therapy is strongly preferred for treatment to the liver. The use of radiation therapy must be considered whenever one is confronted by a localized tumor mass which is, or soon will be, producing symptoms. Occasionally radon seeds can be implanted into an accessible tumor mass, such as a superior sulcus tumor, with beneficial results. External radiation is specifically indicated in the treatment of situations such as a superior vena caval syndrome or spinal cord compression, but the discussion of this use is deferred until the later section on alkylating
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agents since it is our practice to use x-ray in conj unction with chemotherapy in these situations unless the chemotherapy is specifically contraindicated. Discussion of the use of radioactive colloid suspensions in the treatment of malignant effusions is similarly deferred since we prefer chemotherapeutic agents as the treatment of choice in most of these eases. Chemotherapy
Almost every drug that is introduced into clinical trial is tested against bronchogenic carcinoma. Many of them have demonstrated an ability to affect the growth of the tumor in an occasional case, but with only one class of compounds, the alkylating agents, have the results been sufficiently useful in frequency, in degree, in duration and in being accompanied by an acceptable toxicity risk, to merit mention in a clinical paper. The alkylating agents are a group of chemical compounds which are diverse in structure but similar in their mode of action, their major toxic manifestations and their therapeutic effects. They are as a class called "radiomimetic" because their biological effects, although mediated through different chemical reactions, resemble those of ionizing radiations. The effects of these drugs, like those of radiation, are most profound on rapidly dividing cells, so that the greatest antitumor effect can be expected against the more anaplastic cells, and the major toxicity at therapeutic doses is seen in their effects on the rapidly growing cells of the bone marrow, gastrointestinal mucosa and germinal epithelium. Some authors 12. 13 have described what they believe to be evidence of a specificity of one or another of these drugs in its action against a particular cell type, while others have indicated that these differences represent, at most, quantitative variations rather than qualitative specificity.14 It is the latter view which is subscribed to here and for this reason we would suggest that every doctor treating malignant disease become thoroughly familiar with one standard intravenous and one standard oral alkylating agent, before becoming concerned with the minor refinements of dose form, stability and side effects which distinguish one alkylating agent from another, in their use against human tumors. The first reports on the usefulness of nitrogen mustard in lung cancer appeared in 1948. 16 This drug is the prototype of all alkylating agents and is the standard against which claims of unique activity for other alkylating agents should be measured. In our current usage we administer nitrogen mustard (HN2; Mustargen) intravenously in a dose of 0.4 mg./kg. This dose will regularly produce a tolerable degree of bone marrow depression beginning in about one week, becoming maximal at about two weeks, and returning to normal in about three weeks. Other manifestations of systemic toxicity are not usually seen although nausea
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and vomiting may be troublesome for some hours after the HN2 is administered, unless controlled by antiemetics and sedation. Some observers have reported that patients having lung cancer but with normal bone marrows will tolerate up to twice this dose. This does not appear to offer any advantage over the practice of giving 0.4 mg./kg. and then repeating this dose or some fraction of it if a fall in white blood cells or platelets have not occurred in seven to ten days. Using essentially this dosage regimen, Karnofsky reported: "Nitrogen mustard was used in the treatment of 35 patients with inoperable carcinoma of the lung. In 74 per cent of the patients some clinical improvement occurred. This was evidenced by an alleviation in symptoms such as cough, dyspnea, hemoptysis, pain, weakness, and the syndrome associated with obstruction to the superior vena cava; and such objective changes as regression of pulmonary and metastatic lesions and absorption of pleural effusions. The improvement usually lasted from two weeks to two months and further courses of HN2 were usually not as effective as the first." Continued experience with this drug for the past 12 years has made the series larger, but has not changed the basic conclusions quoted. Similar results can be obtained with triethylene melamine, Thio-TEPA and Cytoxan given intravenously, or Leukeran, Myleran, Cytoxan, triethylene melamine and Thio-TEPA orally. The alkylating agents are of particular usefulness in three frequently occurring situations. The first is that in which symptoms are produced by the pressure of the growing tumor on a vital structure such as a nerve, bronchus or vein. Relatively minor reductions in the size of the tumor may be sufficient to relieve the pressure or the obstruction, and thereby provide major symptomatic relief of pain or of bronchial, biliary or other obstruction. An example of this effect is the way in which relief of the superior vena caval syndrome can frequently be obtained. Since this condition frequently is, or can easily become, a medical emergency, we initiate treatment with a full course (0.4 mg./kg.) of nitrogen mustard. The onset of relief is generally within 24 hours. The duration of benefit after HN2 alone is short. We therefore follow the drug with a course of radiation therapy to the superior mediastinum. This prolongs the effect so that this particular complication frequently does not recur during the period of survival of the patient. Even where rapidity of onset of effect is not essential, but where the edema that frequently accompanies the first doses of radiation could cause an initial worsening of symptoms, it is useful to pretreat the patient with an alkylating agent intravenously, since at the doses used it does not cause a reactive edema as does x-ray. The x-ray dosage can be increased more rapidly after such pretreatment. This effect of alkylating agents is also of great importance when multiple sites of involvement require treatment at the same time. The systemic action of these agents is then preferable to the localized effect of x-rays. The second area of specific usefulness of these drugs is in the treatment
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of malignant effusions. Systemic administration of the drug will be sufficient to clear some effusions, but if it is not, it is possible to inject the drug in the same dosage that would be used intravenously, directly into the pleural or pericardial cavities after first removing most of the fluid. The absorption of the drug from the body cavity is unpredictable, so that doses no higher than those that would be used systemically are recommended. Whatever part of the dose is absorbed, the initial concentration in the cavity is higher than could possibly be achieved by systemic therapy. Our experience with this form of treatment parallels that of Weisbergcr,16 who reported that 55 per cent of patients with lung cancer were improved after intracavitary treatment with HN2. In the same paper, he reports that 64 per cent of all malignant effusions treated with HN2 had benefit and that 60 per cent of similar patients treated with intracavitary AU 198 were comparably benefited. Because of the greater availability and simplicity and the lower cost of treating with an alkylating agent it is recommended as the treatment of choice in this situation. Cyclophosphamide (Cytoxan) is not, on the basis of current knowledge, recommended for intracavitary use since it is injected in an inactive form and is dependent on intracellular enzymatic action for its conversion to an active form. This activation may not occur in the pleural or pericardial spaces. If the initial treatment is partially or totally ineffective, a second course may produce a better result. In patients in whom bone marrow depreRsion secondary to previous treatment or to marrow invasion by turn or is a problem, the use of colloidal AU198 or colloidal radioactive chromic phosphate would be preferable to the use of an alkylating agent. The third situation in which the alkylating'agents can be specifically useful is in those patients with pulmonary metastases who require treatment and in whom previous x-ray therapy has made pulmonary fibrosis an existing or a potential problem. Again, if the chest x-ray cannot distinguish between radiation fibrosis and lymphangitic metastases the administration of an alkylating agent would be the treatment of choice. Status of Various Experimental Approaches in the Treatment of Lung Cancer
Considerable time and effort have been expended in recent years in an attempt to define the usefulness of alkylating agents when administered prophylactically at the time of, or shortly after, surgical intervention. A nationwide cooperative program was set up to provide an answer to this problem. The study is not yet completed, but to date no useful effects have been proved with the prophylactic use of HN2 and Thio-TEPA in lung cancer. In a preliminary report on this study Moore17 states: "We do not think these chemotherapeutic compounds should be used
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by the practicing surgeon until we have some evidence that their beneficial effects outweigh their adverse effects." A number of other drugs, not members of the group of alkylating agents, and not in themselves capable of producing a significant or a consistent effect against lung carcinoma, are being tested for their ability to enhance the effect of x-ray therapy. Among them are actinomycin D and 5-fluorouracil. It may well be that one or~both of these will prove useful in this regard. Proof of this effect is not yet at hand, but a group using x-ray plus fluorouracil are currently obtaining hopeful results. 18 Combinations of two or more chemotherapeutic agents, in which drugs with different mechanisms of action are administered simultaneously, arc also under study. The potential effectiveness of one form of combinatioJl therapy in other forms of cancer has already been demonstrated. 19 , 20 Preliminary studies ha vc shown that some cases of bronchogenic carcinoma can be benefited by various drug combinations but much more work is needed to determine whether this will be a reproducible and useful effect, and to determine which, if any, of the combinations tried so far will have clinical usefulness. The final area of experimental therapy to be mentioned here is the study of the administration of various standard agents by means of more or less complicated and unusual techniques in an attempt to enhance the local effectiveness of the drug while reducing the systemic toxicity. The techniques of isolated perfusion and direct intra-arterial infusion which are currently under investigation 21 do not appear to have any applicability to lung cancer. A technique recently described by Miller et al.,22 however, has promise in the treatment of tumor in the lungs. This is a procedure whereby a catheter with a balloon tip is introduced into the aorta, via the femoral artery. When it is advanced to the level of the diaphragm, the balloon is inflated, cutting off the flow of blood to the lower half of the body. At the same time, the venous return and the collateral circulation are interrupted by the inflation of a pneumatic cuff around the upper abdomen. A dose of nitrogen mustard can then be administered through the normal intravenous route in the arm. Since HN2 is rapidly fixed ill the tissues, the circulation need only be interrupted for ten to fifteen minutes. A dose somewhat higher than the standard intravenous dose is thereby delivered to the upper half of the body, while the bone marrow and the intestinal tract in the lower half of the body are protected from the toxic effects of the drug. Once the details of the optimal dose and the optimal drug have been worked out, this technique may enhance the value of the alkylating agents in the treatment of advanced lung cancer when the symptomatic disease is in the upper one-half of the body. Other tumors in the lungs, mediastinum and neck have already been seen to respond to this technique, to a greater degree than could have been achieved by conventional systemic administration.
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Ineffective Therapy
The list of agents that are without effect on lung cancer is a long one and will not be recorded here, but two of these failures are worthy of specific mention because they are so readily available and the temptation to use them is frequently so great. The agents in question are estrogens and adrenal steroids. The possible value of estrogens was suggested by the 8:1 male:female incidence of epidermoid carcinoma; however, estrogens have had no beneficial effects on the symptoms or on the progression of lung cancer. Parenthetically, androgens have also been tested, with a similar lack of effect. 23 Adrenocortical steroids are even more tempting to employ in this disease than are the sex hormones, because of their general supportive effect and because of the high incidence of adrenal metastases. We cannot confirm or deny from our personal observations the report that adrenal steroids actually have a detrimental effect on the course of bronchogenic carcinoma,23 but we can agree that we have seen no tumor regression with their use. Even in those very rare patients who do develop overt signs of adrenal insufficiency, the benefit derived from their administration is so brief as to be almost without significance. This is not to say that adrenal steroids do not have a role in the symptomatic management of patients with lung cancer. In patients with bronchospasm, hypercalcemia, shock secondary to septicemia and a variety of other conditions, adrenal steroids may well be indicated and may be of considerable supportive usefulness. CONCLUSION
The incidence of lung cancer is increasing, and the available forms of treatment are not very good. A major hope for the future must be that lung cancer can be prevented, and that better therapy will become available for those cases that cannot be avoided. Even now, however, a nihilistic approach to the treatment of this disease'is not justified. If we cannot prolong life, we can at least try to prolong useful and comfortable life. If we diligently attempt to understand the cause and the significance of each sign and symptom, and then apply the appropriate currently available form of treatment, we will help our patients, occasionally far beyond our expectations, provided our expectations at the start were realistic. REFERENCES 1. American Cancer Society: Cancer Facts and Figures, 1960.
2. Wynder, E. L.: Environmental Causes of Cancer in Man. M. CLIN. NORTH AMERICA 40: 629-645 (May) H)56. 3. Karnofsky, D. A., Golbey, R. B. and Pool, J. L.: Preliminary Studies on the Natural History of Lung Cancer. Radiology 69: 477-488 (Oct.) 1957.
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4. Ochsner, A., Ray, C. J. and Acree, P. W.: Cancer of Lung. Am. Rev. Tuberc. 70: 763-783 (Nov.) 1954. 5. Golbey, R. B., Streeter, B. and Karnofsky, D. A.: Clinical Observations on Patterns of Cancer. Acta Internat. Union Against Cancer 16: 1469-1472, 1960. 6. Budinger, J. M.: Untreated Bronchogenic Carcinoma. Cancer 11: 106-116 (Jan.Feb.) 1958. 7. Karnofsky, D. A. Myers, W. P. L. and Phillips, R.: Treatment of Inoperable Pulmonary Cancer, Primary and Metastatic. Am. J. Surg. 89: 526-537 (Feb.) 1955. 8. Karnofsky, D. A.: Panel Meeting. Management of Disseminated Neoplastie Disease. Bull. New York Acad. Med. 33: 681-734 (Oct.) 1957. 9. Southam, C. M.: Panel Meeting. Management of Disseminated Neoplastie Disease. Direct Effects of Cancer. Bull. New York Acad. Med. 33: 720-734 (Oct.) 1957. 9a. Phillips, R: Radiotherapy in Thoracic Neoplasms. Dis. Chest 3.9: 50-55 (Jan.) 1961. 10. Smart, J. and Hilton, G.: Radiotherapy of Cancer of Lung. Lancet 270: 880-881 (June 9) 1956. 11. Chu, F. C. H. and Hilaris, B. B.: Value of Radiation Therapy in Management of Intracranial Metastases. Cancer, May-June, 1961. 12. Rundles, W. and others: Comparison of Chlorambucil and Myleran in Chronic Lymphocytic and Granulocytic Leukemia. Am. J. Med. 27: 424-432 (Sept.) 1959. 13. Zubrod, G. C.: Useful Drugs in Treatment of Cancer. Arch. Internal Med. 106: 663-678 (Nov.) 1960. 14. Gellhorn, A.: Status of Alkylating Agents in Clinical Cancer Chemotherapy. Comparative Clinical and Biological Effects of Alkylating Agents. Ann. New York Acad. Sc. 68: 1254-1257 (April) 1958. 15. Karnofsky, D. A., Abelman, W. H., Craver, L. F. and Burchenal, J. H.: Use of Nitrogen Mustards in Palliative Treatment of Carcinoma. Cancer 1,' 634656 (Nov.) 1948. 16. Weisberger, A. S.: Direct Instillation of Nitrogen Mustard in Management of Malignant Effusions. Comparative Clinical and Biological Effects of Alkylating Agents. Ann. New York Acad. Sc. 68: 1091-1096 (April) 1958. 17. Moore, G.: Present Status of Investigation in Surgical Adjuvant Therapy. COI1ference on Experimental Clinical Cancer Chemotherapy. National Cancer Institute Monograph No. 3, 107-126, August 1960. 18. Willett, F. N., Foye, L. V. Jr., Roth, M. and Hall, B. E.: Combined Therapy of Inoperable Lung Carcinoma with 5-Fluoracil and Irradiation. Dis. Chest 39: 38-41 (Jan.) 1961. Hl. Li, M. C., Whitmore, W. F. Jr., Golbey, R. B. and Grabstald, H.: Effects of Combined Drug Therapy on Metastatic Cancer of Testis. ,LA.M.A. 17-'r: 1291-1299 (Nov. 5) 1960. 20. Golbey, R R, Li, M. C. and Levick, S.: Results of Treatment with Actinomycin D, Methotrexate, and an Alkylating Agent; A Progress Report. Proc. Am. A. Cancer Res., 1961. 21. Pierpont, H.: Techniques of Lung Perfusion with Cancer Chemotherapeutic Agents. Cancer Chemotherapy Reports No. ID (Perfusion ConfereIwe), 15-19, (Dec.) 1960. 22. Miller, D. G. and Lawrence, W.: Successful Bone Marrow Protection by Vascular Occlusion Following Large Doses of Nitrogen Mustard Therapy. Proc. Am. A. Cancer Res., 1961. 2:~. Wolf, J., Spear, P., Yesner, It. and Patno, M. E.: Sex Hormones and Cortisone in Treatment of Inoperable Bronchogenic Carcinoma. In: Biological Activities of Steroids in Relation to Cancer, G. Pincus, and E. P. Vollmer, Eds. New York, Academic Press, 1960, pp. 413-423. 24. Karnofsky, D. A. and Burchenal, J. H.: Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: Evaluation of Chemotherapeutic Agents, C. M. McLeod, Ed. New York, Columbia University Press, 1949, pp. 191-205.