Small cell lung cancer

SMALL CELL LUNG CANCER

A B S T R A C T . w L u n g c a n c e r is t h e m o s t c o m m o n c a u s e of c a n c e r d e a t h in t h e United States, w i t h a p p r o x i m a t e l y 135,000 m e n a n d w o m e n d y i n g e a c h y e a r . While m u c h h a s b e e n l e a r n e d a b o u t t h e etiologic risk f a c t o r s , l e s s p r o g r e s s h a s b e e n m a d e in t h e r a p y . Fivey e a r survival r a t e s r e m a i n at ( 1 0 % . H o w e v e r , t h e r e h a s b e e n s o m e p r o g r e s s in t h e t h e r a p y of o n e histological s u b t y p e o f l u n g c a n c e r , s m a l l cell l u n g c a n c e r . T o t a l i n g a r o u n d 20% o f l u n g c a n c e r c a s e s , s m a l l cell l u n g c a n c e r is d i s t i n c t f r o m t h e o t h e r histologic subt y p e s in its biologic b e h a v i o r a n d r e s p o n s i v e n e s s to t h e r a p y . I n t h e 1960s, t h e m e d i a n survival f o r p a t i e n t s w i t h s m a l l cell l u n g c a n c e r w a s a p p r o x i m a t e l y 3 m o n t h s . With c o m b i n a t i o n c h e m o t h e r a p y a n d radiot h e r a p y m e d i a n survivals n o w r a n g e f r o m 1 to 2 y e a r s , a n d t h e r e is e v i d e n c e f o r a c u r a t i v e p o t e n t i a l s i n c e app r o x i m a t e l y 10% of p a t i e n t s w h o initially p r e s e n t w i t h limited d i s e a s e survive ~ 2 y e a r s . T h e u n i q u e clinical a s p e c t s of this h i s t o l o g i c a l s u b t y p e p o t e n t i a l l y r e l a t e to its u n d e r l y i n g cell of origin. T h i s b e h a v i o r is r e f l e c t e d in t h e n u m e r o u s p a r a n e o p l a s t i c s y n d r o m e s t h a t freq u e n t l y a c c o m p a n y s m a l l cell l u n g c a n c e r . Its p r o p e n sity f o r e a r l y d i s s e m i n a t i o n h a v e m a d e s t a g i n g t h e ext e n t of d i s e a s e a n i m p o r t a n t p a r t of t h e clinical e v a l u a t i o n . S i n c e s m a l l cell l u n g c a n c e r is sensitive to both chemotherapy and radiation therapy, there have b e e n multiple clinical trials e v a l u a t i n g d r u g / r a d i o t h e r a p y c o m b i n a t i o n s . T h i s article will b r i e f l y d e s c r i b e t h e u n i q u e a s p e c t s of s m a l l cell l u n g c a n c e r as o p p o s e d to o t h e r h i s t o l o g i c a l s u b t y p e s of l u n g c a n c e r a n d give a n o v e r v i e w o f t h e c u r r e n t clinical a p p r o a c h a n d t r e a t m e n t of t h i s d i s e a s e .

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BRIEF

Lung cancer is the m o s t c o m m o n cause of cancer d e a t h in the United States. It is estimated that approximately 135,000 m e n a n d w o m e n died in 1988 because of this malignancy. Small cell lung cancer, comprising 20% to 30% of all cases of lung cancer, is distinct from the other histologic subtypes in its biologic behavior and responsiveness to therapy. This fact is reflected in the improved median survival from approximately 3 m o n t h s to over 1 year with current treatment modalities. This therapeutic advance with treatment makes the recognition of this histologic subtype important for the practicing physician. The etiology a n d prevention of small cell lung cancer is not distinguished from the other cell types of lung cancer. The inhalation of tobacco smoke is the most clearly defined a n d important risk factor ['or lung cancer. This relationship appears to be especially strong for small cell lung cancer. Other chemical agents s h o w a risk relationship to lung cancer, but tobacco smoke remains the overwhelming factor. The concept of chemoprevention, the use of agents to decrease the incidence of cancer in high risk populations, remains an attractive potential a n d is currently being evaluated in nationwide trials. Distinguishing small cell lung cancer from the other histologic subtypes of lung cancer is of prime importance for the pathologist a n d clinician. Currently most patients have a diagnosis m a d e by bronchial biopsy or cytology, p e r c u t a n e o u s needle biopsy, or surgical biopsy. If questions arise as to the exact cell type because of inadequate or poorly p r e p a r e d material, repeat biopsies or review of the original tissue is frequently advised. With adequate material a light microscopic diagnosis is usually sufficient, although electron microscopy showing electron-dense neurosecretory granules is pathognomonic. The subtyping of small cell lung cancer has a low degree of reproducibility a m o n g pathologists and its clinical significance is unproven. Pearse in 1969 p r o p o s e d that small cell lung cancer arises in pulm o n a r y cells w h i c h originally migrated from the embryonic neuro crest. Small cell lung cancer was p r o p o s e d as one of several amine precursor uptake and decarboxylation (APUD) tumors. This theory explained the presence of neurosecretory granules a n d the frequent occurrence of ectopic h o r m o n e p r o d u c t i o n by these t u m o r cells. Newer theories have suggested a more diverse cell of origin. In vitro cell culture a n d animal studies suggest that all histologic subtypes of lung cancer have a c o m m o n cell of origin and that differentiation to a specific cell type occurs during the "life cycle" of a specific tumor. Supporting this therapy is the d o c u m e n t a t i o n of histologic transi'ormation within a single patient over time. DM, December 1989

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One of the u n iq u e biologic features of small cell lung c a n c e r is its p r o p e n s i t y for early a n d w i d e - s p r e a d dissemination. Because of this early spread, staging, d e t e r m i n i n g the extent of disease at the time of presentation, has b e c o m e an integral part of the evaluation of a patient with small cell lung cancer. T he extent of disease, a r o u g h equivalent to the total b o d y t u m o r bur den, gives a reference p o i n t for evaluating the results of t r e a t m e n t a n d i m p o r t a n t prognostic information to the patient a n d family. Current a p p r o a c h e s to staging are b as ed on the f r e q u e n c y distribution of metastatic disease. The most c o m m o n metastatic sites are mediastinal and hilar l y m p h nodes, liver, bone marrow, cortical bone, central nervous system, and adrenal glands. Staging involves a c o m p l e t e evaluation of t hese organs. It b e c o m e s obvious that deten13ining the extent of metastatic involvement is related to the intensity of the search. It is suggestive that prognosis relates m o r e to total b o d y t u m o r b u r d e n than to specific organ involvement. One of the mo s t fascinating aspects of small cell lung c a n c e r is its fr e q u e n t association with p a r a n e o p l a s t i c s yndrom es. F r e q u e n t l y a patient will p r e s e n t to the non-oncologist b e c a u s e of the o c c u r r e n c e of one or a n u m b e r of par a ne opl a s t i c s y n d r o m e s . Careful evaluation reveals the u n d e I t y i n g small cell carcinoma. Many of these synd r o m e s are c a u s e d by the ectopic p r o d u c t i o n of p e p t i d e h o r m o n e s including anti-diuretic h o r m o n e , (ADH), a nd a d r e n o c o r t i c o t r o p i c h o r m o n e (ACTH). A n u m b e r of par a ne opl a s t i c neurologic disorders can also a c c o m p a n y this disease. Patients can p r e s e n t with p e r i p h eral n e u r o p a t h i e s , weakness, dementia, cerebel]ar degeneration, a n d Eaton-Lambert S y n d r o m e with its m y a s t h e n i a gravis-type findings. An u n d e r s t a n d i n g of t hes e par a ne opl a s t i c s y n d r o m e s allows the clinician to s u s p ect a n d confirm the u n d e r l y i n g diagnosis of small cell lung cancer. T r e a t m e n t of small cell lung c a n c e r has u n d e r g o n e major changes over the past 15 to 20 years. Early r e por t s using the modalities of radiation or surge~y rarely resulted in survivors at 2 years. T he advent of c h e m o t h e r a p y has h a d a significant i m pact on this disease a n d the m e d i a n survival has i ncr e a s ed from less t han 3 m o n t h s to approximately 1 year. Current t h e r a p e u t i c a p p r o a c h e s are di rect ed by the extent of disease at presentation. For patients with disease limited to the thorax, c h e m o t h e r a p y is the p r i m a r y t herapeut i c app r o a c h to control t he micrometastatic disease. However, in this group of patients, local control remains an i m p o r t a n t goal. Since patients t e n d to relapse at the site of bulk disease, a c o m b i n e d modality a p p r o a c h with c o n c u r r e n t c h e m o t h e r a p y a n d r a d i o t h e r a p y is utilized to control the p r i m a r y t u m o r a n d m i cr o m et ast at i c disease. In patients with limited disease, m e d i a n survival ranges from 1 to 2 years a n d ap p r o x im a t e l y 10% to 20% of the patients r e m a i n alive at 2 years. There is a potential for long-term cure. 776

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For patients with extensive disease, c h e m o t h e r a p y b e c o m e s t he p r i m a r y ap p r o ach . In these patients control of metastatic disease is the t h e r a p e u t i c goal. Most patients with extensive disease t e n d to die as a result of progressive metastatic disease, s u c h as liver metastases, brain metastases, or general inanition, r a t her than specifically of their p u l m o n a r y primary. Median survival ranges from 6 to 8 m o n t h s ; few patients r e m a i n alive at 2 years. Although c h e m o t h e r a p y is usually initially effective in decreasing t u m o r burden, mo st patients eventually relapse b e c a u s e of the dev e l o p m e n t of acq u ire d drug resistance. New a p p r o a c h e s are investigating n e w drugs that are n o n - c r o s s resistant, with the m o r e comm o n agents, non-cytotoxic therapies (immunotherapy) a n d the d e v e l o p m e n t of m e t h o d s to over c om e a c qui r ed drug resistance. Radiotherapy remains an i m p o r t a n t t h e r a p e u t i c modality in controlling the p r i m a r y t um or . Since a p p r o x i m a t e l y 20% to 30% of patients with small cell lung c a n c e r p r e s e n t or relapse with brain metastases, r a d i o t h e r a p y is frequently a d m i n i s t e r e d prophylactically to decrease the i n c i d e n c e of brain relapse. Because few patients die solely from brain metastases, the use of p r o p h y l a c t i c cranial radiation has not i m p r o v e d survival a n d is usually reserved for patients w h o have h a d a good r e s p o n s e to t r e a t m e n t - - t h o s e patients w h o are felt to have a potential for p r o l o n g e d survival. The use of surgery in small cell lung c a n c e r remains debatable. Because of its t e n d e n c y for metastases, surgical a p p r o a c h e s have n o t h a d survival advantages. Recently the use of surgery in addition to c o m b i n atio n c h e m o t h e r a p y a n d radiation has d r a w n interest. However, in the majority of patients it is unlikely that aggressive resection of either the p r i m a r y t u m o r or residual disease will have an i m pact on survival. Its use in the t r e a t m e n t of this disease remains experimental. Small cell lung c a n c e r remains a solid t u m o r in w h i c h t here is a great deal of clinical r e s e a r c h interest. Because it is sensitive to c h e m o t h e r a p y an d radiation it is one of the major" solid t u m o r s that are potentially curable.

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Gary E. Goodman, M.D., M.S., is a S t a f f Oncologist at the Swedish Hospital Medical Center Tumor Institute. He is a Clinical Associate Professor o f Medicine at the Fred Hutchinson Cancer Research Center and the University o f Washington in Seattle, Washington. After receiving his M.D. degree and M.S. degree in pharmacology at the University o f Illinois in 1970, he w e n t on to complete his internship and residency in internal medicine at the University o f Oregon Health Sciences Center in Portland, Oregon. Additional training in medical oncology was taken at the University o f Arizona Health Sciences Center in Tuscon. Dr. Goodman's main academic and research interests are t r e a t m e n t o f small cell lung cancer and chemoprevention o f lung cancer. A n o t h e r area o f interest is the developmental use o f biologics in treating patients with advanced cancer.

R o b e r t B. Livingston, M.D., is a m e m b e r o f the Clinical Research team at the Fred Hutchinson Cancer Research Center in Seattle. After receiving his M.D. degree f r o m the University o f Oklahoma in 1967, he c o m p l e t e d an internship at Southwestern Medical School, Parkland Hospital in Dallas. He returned to the University o f Oklahoma in 1970 to complete his residency in internal medicine. Further training included an oncology fellowship at the University o f Texas Systems Cancer Center in Houston. His academic and research interests include c o m b i n e d modality treatment o f small and non-small cell lung cancer, alternative approaches to predicting chemotherapy response , and use o f c h e m o t h e r a p y with breast cancer. DM, D e c e m b e r

1989

SMALL CELL LUNG CANCER

L u n g c a n c e r is t h e m o s t c o m m o n c a u s e of c a n c e r d e a t h in t h e U n i t e d States. D u r i n g t h e p a s t 50 y e a r s its i n c i d e n c e h a s i n c r e a s e d a l m o s t e x p o n e n t i a l l y , a n d it is e s t i m a t e d t h a t a p p r o x i m a t e l y 135,000 m e n a n d w o m e n d i e d in 1986 b e c a u s e of this m a l i g n a n c y ) Since it is a m a j o r c a u s e of m o r b i d i t y a n d mortality, it is c l e a r t h a t a n y effective t h e r a p e u t i c or p r e v e n t i v e m o d a l i t y w o u l d h a v e a m a j o r i m p a c t o n t h e h e a l t h a n d w e l f a r e of this c o u n t r y a n d t h a t of the p e o p l e s of the world. Over t h e p a s t 20 to 30 y e a r s a g r e a t d e a l h a s b e e n l e a r n e d a b o u t t h e etiology of l u n g c a n c e r , a n d a n e w e m p h a s i s is b e i n g p l a c e d o n p r e v e n t i o n a n d a v o i d a n c e of k n o w n risk factors. T h i s is a n a r e a of i n t e n s i v e o n g o i n g r e s e a r c h a n d o n e in w h i c h m u c h h o p e h a s b e e n p l a c e d . I n t h e i n t e r i m a t t e n t i o n h a s b e e n f o c u s e d o n t r e a t m e n t . Unfoi~unately, o n c e l u n g c a n c e r h a s b e e n d i a g n o s e d , w e h a v e h a d little s u c c e s s in its c o n t r o l . T h e t h e r a p e u t i c a p p r o a c h e s to l u n g c a n c e r h a v e n o t r a d i c a l l y c h a n g e d or i m p r o v e d o v e r t h e p a s t 10 to 20 y e a r s , a n d little h a s b e e n a c c o m p l i s h e d in p r o l o n g i n g survival in p a t i e n t s p r e s e n t i n g w i t h a d v a n c e d d i s e a s e . In s p i t e of t h e s e less t h a n e n c o u r a g i n g overall results, t h e r e h a s b e e n s o m e p r o g r e s s in t h e treatm e n t of o n e h i s t o l o g i c a l s u b t y p e of l u n g c a n c e r , s m a l l cell l u n g c a n cer. T h i s r e v i e w will d i s c u s s s m a l l cell l u n g c a n c e r as d i s t i n c t f r o m t h e o t h e r h i s t o l o g i c a l s u b t y p e s of l u n g c a n c e r a n d will f o c u s o n t h e u n i q u e biologic b e h a v i o r a n d r e s p o n s i v e n e s s to t h e r a p y t h a t m a k e it t h e m o s t s u c c e s s f u l l y t r e a t e d f o r m of a d v a n c e d l u n g c a n c e r . ETIOLOGY

L u n g c a n c e r is t h e m a j o r h u m a n c a n c e r t h a t h a s w e l l - d e f i n e d etiologic a g e n t s . Since t h e early 1950s a n u m b e r of w e l l - c o n d u c t e d e p i d e m i o l o g i c a l s t u d i e s h a v e d e f i n e d the risk f a c t o r s a s s o c i a t e d w i t h l u n g c a n c e r . 2' 3 A l t h o u g h m o s t of t h e s e s t u d i e s e x a m i n e d l u n g c a n c e r as a w h o l e a n d n o t t h e i n d i v i d u a l cell t y p e s , a n u m b e r of g e n e r a l i z a t i o n s c a n b e m a d e if o n e a s s u m e s t h a t etiologic a g e n t s are n o t s p e cific to i n d i v i d u a l cell t y p e s of l u n g c a n c e r . For t h e p u r p o s e of this d i s c u s s i o n , it is a s s u m e d t h a t t h e risk f a c t o r s a n d t h e a s s o c i a t e d DM, D e c e m b e r 1989

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etiologic a g e n t s m'e n o t specific to o n e t y p e b u t a p p l y equally to all cell t y p e s i n c l u d i n g small cell l u n g c a n c e r . TOBACCO

T h e i n h a l a t i o n of t o b a c c o s m o k e is the m o s t clearly d e f i n e d risk f a c t o r for t h e d e v e l o p m e n t of lung cancer. This fact c a n n o t be overe m p h a s i z e d a n d s h o u l d be s t r e s s e d in a n y d i s c u s s i o n of l u n g cancer. This c o m m o n disease, so p o o r l y treated, c a n clearly be prev e n t e d in t h e m a j o r i t y of cases b y the a v o i d a n c e of t o b a c c o s m o k e . T h e e v i d e n c e i m p l i c a t i n g t o b a c c o s m o k e is impressive. A large n u m b e r of classic e p i d e m i o l o g i c a l s t u d i e s b o t h r e t r o s p e c t i v e a n d p r o s p e c t i v e have e s t a b l i s h e d a clear r e l a t i o n s h i p b e t w e e n b o t h the d u r a t i o n a n d i n t e n s i t y of cigarette u s e a n d t h e i n c i d e n c e of l u n g c a n c e r . T h e H a m m o n d a n d H o r n A m e r i c a n C a n c e r Society S t u d y of a p p r o x i m a t e l y 1 million s m o k i n g A m e r i c a n m a l e s was o n e of the first large e p i d e m i o l o g i c a l s t u d i e s in this c o u n t r y that r e p o r t e d t h e r e l a t i o n s h i p b e t w e e n s m o k i n g a n d excess d e a t h s d u e to cardiac disease a n d c a n c e r . 2' 3 Given the large n u m b e r of e p i d e m i o l o g y s t u d i e s e x a m i n i n g t h e rel a t i o n s h i p b e t w e e n t o b a c c o a n d l u n g cancer, few have s t u d i e d the r e l a t i o n s h i p to specific histological s u b t y p e s of l u n g cancer. It is likely that at the t i m e t h e s e s t u d i e s w e r e c o n d u c t e d t h e p o t e n t i a l i m p o r t a n c e in d i s t i n g u i s h i n g s u b t y p e s was n o t r e c o g n i z e d ( b e c a u s e of t h e lack of effective t r e a t m e n t for a n y cell type). A few studies, however, have e x a m i n e d this issue. In a large p r o s p e c t i v e s t u d y of British m a l e p h y s i c i a n s that d i d d i s t i n g u i s h specific cell types, Doll a n d Peto o b s e r v e d 114 cases of small cell l u n g c a n c e r in 155,708 m a n - y e a r s of o b s e r v a t i o n a m o n g t o b a c c o smokers; this c o n t r a s t e d w i t h o n l y 1 case a m o n g n o n - t o b a c c o smokers, w i t h 103,383 m a n y e a r s of observation. 4 Doll a n d Peto also s h o w e d a clear d o s e res p o n s e w i t h t h e n u m b e r of cigarettes s m o k e d p e r d a y vs. the incid e n c e of small cell l u n g c a n c e r . This d o s e - r e s p o n s e r e l a t i o n s h i p for small cell l u n g c a n c e r was also c o n f i r m e d b y t h e P h i l a d e l p h i a Pulm o n a r y N e o p l a s m r e s e a r c h p r o j e c t . 5 H e n c e , in t h e s t u d i e s that specifically l o o k e d at small cell l u n g cancer, it (like s q u a m o u s cell l u n g cancer) a p p e a r e d to b e o n e of the histological s u b t y p e s of l u n g cancer t h a t was m o s t clearly r e l a t e d to t o b a c c o use. A n o t h e r e n v i r o n m e n t a l a g e n t s h o w n to be r e l a t e d to b o t h l u n g c a n c e r and, specifically, small cell l u n g cancel" is ionizing radiation. Observational s t u d i e s of u r a n i u m m i n e r s in t h e w e s t e r n U n i t e d States p r o v i d e d e v i d e n c e suggesting t h a t ionizing r a d i a t i o n is a risk factor. 6-8 Risk ratios r a n g e d f r o m 12 to 171 t i m e s t h o s e in n o n e x p o s e d individuals, w i t h the r a n g e s in r e l a t i o n to the i n t e n s i t y of exp o s u r e . Histological s u b t y p e s o t h e r t h a n small cell l u n g c a n c e r w e r e also i n c r e a s e d , a l t h o u g h n o t in the d o s e - r e s p o n s e r e l a t i o n s h i p t h a t 780

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w a s clearly s e e n in s m a l l cell l u n g c a n c e r . Even in this u r a n i u m e x p o s e d g r o u p , cigarette s m o k e r e m a i n e d a v e r y i m p o r t a n t cofactor, w i t h r a t e s v a r y i n g f r o m 0.2 to 13.3, d e p e n d i n g o n c i g a r e t t e / t o b a c c o exposure.9,10 T h e s e s t u d i e s s h o w e d t h a t u r a n i u m m i n e r s are at a n i n c r e a s e d risk for l u n g c a n c e r . T h i s r e l a t i o n s h i p w a s e s p e c i a l l y s t r o n g :{or s m a l l cell l u n g c a n c e r , m o r e so t h a n for t h e o t h e r histological t y p e s . T h e ]ink w i t h a s b e s t o s a n d l u n g c a n c e r h a s b e e n d i s c u s s e d in detail in a n u m b e r of reviews. 11-14 A l t h o u g h m e s o t h e l i o m a is clearly r e l a t e d to a s b e s t o s e x p o s u r e , t h e r e l a t i o n s h i p b e t w e e n a s b e s t o s a n d t h e o c c u r r e n c e of p a r e n c h y i n a l l u n g m a l i g n a n c y (both t h e s m a l l cell a n d n o n - s m a l l cell histologies) s u g g e s t s t h a t a s b e s t o s is a s y n e r g i s t i c p r o m o t i n g a g e n t w i t h t o b a c c o r a t h e r t h a n a p r i m a r y p u l m o n a r y carc i n o g e n . L u n g c a n c e r is a l m o s t as r a r e in n o n s m o k e r s w i t h a h i s t o r y of a s b e s t o s e x p o s u r e as it is in n o n s m o k e r s w i t h o u t a h i s t o r y of asb e s t o s e x p o s u r e .15,16 E x p o s u r e to a n u m b e r of c h e m i c a l s a n d h e a v y m e t a l s h a s also b e e n r e l a t e d to l u n g c a n c e r , i n c l u d i n g arsenic, 1~'18 nickel,19, 20 c h r o m a t e , 21 a n d c h l o r o m e t h y l e s t e r s . 22-26 A m o n g t h e s e c h e m i c a l c a r c i n o g e n s t h e c h l o r o m e t h y l e s t e r s , specifically, c h l o r o m e t h y l e s t e r s a n d b i s - c h l o r o m e t h y l e s t e r s are m o s t s t r o n g l y a s s o c i a t e d w i t h s m a l l cell lung cancer. PREVENTION

Given t h e relatively w e l l d e f i n e d risk factors, w h i c h collectively p r o b a b l y a c c o u n t for g r e a t e r t h a n 90% of all c a s e s of l u n g c a n c e r , t h e i s s u e of p r e v e n t i o n w o u l d , o n t h e surface, a p p e a r to b e simple; e l i m i n a t i o n of t h e e n v i r o n m e n t a l risk factors. U n f o r t u n a t e l y , t h e e l i m i n a t i o n of t o b a c c o a b u s e f r o m o u r s o c i e t y b y t h e s u c c e s s f u l w e a n i n g of a d d i c t e d s u b j e c t s a n d t h e p r e v e n t i o n of a d d i c t i o n in o t h ers is c o m p l e x . Political, e c o n o m i c , a n d social f a c t o r s c u r r e n t l y overrule a p u r e l y m e d i c a l d e c i s i o n r e g a r d i n g t h e r a t i o n a l m a n a g e m e n t of this d a n g e r o u s s u b s t a n c e . Recently, h o w e v e r , social p r e s s u r e s a n d e v e n s o m e g o v e r n m e n t a l a c t i o n s h a v e s h o w n a less t o l e r a n t v i e w of p u b l i c t o b a c c o use. T h e n e x t d e c a d e m a y s h o w a d r a m a t i c c h a n g e in t h e a t t i t u d e t o w a r d t h e p u b l i c a n d p r i v a t e u s e of t o b a c c o . Unfort u n a t e l y , s i n c e t h e risk of a s m o k e r d e v e l o p i n g l u n g c a n c e r d o e s n o t revert to t h e risk levels of a n e v e r - s m o k e r for 10 to 20 y e a r s , if ever, it is likely t h a t e v e n if t o b a c c o u s e is c o m p l e t e l y e l i m i n a t e d it will b e m a n y y e a r s b e f o r e t h e r e is a significant d e c r e a s e in the i n c i d e n c e of lung cancer. An a l t e r n a t i v e a p p r o a c h to t h e p r e v e n t i o n of l u n g c a n c e r ( a n d o t h e r c a n c e r ) h a s b e e n t h e s e a r c h for a g e n t s t h a t w o u l d p r e v e n t t h e d e v e l o p m e n t of c a n c e r in s u b j e c t s at h i g h risk, " c h e m o p r e v e n t i o n a g e n t s " (i.e., a g e n t s w h i c h w o u l d p r e v e n t or r e v e r s e p r e n e o p l a s t i c DM, D e c e m b e r 1989

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c h a n g e s i n d u c e d b y o f f e n d i n g carcinogens).ZT'2s'32 B e c a u s e of its ass o c i a t i o n w i t h a d e f i n e d c a r c i n o g e n (tobacco smoke), l u n g c a n c e r is o n e of the t u m o r t y p e s m o s t f r e q u e n t l y s t u d i e d as a target for c h e m o p r e v e n t i o n agents. A large effort is u n d e r w a y to identify subs t a n c e s that have p o t e n t i a l c h e m o p r e v e n t i o n activity. As of 1988, the m a j o r i t y of the p r o p o s e d m a n i p u l a t i o n s have b e e n w i t h " n a t u r a l app r o a c h e s " s u c h as r e d u c i n g d i e t a r y fat, i n c r e a s i n g d i e t a r y fiber, or i n c r e a s i n g essential m i c r o n u t r i e n t s a n d vitamins. Vitamin A a n d its family of n a t u r a l l y o c c u r r i n g a n d s y n t h e t i c derivatives, the retinoids, have a t t r a c t e d the m o s t a t t e n t i o n a m o n g t h e m i c r o n u t r i e n t s . T h e r e is a large b o d y of a n i m a l a n d t i s s u e c u l t u r e d a t a to suggest that v i t a m i n A a n d a n a l o g u e s c a n p r e v e n t the i n d u c tion of b o t h s p o n t a n e o u s l y o c c u r r i n g a n d c a r c i n o g e n - i n d u c e d n e o plasia. 32-34 R e t r o s p e c t i v e e p i d e m i o l o g i c a l s t u d i e s m e a s u r i n g t h e sei~3m c o n c e n t r a t i o n of v i t a m i n A (retinol) o r its d i e t a r y p r e c u r s o r s (~-carotene) in large p o p u l a t i o n s have s u g g e s t e d t h a t t h o s e s u b j e c t s d e v e l o p i n g l u n g c a n c e r have l o w s e r u m c o n c e n t r a t i o n s of t h e s e n u trients y e a r s p r i o r to t h e d e v e l o p m e n t of c a n c e r . 35-41 T h e s e s t u d i e s have s u g g e s t e d t h a t a l o w s e r u m c o n c e n t r a t i o n of retinol or ~-carot e n e m a y b e a n a d d i t i o n a l risk f a c t o r for t h e d e v e l o p m e n t of l u n g c a n c e r . T h e s e c o r r e l a t i o n s have b e e n s e e n m o s t s t r o n g l y for small cell l u n g c a n c e r a n d s q u a m o u s cell l u n g c a n c e r . 42 In a d d i t i o n to t h e s e e p i d e m i o l o g i c a l s t u d i e s t h e r e are in vivo h u m a n s t u d i e s to suggest that t h e s e c o m p o u n d s c a n reverse p r e m a l i g n a n t lesions in subjects e x p o s e d to t o b a c c o s m o k e a n d o t h e r r e c o g n i z e d orally app l i e d c a r c i n o g e n s . 43'44 C u r r e n t l y a n u m b e r of l o n g - t e r m p r o s p e c t i v e l y r a n d o m i z e d d o u ble-blind clinical trials are u n d e r w a y to d e t e r m i n e w h e t h e r s u p p l e m e n t a t i o n w i t h e i t h e r B - c a r o t e n e a n d / o r retinol c a n d e c r e a s e t h e i n c i d e n c e of c a n c e r in high-risk subjects. A n u m b e r of differing patient p o p u l a t i o n s are b e i n g s t u d i e d , i n c l u d i n g h e a v y t o b a c c o s m o k ers a n d subjects e x p o s e d to asbestos. 4"~ It will b e a n u m b e r of y e a r s before t h e s e s t u d i e s m a t u r e a n d it is k n o w n w h e t h e r t h e s e a g e n t s are effective in d e c r e a s i n g t h e i n c i d e n c e of l u n g c a n c e r in t h e s e high-risk p o p u l a t i o n s . PATHOLOGY

Classically l u n g c a n c e r has b e e n c a t e g o r i z e d into f o u r m a j o r histological s u b t y p e s . 1. S q u a m o u s cell c a n c e r , t h e m o s t c o m m o n histology, a c c o u n t ing for a r o u n d 30% to 40% of cases 2. A d e n o c a r c i n o m a , t h e s e c o n d m o s t c o m m o n histology, w h i c h over the p a s t 10 y e a r s h a s b e c o m e i n c r e a s i n g l y f r e q u e n t a n d c u r r e n t l y is r e s p o n s i b l e for a b o u t 30% to 40% of c a s e s 782

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3. Small cell lung cancer, approximately 20% to 30% of cases 4. Large cell carcinoma, 5% to 10% of cases Small cell lung cancer differs not only in its histological appearance from the other subtypes of lung cancer but in its clinical behavior and, hence, natural history. Because of the differences in responses to t h e r a p y a n d the pathologist's desire to provide clinically relevant information, lung cancer is n o w frequently categorized into two broad subtypes: small cell lung cancer a n d n o n - s m a l l cell lung cancer. This division is useful for the clinician w h o m u s t make therapeutic decisions about patient cm-e since all the aforementioned n o n - s m a l l cell histologies are currently treated in a similar fashion w h i c h is distinct from small cell lung cancer. It also acknowledges the low concordance rate a m o n g pathologists in differentiating the specific subtypes of n o n - s m a l l cell lung cancer (squamous cell vs. a d e n o c a r c i n o m a vs. large cell carcinoma) and hence the relevance of the diagnosis of a specific subtype in an individual patient. Because of the differences in treatment a n d prognosis, the pathological distinction b e t w e e n small cell lung cancer a n d the n o n small cell histologies has b e c o m e one of the pathologist's most clinically important tasks. In spite of the importance of this diagnosis, it is rare for the pathologist to have the luxury of a large wedge resection or a lobectomy or p n e u m o n e c t o m y specimen. The pathologist is often faced with scanty material obtained from a bronchial biopsy, washings obtained by bronchoscopy, s p u t u m for cytological evaluation, or an occasional regional l y m p h n o d e obtained by biopsy or mediastinoscopy. The specimens are usually small a n d frequently have a great deal of crush artifact. Overinterpretation can be a problem because of the inability to clearly evaluate the darkly staining c r u s h e d cells. Bronchial washings, sputum, a n d small bronchial biopsy specimens m a y contain cells the pathologist is comfortable in declaring as malignant but might feel uncomfortable in subtyping the t u m o r as definitely small cell lung cancer. Repeat b r o n c h o s c o p y or biopsy is frequently necessary in order to confirm the diagnosis. Because of its importance in guiding treatment choices, the clinician s h o u l d emphasize to the pathologist the importance of clearly distinguishing small cell lung cancer from the other histologic subtypes. There s h o u l d be a low threshold for repeating diagnostic procedures if scanty findings from s p u t u m examination result in an unclear diagnosis. The current World Health Organization (WHO) classification of lung cancer is based on light microscopic findings.46 With light microscopy most pathologists can differentiate small cell lung cancer from the n o n - s m a l l cell histologies. In a s t u d y c o n d u c t e d by the Southwest Ontology Group, (SWOG), there was a 90% concordance rate in the diagnosis of small cell lung cancer among three patholoDM, D e c e m b e r 1989

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gists. In a n o t h e r s t u d y w i t h eight p a t h o l o g i s t s reviewing e a c h case, in 90% of cases, seven o r m o r e of the eight p a t h o l o g i s t s a g r e e d w i t h the diagnosis of small cell l u n g cancer. 47'48 H e n c e , the p a t h o l o g i c a l diagnosis of small cell l u n g c a n c e r t e n d s to b e r e p r o d u c i b l e f r o m p a t h o l o g i s t to pathologist. In 1977, t h e WHO subclassified small cell l u n g c a n c e r into t h r e e different categories: i n t e r m e d i a t e , l y m p h o c y t i c , a n d m i x e d . 46 T h e diagnosis of t h e s e s u b t y p e s is m u c h less r e p r o d u c i b l e t h a n is the general diagnosis of small cell l u n g cancer. One review r e p o r t s t h e a g r e e m e n t in d i a g n o s i n g specific s u b t y p e s to be o n l y 54% .47 This m a k e s the reliability of a specific s u b t y p e of small cell l u n g c a n c e r by a n individual p a t h o l o g i s t of d u b i o u s value. In a d d i t i o n to the lack of a g r e e m e n t in d i a g n o s i n g a specific subtype of small cell l u n g cancer, this diagnosis a p p e a r s to have little clinical i m p o r t a n c e . Several s t u d i e s have s h o w n that t h e r e s p o n s e rate to chemotherapy a n d r a d i a t i o n as well as smvival are similar for the l y m p h o c y t e (oat cell) a n d i n t e r m e d i a t e cell t y p e s . 49-53 T h e Na-tional C a n c e r Institute (NCI) registry of p a t i e n t s smviving over 30 m o n t h s h a d e q u a l r e p r e s e n t a t i o n of all t h r e e s u b t y p e s , w h i c h suggests t h a t t h e r e was n o t an i n c r e a s e in c u r e rate for a specific subcell type. 54 B e c a u s e of the q u e s t i o n a b l e clinical utility as well as the p o o r r e p r o d u c i b i l i t y of diagnosis b e t w e e n pathologists, s u b t y p i n g of small cell l u n g c a n c e r is n o t u s e d in m a k i n g clinical decisions. T h e histological findings of small cell l u n g c a n c e r are u s u a l l y distinct. U n d e r light m i c r o s c o p y , t h e m o s t typical f e a t u r e is the n u c l e a r detail. C h r o m a t i n is u s u a l l y u n i f o r m l y d i s t r i b u t e d in a very fine or c o a r s e l y s t i p p l e d p a t t e r n t h r o u g h o u t the n u c l e u s . Nucleo]i are u n u sual, a n d t h o s e that are visible are u s u a l l y small a n d indistinct. Mitoses are f r e q u e n t . T h e m a j o r i t y of cells have s c a n t y c y t o p l a s m , w h i c h c a u s e s p r o m i n e n t m o l d i n g a n d c o n t o u r i n g of a d j a c e n t cells. In t u m o r s classified as i n t e r m e d i a t e cell type, t h e r e c a n be a m o d erate a m o u n t of c y t o p l a s m . O t h e r p a t t e r n s are also o c c a s i o n a l l y s e e n s u c h as s p i n d l e or f u s i f o r m cells a r r a n g e d in b u n d l e s o n t r a b e c u l a r p a t t e r n s . P s e u d o r o s e t t e s c a n be f o r m e d b y t h e n e o p l a s t i c cells cuffing n u m e r o u s b l o o d vessels. Cell aggregates c a n a p p e a r a l m o s t gland u l a r a n d f o r m l u m i n a w i t h o u t s h a r p l y d e m a r c a t e d cell b o r d e r s . M o r e distinct l u m i n a c a n fol~n w i t h c u b o i d a l o r c o l u m n a r cells. Stromal cells are rare a n d u s u a l l y consist of a t h i n fibrous or vascular n e t w o r k . T h e r e is r a r e l y a n i n f l a m m a t o r y infiltrate, a n d t h e r e are o c c a s i o n a l areas of extensive necrosis. In the i n t e r m e d i a t e , m i x e d cell type, t h e r e is a n o c c a s i o n a l f o c u s of s q u a m o u s differentiation o r s y n c o p a l m u l t i n u c l e a t e d giant cells. T h e r e c a n also be clusters of e n l a r g e d cells w i t h m o d e r a t e a m o u n t s of c y t o p l a s m - d e n s e n u c l e a r c h r o m a t i n w i t h p r o m i n e n t nucleoli.

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E L E C T R O N MICROSCOPIC FINDINGS

The electron m i c r o s c o p i c findings of small cell lung c a n c e r are distinct an d help differentiate this t u m o r from o t h e r diagnoses. 5s-st A m a j o r finding differentiating small cell lung c a n c e r from the o t h e r histological subtypes of lung c a n c e r is the p r e s e n c e of cytoplasmic m e m b r a n e - b o u n d n e u r o s e c r e t o r y granules. T h e se e l e c t r o n - d e n s e granules range in size from 500 to 2,000 A a n d have b e c o m e a pathological hallmark for the diagnosis of small cell lung cancer. However, b e c a u s e the light m i c r o s c o p i c findings are usually diagnostic, electron m i c r o s c o p y is usually not r e q u i r e d to make a diagnosis of small cell lung cancer. However, in an atypical case or case with m i x e d histological findings, electron microsc o p y m a y be w a r r a n t e d to confirm the diagnosis of small cell lung cancer. If n e u r o s e c r e t o r y granules are absent, it is unlikely that the t u m o r will have the clinical behavior of small cell lung cancer. In a r e c e n t review of 45 cases with a light m i c r o s c o p i c diagnosis of small cell lung cancer, 42 w e r e f o u n d to have n e u r o s e c r e t o r y granulesff s In the 3 patients w h e r e n e u r o s e c r e t o r y granules w ere absent, f u r t h e r review of the light m i c r o s c o p i c findings suggested a diagnosis of n o n - s m a l l cell lung cancer. In addition, in all three cases, the subs e q u e n t clinical behavior of the t u m o r was that of n o n - s m a l l cell lung cancer. Hence, while e l e c t r on m i c r o s c o p y is usually not req u i re d for the diagnosis of small cell lung c a n c e r it is confirmatory. The a bs en ce of n e u r o s e c r e t o r y granules makes that diagnosis less likely a n d m o r e i m p o r t a n t l y is an indication that the t u m o r will not "clinically" act like small cell lung cancer. CELL OF ORIGIN

The cell of origin of small cell lung c a n c e r has b e e n o p e n to debate for m a n y years. T he classic t h e o r y of the cell of origin of small cell lung c a n c e r was p r o p o s e d by Pearse in 1969. a9 He suggested that small cell lung c a n c e r was one of a n u m b e r of amine p r e c u r s o r uptake a n d decarboxylation (APUD) tumors. T he cell of origin of these t u m o r s is derived from e m b r y o n i c cells that originate within the neural crest a n d s u b s e q u e n t l y migrate widely t h r o u g h o u t the body. T h e s e cells main tai n their u n i q u e activity of actively transporting amine p r e c u r s o r s intracellularly a n d decarboxylating t h e m to biologically active amines. This t h e o r y was u s e d to explain the occasional o c c u r r e n c e of small cell cancers indistinguishable from small cell lung c a n c e r in o t h e r sites t h a n the lung. Pearse a n d others felt that the Kulchitsky cell, w h i c h is widely distributed t h r o u g h o u t the adult lung, r e p r e s e n t e d the migrated APUD cell a n d h e n c e the cell of origin of small cell lung cancer. Recently an alternative t h e o r y has been p r o p o s e d that takes into DM, D e c e m b e r

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c o n s i d e r a t i o n the o c c a s i o n a l histological drift t h a t o c c u r s d u r i n g the n a t u r a l h i s t o r y of small cell l u n g c a n c e r . G a z d a r a n d o t h e r s have s u g g e s t e d a m o r e diverse cell of origin for small cell l u n g c a n c e r : n° In t h e i r s t u d i e s w i t h in vitro c u l t u r e s of small cell l u n g c a n c e r a n d n o n - s m a l l cell l u n g c a n c e r t h e y have s h o w n that after l o n g - t e r m tissue c u l t u r e small cell l u n g c a n c e r c a n t r a n s f o r m into all the n o n small cell histologies. This histological t r a n s f o r m a t i o n is a c c o m p a n i e d b y a c h a n g e in g r o w t h p a t t e r n , t u m o r i g e n i c i t y , histology, a n d e n z y m e c o n t e n t : all the n o r m a l f e a t u r e s t h a t d i s t i n g u i s h small cell l u n g c a n c e r f r o m n o n - s m a l l cell l u n g c a n c e r . T h e s e s t u d i e s suggest t h a t all histological t y p e s of l u n g c a n c e r c a n b e d e r i v e d f r o m a c o m m o n cell. This s u p p o r t s t h e clinical o b s e r v a t i o n s a n d c o n c e p t that t r a n s f o r m a t i o n of small cell l u n g c a n c e r to a n o t h e r histological t y p e c a n take place. It h a s b e e n p r o p o s e d t h a t the m a l i g n a n t t r a n s f o r m a t i o n of a c o m m o n "cell of origin" o c c u r s a n d t h a t differentiation a n d g r o w t h can p r o c e e d to a n y of t h e familiar cell types, small cell l u n g c a n c e r ine l u d e d . At t h e t i m e of diagnosis o n e histological p a t t e r n t e n d s to p r e d o m i n a t e . However, the " s t i m u l u s " for differentiation to a specific cell t y p e m a y c h a n g e d u r i n g the lifetime of t h e t u m o r . In addition, differences in g r o w t h rates a n d r e s p o n s i v e n e s s to t r e a t m e n t c a n result in o u t g r o w t h of varying celt types. T h e s e c a n r e s u l t in a different histological p i c t u r e t h a n is f o u n d at diagnosis. This t h e o r y p r o v i d e s an alternative to t h e m o r e classic e x p ] a n a t i o n of the origin of small ceil l u n g c a n c e r . It c a n explain m a n y of the clinical o b s e r v a t i o n s d o c u m e n t i n g a c h a n g e in histology. This u n i t a r i a n t h e o r y of t h e origin of all histological t y p e s of l u n g c a n c e r r e m a i n s to b e c o n f i r m e d . HISTOLOGICAL TRANSFORMATION

Over the p a s t 5 y e a r s it h a s b e e n r e c o g n i z e d t h a t occasionally, w h e n a p a t i e n t w i t h k n o w n small cell l u n g c a n c e r r e l a p s e s or, m o r e frequently, w h e n a n a u t o p s y is p e r f o r m e d , the h i s t o l o g y of small cell l u n g c a n c e r a p p e a r s to h a v e c h a n g e d . At r e l a p s e if t h e p a t i e n t u n d e r g o e s biopsy, the histological diagnosis is f r e q u e n t l y a m i x e d tum o r or a t u m o r t h a t is p r e d o m i n a n t l y s q u a m o u s cell, a d e n o c a r c i n o m a , or large cell u n d i f f e r e n t i a t e d c a r c i n o m a . In t h r e e a u t o p s y series w i t h a total of 152 p a t i e n t s w h o w e r e originally d i a g n o s e d as having small cell l u n g cancer, 12 p a t i e n t s w e r e f o u n d to have exclusively n o n - s m a l l cell histologies, a n d 39 h a d a n o n - s m a l l cell c o m p o n e n t along w i t h t h e small c e l l histology. 61-63 In t h e s e studies, all p a t i e n t s h a d u n d e r g o n e r o u t i n e staging a n d h a d r e c e i v e d t r e a t m e n t w i t h c o m b i n a t i o n c h e m o t h e r a p y w i t h or w i t h o u t r a d i o t h e r a p y . It is u n c l e a r w h e t h e r this p h e n o m e n o n of a n a p p a r e n t c h a n g e in histology r e p r e s e n t s a n i n c o m p l e t e initial diagnosis a n d t h a t w i t h additional b i o p s i e s a m i x e d t u m o r w o u l d have b e e n f o u n d , or w h e t h e r 786

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at the t i m e of t h e diagnosis the t u m o r was truly a t u m o r w i t h m i x e d histologies a n d t h a t effective t r e a t m e n t e l i m i n a t e d o n l y the small cell c o m p o n e n t a n d a l l o w e d the n o n - s m a l l cell c o m p o n e n t to recur. O t h e r e x p l a n a t i o n s i n c l u d e an i n d u c t i o n of cellular differentiation b y t h e r a p y or c o n t i n u e d differentiation a s s o c i a t e d w i t h clonal evalu a t i o n of the pa3-ticu]ar t u m o r . In subjects w h o c o n t i n u e to s m o k e cigaret~tes (and even in t h o s e w h o quit) the d e v e l o p m e n t of a s e c o n d n o n - s m a l l cell p r i m a r y is a n o t h e r possible e x p l a n a t i o n . This latter view h a s b e e n s u p p o r t e d b y a n NCI r e v i e w of 360 p a t i e n t s w i t h small cell l u n g c a n c e r . In this r e v i e w 6 of 40 l o n g - t e r m survivors d e v e l o p e d a s e c o n d p r i m a r y l u n g c a n c e r . 64 T h e clinical significance of this p o t e n t i a l histological h e t e r o g e n e i t y b e c o m e s a p p a r e n t w h e n evaluating a p a t i e n t ' s r e s p o n s e to treatm e n t . M i n n a et al. have d e s c r i b e d 16 p a t i e n t s w h o h a d a n original histological diagnosis of m i x e d small cell/large cell t u m o r . 6s A l t h o u g h t h e s e p a t i e n t s did r e s p o n d to t r e a t m e n t , t h e n u m b e r achieving a c o m p l e t e r e s p o n s e was l o w e r t h a n e x p e c t e d for small cell l u n g cancer. T h e s e o b s e r v a t i o n s s u g g e s t e d to the a u t h o r s t h a t in t u m o r s of m i x e d h i s t o l o g y the small cell e l e m e n t is sensitive to t r e a t m e n t w h e r e a s t h e n o n - s m a l l cell c o m p o n e n t is n o t sensitive a n d r e m a i n s after t h e r a p y , w h i c h a c c o u n t s for t h e r e s i d u a l mass. This c o n c e p t of histological h e t e r o g e n e i t y s h o u l d b e t a k e n into c o n s i d e r a t i o n w h e n evaluating a p a t i e n t w h o has h a d a p o o r r e s p o n s e to s t a n d a r d small cell t h e r a p y . B e c a u s e of t h e possibility of a m i x e d t u m o r , a review of t h e initial b i o p s y or r e b i o p s y m a y be w a r r a n t e d to d e t e r m i n e t h e d e g r e e of histological h e t e r o g e n e i t y . If a p a t i e n t r e l a p s e s after p r i m a r y t r e a t m e n t , r e t r e a t m e n t w i t h eit h e r c h e m o t h e r a p y or r a d i a t i o n is u s u a l l y m e t w i t h limited success. Relapsing small cell l u n g c a n c e r is u s u a l l y resistant to alternative c o m b i n a t i o n c h e m o t h e r a p y . However, this lack of r e s p o n s e m a y indicate c o n v e r s i o n to a n o n - s m a l l cell histology. As p r e v i o u s l y disc u s s e d o n e s h o u l d always c o n s i d e r that t h e " r e c u r r e n t d i s e a s e " m a y i n d e e d be a s e c o n d p r i m a r y , especially if it o c c u r s in the c o n t r a l a t eral l u n g o r a w a y f r o m t h e original p r i m a r y lesion. If the original small cell l u n g c a n c e r r e m a i n s in r e m i s s i o n , if a p p r o p r i a t e , surgical r e s e c t i o n s h o u l d be c o n s i d e r e d for a s e c o n d p r i m a r y . STAGING

D e t e r m i n i n g t h e e x t e n t of disease at the t i m e t h e p a t i e n t p r e s e n t s to the p h y s i c i a n has b e c o m e a n integral p a r t of t h e e v a l u a t i o n of a p a t i e n t w i t h small cell l u n g c a n c e r . A c c u r a t e staging is n o t a n exercise u n d e r t a k e n o n l y for p a t i e n t s e n r o l l e d in clinical trials b u t s h o u l d b e d o n e o n all p a t i e n t s w i t h a d i a g n o s i s of small cell l u n g c a n c e r . Staging p r o v i d e s i n f o r m a t i o n r e q u i r e d for p l a n n i n g t h e m o s t a p p r o p r i a t e t r e a t m e n t , a n d m o s t i m p o r t a n t l y , it p r o v i d e s p r o g n o s t i c DM, D e c e m b e r 1989

787

i n f o r m a t i o n for t h e p a t i e n t a n d his family. D e t e r m i n i n g t h e e x t e n t of d i s e a s e at t h e t i m e t r e a t m e n t is i n i t i a t e d also p r o v i d e s a r e f e r e n c e p o i n t for t h e l a t e r e v a l u a t i o n of t h e r e s u l t s of t r e a t m e n t . With a c c u rate staging b e f o r e a n d after t r e a t m e n t o n e c a n get a c l e a r p i c t u r e of response status and hence, prognostic information. These argum e n t s h a v e m a d e c o m p l e t e staging of p a t i e n t s w i t h s m a l l cell l u n g c a n c e r a r o u t i n e p a r t of t h e initial e v a l u a t i o n . T h e i s s u e of staging is a n e s p e c i a l l y r e l e v a n t o n e for s m a l l cell l u n g cancer. Patients frequently have disseminated disease not detectable b y r o u t i n e e x a m i n a t i o n . In 1973, M a t h e w s a n d a s s o c i a t e s d o c u m e n t e d t h a t at a u t o p s y 70% of p a t i e n t s w h o p r e v i o u s l y h a d c u r a t i v e r e s e c t i o n s for s m a l l cell l u n g c a n c e r (who w e r e t h o u g h t to h a v e dis.e a s e c o n f i n e d to t h e r e s e c t e d lung) a n d w h o h a d d i e d f r o m n o n m a l i g n a n t c a u s e w i t h i n 3 w e e k s of t h e i r l u n g c a n c e r s u r g e r y h a d d i s t a n t m e t a s t a s e s . 66 O t h e r series h a v e c o n f i r m e d t h e s e f i n d i n g s d o c u m e n t i n g t h e t e n d e n c y of s m a l l cell l u n g c a n c e r to d e v e l o p e a r l y w i d e s p r e a d m e t a s t a s e s . I n v i e w of t h e s e s t u d i e s as well as its k n o w n n a t u r a l history, p a t i e n t s d i a g n o s e d as h a v i n g s m a l l cell l u n g c a n c e r s h o u l d b e c o n s i d e r e d to h a v e a s y s t e m i c d i s e a s e . T h a t is, at t h e t i m e of d i a g n o s i s t h e p a t i e n t s h o u l d b e p r e s u m e d to h a v e d i s s e m i n a t e d d i s e a s e . With this p r e s u m p t i o n staging b e c o m e s a n e x e r c i s e in estim a t i n g t h e v o l u m e of t h e m e t a s t a t i c d i s e a s e . Since t h e p r e s u m e d m e t a s t a s e s c a n b e e i t h e r m a c r o s c o p i c or m i c r o s c o p i c , d o c u m e n t a t i o n of t h e p r e s e n c e o r a b s e n c e of m e t a s t a s e s in a specific o r g a n will c o r r e l a t e w i t h t h e i n t e n s i t y of t h e s e a r c h for t h o s e m e t a s t a s e s . H e n c e , staging c a n v a r y f r o m d e t e c t i n g o n l y g r o s s clinically e v i d e n t m e t a s t a t i c d i s e a s e to d e t e c t i n g m i c r o s c o p i c m e t a s t a t i c d i s e a s e f o u n d b y b i o p s y i n g a f u n c t i o n a l l y n o r m a l organ. This c o n c e p t of a s p e c t r u m of m e t a s t a t i c d i s e a s e s h o u l d b e c o n s i d e r e d w h e n e v a l u a t ing p u b l i s h e d t r e a t m e n t r e s u l t s (since p r o g n o s i s c o r r e l a t e s w i t h tum o r b u r d e n ) a n d in d e t e r m i n i n g t h e o p t i o n a l t r e a t m e n t for a n individual patient. C u r r e n t l y , m o s t i n v e s t i g a t o r s utilize a staging s y s t e m t h a t divides p a t i e n t s into t w o large g r o u p s : l i m i t e d d i s e a s e a n d e x t e n s i v e d i s e a s e . L i m i t e d d i s e a s e is d e f i n e d as t h a t in p a t i e n t s w i t h n o d e t e c t a b l e m e t a s t a s e s o u t s i d e of t h e h e m i t h o r a x , w i t h or w i t h o u t ipsilateral, m e diastinal, hilar, or s u p r a c l a v i c u l a r l y m p h n o d e s . S o m e g r o u p s also classify p a t i e n t s w i t h u n i l a t e r a l p l u r a l effusion as h a v i n g l i m i t e d disease. 67 P a t i e n t s w i t h d i s e a s e d e t e c t e d o u t s i d e t h e s e sites are classified as h a v i n g e x t e n s i v e s t a g e of disease. Staging c a n b e c o m e b l u r r e d w h e n c o n s i d e r i n g t h e e x t e n t to w h i c h e a c h p a t i e n t is e v a l u a t e d in s e a r c h of m e t a s t a t i c i n v o l v e m e n t . W i t h i n e a c h of t h e s e t w o c a t e g o ries t h e r e is o b v i o u s l y a r a n g e of p a t i e n t s . E x t e n s i v e - d i s e a s e p a t i e n t s i n c l u d e t h o s e w i t h b u l k y liver m e t a s t a s e s a n d t h o s e w h o s e o n l y evid e n c e of m e t a s t a t i c d i s e a s e is a m i c r o s c o p i c f o c u s o n a b o n e m a r row biopsy. 788

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B e c a u s e of t h e t e n d e n c y for early w i d e s p r e a d m e t a s t a s e s , t h e A m e r i c a n Joint C o m m i t t e e T u m o r size, N o d e status, Metastasis status (TNM) staging system, p r o g n o s t i c a l l y useful for n o n - s m a l l cell l u n g cancers, h a s failed to be u s e f u l for small cell lung cancer'. Alt h o u g h m a n y p a t i e n t s are f r e q u e n t l y d i a g n o s e d surgically a n d d o have a n a c c u r a t e TNM stage, the p r e s e n c e of m i c r o s c o p i c m e t a s t a t i c disease is n o t d e t e c t e d at the t i m e of t h o r a c o t o m y . B e c a u s e even p a t i e n t s w i t h small p u l m o n a r y p r i m a r i e s a n d n o n o d a l disease u s u ally have m e t a s t a t i c disease ( m i c r o s c o p i c o r otherwise), t h e r e h a s b e e n a p o o r c o r r e l a t i o n b e t w e e n early stage disease in the TNM classification a n d p r o g n o s i s . As o p p o s e d to n o n - s m a l l cell l u n g cancer, t h e r e is a pool" r e l a t i o n s h i p b e t w e e n n o d a l status a n d smvival. H e n c e , t h e TNM staging s y s t e m is rarely u s e d for small cell l u n g cancer'. T h e c u r r e n t a p p r o a c h in evaluating a p a t i e n t for m e t a s t a t i c disease is g u i d e d b y the f r e q u e n c y d i s t r i b u t i o n of m e t a s t a t i c involvem e n t . T h e liver is o n e of t h e nlost f r e q u e n t sites of m e t a s t a t i c s p r e a d Ibr small cell l u n g cancer. A p p r o x i m a t e l y 15% to 28% of p a t i e n t s p r e s e n t w i t h liver m e t a s t a s i s at the time of diagnosis, a n d in a b o u t 6% to 10% of p a t i e n t s it is the o n l y d e t e c t a b l e site of m e t a s t a t i c disease. 68-70 S e r u m liver f u n c t i o n tests i n c l u d i n g d e t e r m i n a t i o n s of alkaline p h o s p h a t e , lactic d e h y d r o g e n a s e (LDH), a n d s e r u m g l u t a m i c oxalo a c e t i c t r a n s a m i n a s e (SGOT) levels are g o o d s c r e e n i n g tests in d e t e r m i n i n g w h i c h p a t i e n t s m a y have m e t a s t a t i c liver disease. In a series of s t u d i e s b y D o m b e r n o w s k y et al., 68% of p a t i e n t s w i t h biopsyp r o v e n liver m e t a s t a s e s h a d two or m o r e s e r u m e n z y m e s elevated. 7° In t h e i d e n t i c a l series, o n l y 3% of p a t i e n t s w h o w e r e p r o v e d by bio p s y to b e free of liver m e t a s t a s e s h a d t w o o r m o r e elevated levels. T h e c o n v e r s e is n o t t h e case, however, b e c a u s e o n l y 68% of t h e s e cases w i t h liver m e t a s t a s e s h a d two out of t h r e e a b n o r m a l liver functions, as In a given p a t i e n t w i t h a b n o r m a l liver f u n c t i o n s a d d i t i o n a l e v a l u a t i o n is u s u a l l y w a r r a n t e d . This u s u a l l y i n c l u d e d imaging techniques. C u r r e n t l y c o m p u t e d t o m o g r a p h y (CT) has to a great d e g r e e r e p l a c e d r a d i o n u c l i d e liver-spleen s c a n n i n g as t h e m o s t c o m m o n l y u t i l i z e d s c a n n i n g t e c h n i q u e . 71 T h e sensitivity of m a g n e t i c r e s o n a n c e imaging s c a n n i n g r e m a i n s to be c o m p l e t e l y evaluated, b u t it appem-s to be similar in efficacy to CT. If s c a n n i n g s t u d i e s s h o w a b n o r m a l i ties w i t h obvious s p a c e - o c c u p y i n g lesions, this in a d d i t i o n to a b n o r mal liver c h e m i s t r i e s p r o b a b l y m a k e it u n n e c e s s a r y to p r o c e e d w i t h p e r i t o n e o s c o p y or p e r c u t a n e o u s liver biopsy. However, if liver c h e m istry findings are a b n o r m a l a n d t h e s c a n is n o r m a l , a liver b i o p s y is u s u a l l y w a r r a n t e d to c o n f i r m the p r e s e n c e o r a b s e n c e of liver m e t a s tases. If results of s c a n n i n g studies as well as s e r u m studies are norreal, a b l i n d b i o p s y is unlikely to y i e l d a d d i t i o n a l i n f o r m a t i o n a n d is u s u a l l y n o t justified. As p r e v i o u s l y d i s c u s s e d , the significance of miDM, D e c e m b e r 1989

789

c r o s o c p i c d i s e a s e o n liver b i o p s y or o n p e r i t o n e o s c o p y in the s e t t i n g of n o r m a l n o n i n v a s i v e e v a l u a t i o n (scans a n d liver f u n c t i o n tests) is u n c l e a r in o u r c u r r e n t s t a g i n g s y s t e m . W i t h t h e b i o p s y i n f o r m a t i o n available t h e s e p a t i e n t s w o u l d b e u p s t a g e d f r o m l i m i t e d to e x t e n s i v e d i s e a s e ; h o w e v e r , p r o g n o s t i c a l l y it is likely t h a t t h e y fall into a different category from patients with bulky hepatomegaly or those with a b n o r m a l findings o n liver f u n c t i o n t e s t s a n d scans. T h e b o n e m a r r o w is a n o t h e r c o m m o n site of m e t a s t a t i c s p r e a d tbr s m a l l cell l u n g c a n c e r ; it o c c u r s in 15% to 25% of t h e p a t i e n t s at t h e t i m e of d i a g n o s i s . 72-7"~ As in t h e staging of o t h e r o r g a n sites, t h e m o r e i n t e n s i v e e v a l u a t i o n , i.e., bilateral b o n e m a r r o w a s p i r a t i o n s a n d biopsy, t h e m o r e f r e q u e n t l y m e t a s t a t i c i n v o l v e m e n t is d o c u m e n t e d , r2-r5 Generally, t u m o r cells are p r e s e n t in the b i o p s y s p e c i m e n as well as in t h e a s p i r a t e , a l t h o u g h s o m e g r o u p s h a v e f o u n d t h a t t h e a s p i r a t e s are m o r e f r e q u e n t l y positive, r6, 77 B o t h b i o p s y a n d a s p i r a t i o n a p p e a r to b e w a r r a n t e d . B o n e m a r r o w i n v o l v e m e n t u s u ally o c c u r s in t h e s e t t i n g of o t h e r m e t a s t a t i c disease; h o w e v e r , 4% to 10% of p a t i e n t s p r e s e n t w i t h t h e b o n e m a r r o w as t h e sole site of m e t a s t a t i c d i s e a s e .78, 79 N u m e r o u s g r o u p s h a v e e v a l u a t e d t h e s i g n i f i c a n c e of a p o s i t i v e b o n e m a r r o w as t h e o n l y site of m e t a s t a t i c d i s e a s e . I h d e a n d o t h e r s f o u n d t h a t p a t i e n t s w i t h b o n e m a r r o w as t h e i r sole site of m e t a s t a t i c d i s e a s e w h i c h h a d u p s t a g e d t h e m f r o m l i m i t e d to e x t e n s i v e dise a s e - - h a d a m e a n survival of 8 m o n t h s . 8° P a t i e n t s w i t h o u t b o n e m a r r o w i n v o l v e m e n t (the l i m i t e d - d i s e a s e p a t i e n t ) h a d a m e a n survival of 10 m o n t h s . T h i s g r o u p felt t h a t t h e s e p a t i e n t s h a v e a p r o g n o s i s m o r e s i m i l a r to t h e l i m i t e d - d i s e a s e p a t i e n t . T h e P i e d m o n t Onc o l o g y G r o u p , h o w e v e r , felt t h a t p a t i e n t s w i t h positive b o n e m a r r o w i n v o l v e m e n t o n l y h a d a p r o g n o s i s m o r e c o m p a r a b l e to t h o s e w i t h e x t e n s i v e d i s e a s e P l A n u m b e r of s t u d i e s h a v e c o n f i r m e d t h a t s u b jects w i t h g r o s s b o n e m a r r o w i n v o l v e m e n t a n d p a n c y t o p e n i a h a v e a u n i f o r m l y p o o r p r o g n o s i s , w i t h a m e a n survival of a p p r o x i m a t e l y 2 m o n t h s vs. 6 m o n t h s for p a t i e n t s w i t h b o n e m a r r o w i n v o l v e m e n t b u t w i t h relatively n o r m a l p e r i p h e r a l c o u n t s , s2 T h e s e findings go a l o n g w i t h t h e o v e r v i e w t h a t p r o g n o s i s r e l a t e s to t h e t o t a l - b o d y b u r d e n of t u m o r r a t h e r t h a n t h e specific site involved. B o n e m a r r o w b i o p s y a n d a s p i r a t i o n e v a l u a t e m e t a s t a t i c s p r e a d o n a m i c r o s c o p i c scale a n d c a n reflect a m i n i m a l t u m o r i n v o l v e m e n t . H e n c e , p a t i e n t s w i t h m i c r o s c o p i c b o n e m a r r o w i n v o l v e m e n t o n l y h a v e a relatively favorable p r o g n o s i s m o r e c o m p a r a b l e to t h o s e p a t i e n t s w i t h " l i m i t e d disease." P a t i e n t s w i t h b u l k y b o n e m a r r o w d i s e a s e l e a d i n g to p a n c y t o p e n i a s h a v e a p r o g n o s i s s i m i l a r to t h o s e w i t h e x t e n s i v e d i s e a s e . As w i t h o t h e r o r g a n sites, b o n e m a r r o w i n v o l v e m e n t c a n r e p r e s e n t a s p e c t r u m of m e t a s t a t i c i n v o l v e m e n t f r o m a f u n c t i o n a l l y n o r m a l e n d o r g a n h a r b o r i n g m i c r o s c o p i c i n v o l v e m e n t to a m a l f u n c t i o n i n g e n d o r g a n as t h e r e s u l t of b u l k y t u m o r . 790

DM, D e c e m b e r 1989

Cortical b o n e i n v o l v e m e n t o c c u r s in a p p r o x i m a t e l y 22% of p a t i e n t s p r e s e n t i n g w i t h s m a l l cell l u n g c a n c e r , s3 It o c c u r s as a n isol a t e d site of m e t a s t a t i c d i s e a s e in a p p r o x i m a t e l y 10%. In this context, cortical b o n e i n v o l v e m e n t is r e g a r d e d as d i s t i n c t f r o m b o n e m a r r o w i n v o l v e m e n t . Cortical b o n e d i s e a s e l e a d i n g to lytic b o n e l e s i o n s o n x - r a y films are u n c o m m o n w i t h s m a l l cell l u n g c a n c e r , a n d t h e m a jority of p a t i e n t s w i t h a d i a g n o s i s of b o n e m e t a s t a s e s h a v e positive b o n e s c a n f i n d i n g s only. 84' 85 In a large SWOG s t u d y w h e r e a b o n e s c a n w a s r e q u i r e d o n all p a t i e n t s at the t i m e of diagnosis, 21% h a d e v i d e n c e of b o n e i n v o l v e m e n t b y scan. 83 I n m o s t c a s e s a n e l e v a t e d alkaline p h o s p h a t a s e c o n c e n t r a t i o n is a u s e f u l m a r k e r for d e t e c t i n g m e t a s t a t i c cortical b o n e i n v o l v e m e n t . B e c a u s e of t h e c r o s s - r e a c t i v i t y w i t h h e p a t i c alkaline p h o s p h a t a s e , i s o e n z y m e s p a t t e r n s or o t h e r s e r u m e n z y m e s n e e d to b e e v a l u a t e d in c o m p a r i s o n . B e c a u s e falsep o s i t i v e b o n e s c a n s are c o m m o n in t h e e l d e r l y p o p u l a t i o n a b o n e b i o p s y m a y b e r e q u i r e d to c o n f i r m t h e d i a g n o s i s of m e t a s t a t i c disease, e s p e c i a l l y ff t h e b o n e s c a n is t h e o n l y e v i d e n c e for m e t a s t a t i c spread. In t h e a b s e n c e of a n a b n o r m a l b o n e scan, skeletal s u r v e y s are relatively i n s e n s i t i v e in d e t e c t i n g b o n e m e t a s t a s e s . In a series of 119 p a t i e n t s f r o m a n NCI series w i t h positive p r e t r e a t m e n t skeletal x - r a y findings, o n l y o n e p a t i e n t h a d negative b o n e s c a n results, s~ H e n c e , skeletal x-rays are less sensitive in d e t e c t i n g d i s e a s e t h a n is a b o n e s c a n a n d are of v a l u e o n l y in e v a l u a t i n g a n abnol~nality d e t e c t e d o n a b o n e scan. C e n t r a l n e r v o u s s y s t e m m e t a s t a s e s are a significant c a u s e of m o r b i d i t y a n d m o r t a l i t y in p a t i e n t s w i t h s m a l l cell l u n g c a n c e r . At t h e t i m e of p r e s e n t a t i o n t h e c e n t r a l n e r v o u s s y s t e m is i n v o l v e d w i t h t h e m e t a s t a t i c d i s e a s e in a b o u t 10% of cases. 84'88 However, s o m e t i m e d u r i n g t h e c o u r s e of this d i s e a s e a p p r o x i m a t e l y 30% of p a t i e n t s will develop parenchymal brain metastases. Patients who develop sympt o m a t i c c e n t r a l n e r v o u s s y s t e m (CNS) m e t a s t a s e s suffer significant morbidity. Currently, many investigators have adopted adjuvant t r e a t m e n t of b r a i n m e t a s t a s e s . C h e m o t h e r a p y trials h a v e n o t s h o w n a d e c r e a s e d i n c i d e n c e of b r a i n m e t a s t a s e s ; t h e b l o o d - b r a i n b a r r i e r effectively e x c l u d e s m o s t c h e m o t h e r a p e u t i c agents, a n d t h o s e t h a t c r o s s (e.g., n i t r o s o u r e a s ) h a v e n o t b e e n effective. R a d i o t h e r a p y h a s b e e n e x t e n s i v e l y e v a l u a t e d as a n elective o r " p r o p h y l a c t i c " agent. It is n o w g e n e r a l l y a c c e p t e d t h a t p r o p h y l a c t i c cranial r a d i o t h e r a p y is effective in r e d u c i n g t h e i n c i d e n c e of b r a i n m e t a s t a s e s d u r i n g t h e c o u r s e of d i s e a s e f r o m b e t w e e n 25% a n d 30% to a p p r o x i m a t e l y 5% to 10%. H o w e v e r , as w i t h r a d i o t h e r a p y to t h e p r i m a ~ y l u n g disease, p r o p h y l a c t i c c r a n i a l iiTadiation h a s n o t r e s u l t e d in i n c r e a s e d overall survival. M o s t p a t i e n t s w h o d e v e l o p b r a i n m e t a s t a s e s die of d i s s e m i n a t e d d i s e a s e a n d n o t solely b e c a u s e of t h e i r b r a i n m e t a s t a s e s . 89 P a t i e n t s c o n t i n u e to r e l a p s e a n d die of visceral m e t a s t a t i c d i s e a s e DM, D e c e m b e r 1989

791

b u t are m o r e often p r e v e n t e d f r o m d e v e l o p i n g brain disease. Bec a u s e of the significant m o r b i d i t y f r o m r e l a p s e in the b r a i n a n d t h e g e n e r a l l y m i n o r side effects of b r a i n i r r a d i a t i o n m o s t p a t i e n t s c o n t i n u e to receive p r o p h y l a c t i c cranial i r r a d i a t i o n in spite of the lack of effect o n survival. To avoid utilizing p r o p h y l a c t i c cranial irradiation o n p a t i e n t s w h o have c h e m o t h e r a p y - r e s i s t a n t disease a n d p r o g ress a n d die early after diagnosis, h o w e v e r , it is r e a s o n a b l e to d e l a y p r o p h y l a c t i c cranial i r r a d i a t i o n until i n d u c t i o n c h e m o t h e r a p y is c o m p l e t e a n d it is p o s s i b l e to d e t e r m i n e t h e quality of t h e r e s p o n s e . Patients w i t h p r o g r e s s i v e disease or t h o s e w h o o n l y achieve partial r e s p o n s e s are unlikely to r e l a p s e w i t h b r a i n m e t a s t a s e s p r i o r to p r o g r e s s i o n of disease o u t s i d e t h e central n e r v o u s system. However, patients achieving a c o m p l e t e r e m i s s i o n have a b e t t e r c h a n c e for longt e r m survival a n d m a y have a subjective t h e r a p e u t i c benefit of receiving p r o p h y l a c t i c cranial irradiation. Patients achieving a cornp l e t e r e m i s s i o n are t h o s e m o s t likely to benefit f r o m p r o p h y l a c t i c cranial radiation, PARANEOPLASTIC

SYNDROMES

One of the clinically fascinating a n d intriguing a s p e c t s of small cell l u n g c a n c e r is the f r e q u e n t o c c u r r e n c e of a s p e c t r u m of a s s o c i a t e d clinical s y n d r o m e s . F r e q u e n t l y p a t i e n t s p r e s e n t to t h e i r p h y s i c i a n s n o t b e c a u s e of signs o r s y m p t o m s d i r e c t l y r e l a t e d to t h e p r e s e n c e of t h e p r i m a r y t u m o r or m e t a s t a s e s b u t b e c a u s e of signs a n d s y m p t o m s that a p p e a r to be u n r e l a t e d to t h e p r i m a r y diagnosis. "Paran e o p l a s t i c syndromes" c a n a c c o m p a n y small cell l u n g c a n c e r (or a n y malignancy) a n d are s y m p t o m s o r findings that are i n d i r e c t l y c a u s e d b y the p r i m a r y t u m o r a n d its m e t a s t a s e s . M a n y of t h e s e synd r o m e s are t h e result of m e t a b o l i c a b n o r m a l i t i e s d u e to specific organ d y s f u n c t i o n a n d have w e l l - d e s c r i b e d h o r m o n a l i n t e r m e d i a t e s . T h e etiologic basis of m a n y o t h e r s y n d r o m e s r e m a i n u n d e f i n e d . If a p a r a n e o p l a s t i c s y n d r o m e is going to o c c u r in c o n j u n c t i o n w i t h a p a t i e n t ' s disease course, it is u s u a l l y p r e s e n t at the t i m e of diagnosis. However, s o m e p a t i e n t s first d e v e l o p a p a r a n e o p l a s t i c s3nl d r o m e d u r i n g the c o u r s e of t h e i r disease. It h a s b e e n e s t i m a t e d t h a t a p p r o x i m a t e l y 20% of p a t i e n t s will d e v e l o p s o m e t y p e of p a r a n e o plastic s y n d r o m e s o m e t i m e d u r i n g the c o u r s e of t h e i r disease. If o n e c o n s i d e r s the a n o r e x i a a n d the c a c h e x i a t h a t u s u a l l y a c c o m p a n y small cell l u n g c a n c e r as a p a r a n e o p l a s t i c s y n d r o m e , this p e r c e n t a g e p r o b a b l y a p p r o a c h e s 100%. It is u n c l e a r w h y small cell lung c a n c e r is m o r e f r e q u e n t l y a c c o m p a n i e d b y p a r a n e o p l a s t i c s y n d r o m e s . As d i s c u s s e d in the s e c t i o n d i s c u s s i n g etiolo&*y a n d p a t h o l o g y , t h e r e is s o m e e v i d e n c e to suggest that the cell of origin of small cell l u n g c a n c e r is of n e u r o e n d o c r i n e origin. It is well k n o w n t h a t t u m o r s of n e u r o e n d o c r i n e origin c a n 792

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e l a b o r a t e a n u m b e r of h o r m o n e s a n d o t h e r biologically active p r o teins. T h i s r e l a t i o n s h i p is i m p o r t a n t a n d in fact etiologically r e l a t e d to s o m e p a r a n e o p l a s t i c s y n d r o m e s , i.e., a n u m b e r of h o r m o n e s a n d t h e i r p r e c u r s o r m o l e c u l e s h a v e b e e n i s o l a t e d f r o m in vitro c u l t u r e s of s m a l l cell l u n g c a n c e r . ~°

ANTIDIURETIC HORMONE The hormonal syndrome most frequently associated with small cell l u n g c a n c e r is t h e s y n d r o m e of i n a p p r o p r i a t e a n t i d i u r e t i c h o r m o n e (SIADH). This s y n d r o m e w a s first d e s c r i b e d in 1938 in a p a tient w i t h l u n g c a n c e r w h o h a d h y p o c h l o r e m i a a n d h i g h urinm~y e x c r e t i o n of c h l o r i d e ) " T h e s y n d r o m e w a s f u r t h e r d e f i n e d b y S c h w a r t z et ,ll. in 1957 w h o d e s c r i b e d t w o p a t i e n t s w i t h b r o n c h o genic c a r c i n o m a w h o h a d h y p o n a t r e m i a , n o r m a l v o l u m e s t a t u s a n d a d r e n a l / r e n a l f u n c t i o n , a n d t h e e x c r e t i o n of large a m o u n t s of sod i u m in t h e i r urine. 92 Since t h a t time, SIADH h a s b e c o m e a wellr e c o g n i z e d clinical s y n d r o m e a n d is the m o s t well d e f i n e d a n d u n d e r s t o o d p a r a n e o p l a s t i c s y n d r o m e a c c o m p a n y i n g small cell l u n g c a n c e r . A p p r o x i m a t e l y 5% to 10% of p a t i e n t s p r e s e n t w i t h this clinical s y n d r o m e . 93 H o w e v e r , a n a d d i t i o n a l 40% to 50% of p a t i e n t s c a n b e s h o w n to have s u b c l i n i c a l a b n o r m a l i t i e s c o m p a t i b l e w i t h SIADH o n a p p r o p r i a t e clinical testing. 93 C u r r e n t l y r a d i o i m m u n o a s s a y (RIA) m e a s u r e m e n t or t h e s e r u m concentration of a n t i d i u r e t i c h o r m o n e (ADH) is t h e m o s t f r e q u e n t m e t h o d to c o n f i r m t h e d i a g n o s i s . Using t h e criteria of a n e l e v a t e d level of ADH, a p p r o x i m a t e l y 5% to 10% of all p a t i e n t s w i t h s m a l l cell l u n g c a n c e r h a v e SlADH. T h e s o u r c e of p r o d u c t i o n of t h e e x c e s s ADH h a s b e e n s h o w n to b e b o t h t h e prim a r y t u m o r a n d its m e t a s t a s e s . As verified b y t h e i n c o r p o r a t i o n of 3H-phenylalanine as a m a r k e r for p r o t e i n s y n t h e s i s , s m a l l cell l u n g c a n c e r cells c u l t u r e d in vitro c a n s y n t h e s i z e the h o r m o n e a n d exc r e t e it into s u r r o u n d i n g c u l t u r e m e d i a . A l t h o u g h a large n u m b e r of p a t i e n t s w i t h s m a l l cell l u n g c a n c e r h a v e e l e v a t e d s e r u m c o n c e n t r a t i o n s of ADH, n o t all h a v e t h e clinical s y n d r o m e . H o w e v e r , a l a r g e r n u m b e r of p a t i e n t s c a n b e d e m o n s t r a t e d to h a v e a n a b n o r m a l r e s p o n s e to w a t e r l o a d i n g e v e n in t h e s e t t i n g of a n o r m a l s e r u m ADH c o n c e n t r a t i o n . G i n s b u r g et. al. f o u n d t h a t 27 of 40 p a t i e n t s w i t h s m a l l cell l u n g c a n c e r failed to e x c r e t e a m a x i m a l l y d i l u t e d u r i n e w h e n c h a l l e n g e d . 94 G r e c o et al. f o u n d t h a t 23 of 49 p a t i e n t s h a d a b n o r m a l findings o n t h e w a t e r l o a d i n g test. 95 In this s a m e s t u d y o n l y 17 p a t i e n t s h a d h i g h s e r u m c o n c e n t r a t i o n s of ADH. H e n c e , a p p r o x i m a t e l y , 40% to 50% of p a t i e n t s will h a v e s o m e m a n i f e s t a t i o n s of SIADH, e i t h e r a loss in t h e c a p a c i t y to s e c r e t e m a x i m a l l y dilute u r i n e o r a n e l e v a t e d s e r u m c o n c e n t r a t i o n of ADH. T h e large n u m b e r of s u b j e c t s w i t h a b n o r m a l findings o n t h e w a t e r l o a d i n g test (larger t h a n t h o s e w i t h e l e v a t e d s e r u m c o n c e n t r a t i o n of DM, D e c e m b e r 1989

793

ADH as m e a s u r e d b y RIA) p r o b a b l y reflects t h e h e t e r o g e n e i t y of ADH p r o d u c t i o n via t h e s e t u m o r s . R o b e r t s o n et al. h a v e d o n e w a t e r l o a d ing t e s t s o n a series of p a t i e n t s a n d at t h e s a m e t i m e m e a s u r e d t h e i r c h a n g e s in s e r u m o s m o l a l i t y a n d ADH levels. 96'97 S o m e p a t i e n t s s h o w e d r a n d o m v a r i a t i o n s in ADH c o n c e n t r a t i o n t h a t d i d n o t change with water loading. This population represents those who h a v e a u t o n o m o u s t u m o r p r o d u c t i o n of ADH t h a t is u n r e l a t e d a n d u n a f f e c t e d b y s e r u m osmo]ality, t h e u s u a l r e g u l a t o r of ADH s e c r e tion. M o r e " n o r m a l " r e s p o n s e s w e r e s e e n in 35% of p a t i e n t s , w i t h a rise in ADH c o n c e n t r a t i o n in r e s p o n s e to a n i n c r e a s e in s e r u m osm o l a l i t y i n d u c e d b y saline infusion, b u t this o n l y o c c u r r e d at h i g h osrnolality levels. A n o t h e r g r o u p of p a t i e n t s , 35%, h a d a r e s p o n s e s i m i l a r to t h a t e x p e c t e d in n o r m a l individuals, a n d 10% s h o w e d s u p p r e s s e d ADH levels t h a t o n l y i n c r e a s e d w h e n t h e n o r m a l p l a s m a osmolality was exceeded. These various patterns show the heterog e n e i t y in ADH r e s p o n s e in s u b j e c t s w i t h s m a l l cell l u n g c a n c e r a n d t h a t e v e r y clinical c a s e of "SIADH" c a n n o t a l w a y s b e t i e d to a n ADH mechanism. T r e a t m e n t of SIADH in t h e setting of s m a l l cell l u n g c a n c e r h a s b e e n s i m p l i f i e d s i n c e effective t h e r a p y is available for t h e u n d e r l y i n g c a n c e r . T h e m a j o r i t y of p a t i e n t s w h o a c h i e v e a n a n t i t u m o r r e s p o n s e h a v e p r o m p t r e s o l u t i o n of t h e i r SIADH. H y p o n a t r e m i a r e s o l v e s w i t h i n 3 to 6 w e e k s , a n d t h e s y n d r o m e is u s u a l l y a b s e n t as l o n g as t h e d i s e a s e is c o n t r o l l e d . T h e r e c u r r e n c e of SIADH c a n o c c a s i o n a l l y p r e d a t e a n d p r e d i c t t u m o r r e l a p s e . I n a series of 14 p a t i e n t s f r o m V a n d e r b i l t w i t h SIADH at t h e t i m e of t h e p r e s e n t a t i o n , 8 of t h e 12 w h o d e v e l o p e d r e c u r r e n t d i s e a s e h a d a r e c u r r e n c e of t h e i r SIADH. 93 H e n c e , m o s t p a t i e n t s w h o p r e s e n t w i t h SIADH h a v e a r e c u r r e n c e of that syndrome when their disease relapses. In o c c a s i o n a l p a t i e n t s w h o p r e s e n t w i t h severe SIADH or, m o r e c o m m o n l y , in p a t i e n t s w i t h r e l a p s i n g d i s e a s e w h o are r e f r a c t o r y to a n t i t u r n o r t h e r a p y , SIADH c a n b e c o m e a difficult m a n a g e m e n t p r o b l e m . In t h e s e c a s e s d e m e c l o c y c l i n e is f r e q u e n t l y effective in c o n t r o l ling this s y n d r o m e . T h i s t e t r a c y c l i n e antibiotic c a u s e s a n e p h r o g e n i c d i a b e t e s i n s i p i d u s b y i n t e r f e r i n g w i t h t h e a c t i o n of ADH o n t h e r e n a l t u b u l e s a n d c o l l e c t i n g s y s t e m . A w a t e r d i u r e s i s a n d c o r r e c t i o n of h y p o n a t r e m i a a n d h y p e r o s m o l a r i t y u s u a l l y o c c u r s w i t h i n 4 to 7 d a y s of s t a r t i n g t r e a t m e n t w i t h t h e drug. In p a t i e n t s p r e s e n t i n g w i t h severe SIADH, d e m e c l o c y c l i n e c a n also b e u s e d until effective a n t i t u rnor therapy can be started.

ADRENOCORTICOTROPIC HORMONE In 1932 C u s h i n g d e s c r i b e d a s y n d r o m e of t r u n c a l obesity, h i r s u t ism, hyperpigmentation, a n d diabetes, u s u a l l y in a s s o c i a t i o n w i t h a p i t u i t a r y a d e n o m a " C u s h i n g ' s s y n d r o m e . " At t h e time, it w a s also 794

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n o t e d that occasionally these findings o c c u r r e d in association with n o n p i t u i t a r y tumors. In 1962 M e a d o r a n d colleagues greatly adv a n c e d o u r u n d e r s t a n d i n g of Cushing's disease occurring in the setting of n o n p i t u i t a r y a d e n o m a s by showing that t here were high concentrations of a d e n o c o r t i c o t r o p i c h o r m o n e (ACTH) activity in b o t h the p l a s m a a n d t u m o r s of five patients. 9s Small cell lung c a n c e r is pr oba bl y the m o s t c o m m o n t u m o r associated with ectopic ACTH p r o d u c t i o n . Approximately 60% of patients with ectopic p r o d u c t i o n of ACTH will have a diagnosis of small ceil lung cancer. ~3 The i n c i d e n c e of ectopic p r o d u c t i o n of ACTH in patients with small cell lung c a n c e r varies widely. Like SIADH, the diagnosis will vary d e p e n d i n g on the definition. If one considers only those patients with a clinical p i c t u r e of Cushing's disease, only 3% to 7% of patients with small cell lung c a n c e r have the ectopic p r o d u c t i o n of ACTH. However, a m u c h higher p e r c e n t a g e of patients have a subclinical form of Cushing's s y n d r o m e . An even greater n u m b e r of patients have elevated p l a s m a c o n c e n t r a t i o n s of ACTH activity. Gilby et al. f o u n d evidence of a b n o r m a l regulation of cortisol secretion in 22 of 43 patients with small cell lung cancer, thus suggesting the prod u c t i o n of s u b s tan c e s with ACTH-like activity. 99 Other investigators have f o u n d that 11% to 72% of patients have elevated s e r u m ACTH levels as m e a s u r e d by RIA.1°°' ,01 The clinical a n d laboratory features of excess ACTH in patients with small cell lung c a n c e r differs from that of classic Cushing's synd r o m e associated with a pituitary a d e n o m a . Patients with small cell lung c a n c e r usually fit the d e m o g r a p h i c s of patients with lung cancer, i.e., male cigarette s m o k e r aged 50 to 70 years. Because the onset t e n d s to be m o r e rapid t h a n in classic Cushing's and b e c a u s e patients are frequently anorexic a n d have significant weight loss because of their u n d e r l y i n g tumor, m os t patients lack the classic cushingoid face. In patients with lung c a n c e r the features t e n d to be severe weakness, weight loss, a n d p r o f o u n d m i neral ocort i coi d effects of edema, h y p e r t e n s i o n , a n d hypokalemia. H y p e r p i g m e n t a t i o n also o ccu r s in a p p r o x i m a t e l y 25% to 30% of patients. 1°2 Laboratory features are also useful in distinguishing ectopic ACTH p r o d u c t i o n in t h a t hypokal em i a t e n d s to be severe. Of patients with ectopic ACTH in the setting of small cell lung cancer, 70% to 90% have a p o t a s s i u m of less t h a n 3.0 mEq/L. In addition, u r i n a r y excretion of 17-hydroxycorticoids is usually greatly elevated. ACTH s e r u m c o n c e n t r a t i o n s are usually greatly elevated a n d frequently exceed 200 mg/ml. S u p p r e s s i o n of ur i na r y corticoids a n d s e r u m ACTH with d e x a m e t h a s o n e is usually negligible. Over the past 10 ye a r s the synthetic p a t h w a y s a n d structures of p r o t e i n s with ACTH activity have b e e n b e t t e r defined. It appears that the e n z y m a t i c p a t h w a y s for the p r o d u c t i o n of ACTH in t u m o r s are DM, D e c e m b e r 1989

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s i m i l a r to t h o s e t h a t occur- in t h e p i t u i t m y . However, t h e s y n t h e t i c m a c h i n e W in t u m o r t i s s u e is p o o r l y c o n t r o l l e d , a n d f r e q u e n t l y large a m o u n t s of p r e c u r s o r m o l e c u l e s , ACTH f r a g m e n t s , a n d ACTH itself are s e c r e t e d . T h e s e p r o t e i n s h a v e v a w i n g d e g r e e s of ACTH a g o n i s t i c activity, a n d this r e s u l t s in t h e variable clinical e x p r e s s i o n of C u s h ing's s y n d r o m e . In t h e o l d e r l i t e r a t u r e p a t i e n t s w i t h C u s h i n g ' s s y n d r o m e a n d s m a l l cell l u n g c a n c e r u n i f o r m l y d i d poorly. T h e m a j o r i t y of t h e s e p a t i e n t s , h o w e v e r , d i d n o t die b e c a u s e of p r o g r e s s i v e t u m o r b u t d i e d d u e to the severe metabolic abnormalities caused by their hypercortisolism. W i t h t h e a d v e n t of effective c h e m o t h e r a p y it a p p e a r s t h a t the p r o g n o s i s h a s c h a n g e d a n d that, like o t h e r h o r m o n a l p a r a n e o p l a s t i c synd r o m e s o c c u r r i n g in s m a l l cell l u n g c a n c e r , this s y n d r o m e r e s p o n d s to effective a n t i t u m o r t h e r a p y . As w i t h o t h e r e c t o p i c a l l y p r o d u c e d h o r m o n e s , r e l a p s e of d i s e a s e is f r e q u e n t l y accompanied or p r e c e d e d b y a r e t u r n of t h e e c t o p i c h o r m o n e a n d t h e a c c o m p a n y i n g syndrome.

CALCITONIN C a l e i t o n i n is a p a r a t h y r o i d p e p t i d e h o r m o n e s e c r e t e d in r e s p o n s e to a n e l e v a t e d s e r u m c a l c i u m c o n c e n t r a t i o n . It c a u s e s a n i m m e d i a t e caliuresis. A l t h o u g h t h e r e are n o clinical s y m p t o m s a s s o c i a t e d w i t h e l e v a t e d s e r u m c a l c i t o n i n c o n c e n t r a t i o n s , a g r e a t d e a l of i n t e r e s t h a s f o c u s e d o n c a l c i t o n i n a n d its p o t e n t i a l as a t u m o r m a r k e r in p a t i e n t s w i t h s m a l l cell l u n g c a n c e r . S e r u m c a l c i t o n i n c o n c e n t r a t i o n s are ele v a t e d in 38% to 67% of p a t i e n t s w i t h all histological t y p e s of l u n g c a n c e r . Small cell l u n g c a n c e r is a s s o c i a t e d w i t h t h e h i g h e s t freq u e n c y of e l e v a t e d c a l c i t o n i n levels. 9a In l u n g cancer- p a t i e n t s t h e r e are t w o sites of origin for t h e h y p e r c a l c i t o n i n e m i a . In s m a l l cell l u n g c a n c e r Silva et al. h a v e d e m o n s t r a t e d t h a t in the m a j o r i t y of p a t i e n t s c a l e i t o n i n is d i r e c t l y s e c r e t e d b y t h e t u m o r ; t u m o r v e n o u s c o n c e n t r a t i o n s are m u c h h i g h e r t h a n s y s t e m i c v e n o u s or arterial b l o o d levels, l°a F u r t h e r s u p p o r t i n g this fact is the ability of in vitro c u l t u r e s of u n d i f f e r e n t i a t e d l u n g carcin o m a to e x c r e t e c a l c i t o n i n into t h e c u l t u r e m e d i a . T M To c o n f u s e m a t t e r s it h a s also b e e n s h o w n t h a t in s o m e p a t i e n t s w i t h n o n s m a l l l u n g c a n c e r t h e c a l c i t o n i n c o n c e n t r a t i o n in t h e t h y r o i d a l vein is h i g h e r t h a n the t u m o r - v e n o u s c o n c e n t r a t i o n is, w h i c h s u g g e s t s t h a t t h e c a l c i t o n i n is a c t u a l l y of p a r a t h y r o i d origin. 1°5' 10~ T h e r e p o r t of Silva et al. in w h i c h t h e p l a s m a c o n c e n t r a t i o n of c a l c i t o n i n fell in 12 of 16 p a t i e n t s u n d e r g o i n g e i t h e r surgical or c h e m o t h e r a p e u t i c t r e a t m e n t for t h e i r l u n g cancer" h a s p r o m p t e d o t h e r a u t h o r s to i n v e s t i g a t e c a ] c i t o n i n ' s u s e as a t u m o r m a r k e r . K r a u s e et al. s t u d i e d six p a t i e n t s w i t h s m a l l cell l u n g c a n c e r a n d f o u n d t h a t a falling v a l u e c o r r e s p o n d e d to a clinical r e s p o n s e ) °r 796

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Relapse in disease w a s a c c o m p a n i e d b y an i n c r e a s e in s e r u m c a l c i t o n i n c o n c e n t r a t i o n . Wallach et al. h a s f o u n d similar results in eight p a t i e n t s ) °s H e n c e , a l t h o u g h n o t a c c o m p a n i e d b y a clinical s y n d r o m e , t h e e c t o p i c p r o d u c t i o n of c a l c i t o n i n m a y p r o v e to be a valuable t u m o r m a r k e r for m o n i t o r i n g disease status in patients w i t h small cell l u n g cancer. OTHER H O R M O N A L PRODUCTS

H y p e r c a l c e m i a d u e to the e c t o p i c p r o d u c t i o n of p a r a t h y r o i d h o r m o n e is u n u s u a l in p a t i e n t s w i t h small cell l u n g cancer. This clinic a l / l a b o r a t o r y finding c a n s o m e t i m e s h e l p to d i s t i n g u i s h t h e histological t y p e of c a n c e r in a p a t i e n t p r e s e n t i n g w i t h a hilar mass. H y p e r c a l c e m i a d u e to p a r a t h y r o i d h o r m o n a l - l i k e activity or in fact b o n y m e t a s t a s e s is u n u s u a l in small cell l u n g c a n c e r in c o m p a r i s o n to their m o r e c o m m o n o c c u r r e n c e in p a t i e n t s w h o have n o n - s m a l l cell h i s t o l o g i e s ) °9 In p a t i e n t s p r e s e n t i n g w i t h o r d e v e l o p i n g h y p e r c a l c e m i a d u r i n g t h e c o u r s e of t h e i r disease, o n e s h o u l d raise t h e possibility of a n o n - s m a l l cell histology, c o n t a m i n a n t h y p e r p a r a t h y r o i d i s m in p a t i e n t s w i t h k n o w n small cell l u n g cancer, a n d t h e t r a n s f o r m a t i o n to a n o n - s m a l l cell histology. PARANEOPLASTIC NEUROLOGICAL DISORDERS

A n u m b e r of n e u r o l o g i c a l s y n d r o m e s c a n a c c o m p a n y small cell l u n g c a n c e r . M a n y of t h e s e clinical s y n d r o m e s are p o o r l y defined, a n d t h e i r clinical p i c t u r e s t e n d to overlap. Likewise, the etiologic a n d m e c h a n i s t i c c o n n e c t i o n b e t w e e n the l u n g t u m o r a n d t h e s e synd r o m e s are p o o r l y defined. M a n y a u t h o r s have t h e o r i z e d t h e exist e n c e of specific n e u r o t o x i c t u m o r p r o d u c t s or i m m u n e effects; h o w ever, t h e s e r e m a i n to b e defined. NE UR OMYOPA THIES

This g r o u p of s y n d r o m e s is the o n e m o s t c o m m o n l y a s s o c i a t e d w i t h small cell l u n g c a n c e r . T h e exact i n c i d e n c e h a s b e e n difficult to define b e c a u s e of t h e c o m m o n o c c u r r e n c e of similar s y m p t o m atology in this p a t i e n t p o p u l a t i o n w h o f r e q u e n t l y have a s s o c i a t e d m e d i c a l p r o b l e m s of c h r o n i c p u l m o n a r y disease, t o b a c c o abuse, e t h a n o l abuse, in a d d i t i o n to o t h e r m e d i c a l p r o b l e m s c o m m o n to a n o l d e r p a t i e n t p o p u l a t i o n . T h e f r e q u e n t u s e of n e u r o t o x i c c h e m o t h e r a p e u t i c a g e n t s s u c h as the v i n c a alkaloids a n d c i s - p l a t i n u m also m a k e t h e true i n c i d e n c e of this s y n d r o m e even h a r d e r to define. Croft et al. d e s c r i b e d 162 o u t of 1,465 g e n e r a l c a n c e r p a t i e n t s as having a s s o c i a t e d n e u r o m y o p a t h i e s . 11° In a n analysis of t h e i r large series Croft a n d Wilkinson l o o k e d at the 250 p a t i e n t s w h o h a d a diagDM, D e c e m b e r 1989

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nosis of lung cancer. Out of these, 40 patients h a d n e u r o p a t h i e s , m Hence, the true i n c i d e n c e s of n e u r o m y o p a t h y probabl y varies bet w e e n 10% to 20% of patients with lung cancer. Its association with small cell lung c a n c e r a p p e a r s to be s o m e w h a t higher, m T h e specific diagnosis of c a r c i n o m a t o u s n e u r o m y o p a t h y can freq u e n t l y be difficult to pi n down. Many of the s y m p t o m s can be mimicked by direct t u m o r involvement of the central or p e r i p h e r a l nervous system. Multiple small brain metastases, c a r c i n o m a t o u s meningitis, a n d spinal c o r d or per i phe r al nerve c o m p r e s s i o n by tum o r can all mimic n e u r o m y o p a t h i e s . Metabolic (diabetes) a n d iatrogenic causes (steroids treatment) can also mimic n e u r o p a t h i e s . Drug toxicity d u e to c h e m o t h e r a p y a nd antiemetics m a y also mimic t hese s y n d ro mes . Metabolic d e r a n g e m e n t s caus e d by t r e a t m e n t or ano t h e r p ar an eo p las ti c s y n d r o m e c a u s e d by the t u m o r itself s u c h as 8IADH can also i n d u c e changes suggestive of n e u r o m y o p a t h y . Infectious agents can also be the etiology of n e u r o m y o p a t h i e s s u c h as progressive multffocal l e u k o e n c e p h a l o p a t h y . Hence, defining a p a r a n e o p l a s t i c n e u r o m y o p a t h y is frequently a diagnosis of e x c l w sion, eliminating all k n o w n causes of the specific neurological disorder. T h e n e u r o m y o p a t h i e s are usually a p p a r e n t at the initial p r e s e n tation of the patient. However, an occasional patient can p r e s e n t with a n e u r o m y o p a t h y up to a y e a r before the clinical diagnosis of small cell lung cancer. As o p p o s e d to m a n y of the o t h e r p a r a n e o plastic syndromes, t her e is no a p p a r e n t direct relationship bet w e e n the t u m o r b u r d e n a n d the o c c u r r e n c e of n e u r o p a t h y . This likely explains w h y t h e r e is frequently only m i n o r i m p r o v e m e n t in the n e u r o m y o p a t h i e after t r e a t m e n t of the u n d e r l y i n g tumor. However, as majo r r e s p o n s e s are m o r e c o m m o n a n d their d u r a t i o n lasting, there is evidence that some of the n e u r o m y o p a t h i e s can improve. Peripheral n e u r o p a t h i e s are probably the m o st c o m m o n p a r a n e o plastic s y n d r o m e s that o c c u r in small cell lung cancer. It is u n u s u a l to see a p atien t with this disease w h o does not develop p e r i p h e r a l n e u r o p a t h y s o m e t i m e during the course of disease. This high incid e n c e is no d o u b t related to the c o m m o n use of the vinca alkaloids; however, these patients m o r e t h a n patients with ot her t u m o r types w h o receive similar doses of the vincas s eem to be susceptible to n e u r o p a t h i e s . It m a y be t hat an u n d e r l y i n g subclinical n e u r o p a t h y exists in m o s t patients with small ceil lung c a n c e r a n d the vinca alkaloids precipitate these to clinical detection. The m o s t c o m m o n s y m p t o m s patients c o m p l a i n of are related to d e c r e a s e d sensation a n d paresthesias in the extremities. T he s e s y m p t o m s frequently occ u r in c o n j u n c t i o n with m y o p a t h y a n d e n c e p h a l o p a t h y , with patients complaining of b o t h weakness a n d paresthesias. Classically the p e r i p h e r a l n e u r o p a t h i e s associated with small cell lung c a n c e r 798

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d o n o t i m p r o v e w i t h effective a n t i t u m o r t r e a t m e n t . However, as m e n t i o n e d earlier, t h e f r e q u e n t u s e of t h e v i n c a alkaloids in t h e t r e a t m e n t of this d i s e a s e m a k e it difficult to d e t e r m i n e w h e t h e r a r e m i s s i o n in u n d e r l y i n g n e u r o p a t h y o c c u r s since m a n y p a t i e n t s will c o n t i n u e to have d r u g - i n d u c e d n e u r o p a t h y . T h e etiology of this synd r o m e , like t h e o t h e r n e u r o l o g i c a l p a r a n e o p l a s t i c s y n d r o m e s , is u n clear. A u t o i m m u n i t y h a s b e e n s u g g e s t e d since a n t i b o d i e s that b i n d to n e r v o u s t i s s u e have b e e n d e s c r i b e d in t h e c e r e b r o s p i n a l fluid a n d s e r u m of p a t i e n t s w i t h n e u r o p a t h i e s . However, it is u n c l e a r w h e t h e r t h e s e a n t i b o d i e s are t h e etiologic agent o r a r e s p o n s e to t h e u n d e r lying d a m a g e d tissue. 113 Pathological findings are n o n s p e c i f i c a n d s h o w d e s t r u c t i o n of n e u r o n s in the d o r s a l ganglia w i t h a p a t c h y i n f l a m m a t o r y r e a c t i o n . T h e p e r i p h e r a l n e r v e s s h o w s e g m e n t a l dem y e l i n a t i o n , a n d t h e r e are o c c a s i o n a l l y m p h o c y t i c infiltrates in b o t h the p e r i p h e r a l n e r v e s a n d the spinal cord. 1~4 DEMENTIA

D e m e n t i a is t h e m o s t c o m m o n e n c e p h a l o p a t h y a c c o m p a n y i n g small cell l u n g c a n c e r . T h e o n s e t of d e m e n t i a c a n b e a c u t e or c h r o n i c . It c a n o c c u r e i t h e r d u r i n g t r e a t m e n t , p r i o r to p r e s e n t a t i o n , or after t r e a t m e n t h a s b e e n d i s c o n t i n u e d . T h e d e m e n t i a u s u a l l y p r e sents as a forgetfulness, loss of m e m o r y , or c o n f u s i o n . It c a n r a n g e f r o m o n l y m i n i m a l l y interfering w i t h life-style to a severe organic b r a i n s y n d r o m e r e q u i r i n g total s u p p o r t i v e care. L a b o r a t o r y s t u d i e s p r e m o r t e m a n d p o s t m o r t e m have n o t f o u n d specific p a t h o l o g i c a l findings. Prognosis is variable, a n d p a t i e n t s c a n stabilize at a n y p o i n t or p r o g r e s s to t h e p o i n t of c o m p l e t e disability a n d d e a t h . Like t h e n e u r o m y o p a t h i e s t h e r e is little r e l a t i o n s h i p b e t w e e n t h e p r o g n o s i s of t h e d e m e n t i a a n d t u m o r b u r d e n . R e s p o n s e of the tum o r to a n t i t u m o r a g e n t s d o e s n o t n e c e s s a r i l y c a u s e i m p r o v e m e n t in d e m e n t i a . B e c a u s e of t h e f r e q u e n t u s e of p r o p h y l a c t i c w h o l e - b r a i n irradiation, investigators have s u g g e s t e d an a s s o c i a t i o n b e t w e e n w h o l e b r a i n i r r a d i a t i o n a n d t h e d e v e l o p m e n t of c h r o n i c d e m e n t i a associa t e d w i t h small cell l u n g cancer. 115~116 At this time, the exact relationship b e t w e e n b r a i n r a d i o t h e r a p y a n d d e m e n t i a is u n c l e a r ; h o w e v e r , the i n c i d e n c e of d e m e n t i a d o e s a p p e a r to b e h i g h e r in p a t i e n t s w h o have r e c e i v e d p r o p h y l a c t i c w h o l e - b r a i n irradiation. As t h e m e d i a n survival of p a t i e n t s h a s i n c r e a s e d , t h e r e is a c o n c e r n that p r o g r e s s i v e d e m e n t i a will b e c o m e a c o m m o n l o n g - t e r m c o m p l i c a t i o n in p a t i e n t s w h o have r e c e i v e d p r o p h y l a c t i c w h o l e - b r a i n irradiation. T h e r e a s o n for this u n d e r l y i n g susceptibility to d e m e n t i a is u n c l e a r c o n s i d e r i n g that t h e total d o s e a n d d o s e rate of r a d i o t h e r a p y in small cell l u n g c a n c e r is n o t in e x c e s s of t h a t u s e d in treating p a t i e n t s w i t h b r a i n m e t a s t a s e s of o t h e r etiologies. C o n c u r r e n t u s e of c h e m o t h e r a p y a n d DM, D e c e m b e r 1989

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radiation t h e r a p y has been suggested as one of the underlying factors for the apparent increased development of e n c e p h a l o p a t h y in this disease. High-dose methotrexate, the nitrosoureas, 5-fluorouracil (5-FU), a n d other c o m p o u n d s that penetrate the central nervous system have been implicated as possible causes of a synergistic neurotoxicity.117 A subclinical "paraneoplastic dementia" m a y also make these patients more p r o n e to d e m e n t i a t h a n are other patients without small cell cancer. To decrease the incidence of this d e m e n t i a it has b e e n suggested that prophylactic whole-brain irradiation therapy be eliminated a n d therapeutic radiotherapy administered only to patients w h o develop symptomatic brain metastases. 11s Some authors have suggested that altering the radiation therapy fractionation s c h e m a will result in a lower incidence of chronic encephalopathies.~lu Cerebellar degeneration is a n o t h e r paraneoplastic s y n d r o m e occurring in small ceil lung cancer, l~z These patients usually present with bilaterally symmetrical truncal a n d extremity ataxia. Dysarthria and tremors are also frequently seen. The clinical course is usually rapid, a n d patients can become wheelchair b o u n d within weeks or months. With effective combination c h e m o t h e r a p y some patients can stabilize a n d occasionally improve in parallel with a t u m o r response. Postmortem examination has s h o w n diffuse degeneration of Purkinje's cells and paravascular cerebellar inflammation. The etiology, like m a n y of the other paraneoplastic syndromes affecting the central a n d peripheral nervous system, is u n k n o w n . EATON-LAMBERT SYNDROME

The Eaton-Lambert s y n d r o m e is one of the few clearly defined neurological paraneoplastic syndromes accompanying small cell lung cancer. 12° Clinically it presents with a clinical picture very similar to m y a s t h e n i a gravis, proximal muscle weakness a n d easy fatigability. Symptoms are most p r o n o u n c e d in the lower extremities a n d cause difficulty in walking, climbing stairs, a n d getting up from a chair. As with the other n e u r o m y o p a t h i e s this s y n d r o m e can occur in c o n j u n c t i o n with other neuropathie8. The electromyogram clearly distinguishes this s y n d r o m e from m y a s t h e n i a gravis in that there is facilitation of m u s c u l a r action potentials with repeated stimulation. The pathophysiology of this s y n d r o m e is unclear; patients do not r e s p o n d to m y a s t h e n i a gn.avis-type treatment with anticholinesterase inhibitors. Guanidine is occasionally effective.121 As o p p o s e d to the other neuromyopathies, the Eaton-Lambert s y n d r o m e frequently r e s p o n d s to a n t i t u m o r treatment with gradual resolution of the symptoms. Recurrence of the disease is frequently a c c o m p a n i e d by a recurrence of this myasthenic-like syndrome. 800

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TREATMENT

Since the late seventies it has b e e n k n o w n that small cell lung c a n c e r differs from the o t h e r histological s ubt y pes of lung c a n c e r in that it f r eq u en tly r e s p o n d s to c h e m o t h e r a p e u t i c agents. Since t hese early reports, a large n u m b e r of a n t i c a n c e r drugs have b e e n s h o w n to have significant activity against small cell lung cancer. T he availability of effective drugs has r e s ul t ed in a m u l t i t u d e of clinical trials testing various t r e a t m e n t regimens. The explosion of the use of c h e m o t h e r a p y in this disease has r e s ul t ed in a waning of enthusiasm for b o t h surgery a n d r a d i o t h e r a p y as p r i m a r y t r e a t m e n t modalities. Early studies d o c u m e n t e d that as single modalities n e i t h e r t r e a t m e n t alone altered survival a n d that only with the addition of c h e m o t h e r a p y to either, alone or in combination, was t here an imp r o v e m e n t in overall survival. However, as the use of c h e m o t h e r a p y has e x p a n d e d , it has b e c o m e a p p a r e n t that although t here is a high rate of t u m o r regression a n d smvival is increased, it rarely translates into long-train survival, especially in patients with bulky disease. Because of th e c u r r e n t failings of c h e m o t h e r a p y the integration of t r e a t m e n t modalities is c ur r e nt l y being r e e xa mi ned. Small cell lung c a n c e r is n o w viewed as a disease w h e r e a multimodality a p p r o a c h is m o s t appropriate. This section will focus on r e c e n t t r e a t m e n t a p p r o a c h e s . Readers are referred to o t h e r sources for extensive review a n d additional b a c k g r o u n d information. S Y S T E M I C THERAPY (CHEMOTHERAPY)

It has long b e e n r e c o g n i z e d that small cell lung cancer, m o r e t h a n o t h e r solid tumors, acts as a systemic disease. Although m a n y patients do n o t p r e s e n t with clinically detectable metastatic deposits, localized t h e r a p y s u c h as surgery or r a d i o t h e r a p y ai m ed at the prim a r y t u m o r is usually ineffective in prolonging survival, a n d the majority of patients rapidly relapse with w i d e s p r e a d metastatic disease even if the p r i m a r y t u m o r remains u n d e r control. U n d e r s t a n d i n g the systemic n a t u r e of small cell lung c a n c e r even at the time of presentation has m a d e systemic t r e a t m e n t the m a i n s t a y of therapy. Small cell lung c a n c e r is sensitive to multiple t h e r a p e u t i c agents. One of the earliest agents u s e d in treating this disease a n d c u r r e n t l y the o n e that is the m o s t c o m m o n l y u s e d is c y c l o p h o s p h a m i d e . This alkylating agent, w h i c h requires metabolic activation in t he liver for activity, has a m a j o r r e s p o n s e rate (complete r e s p o n s e s plus partial responses) of a p p r o x i m a t e l y 40% in patients w i t h o u t previous treatment. 122 Th e majority of these r e s p o n s e s are partial, but approxim a t e l y 5% of patients do achieve a c o m p l e t e remission. DM, December 1989

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N u m e r o u s investigators have s h o w n t h a t small cell l u n g c a n c e r exhibits a n i m p o r t a n t d o s e - r e s p o n s e r e l a t i o n s h i p to c y c l o p h o s p h a m i d e . 123-125 T h e classic r e s p o n s e rate of 40% is p r o b a b l y a c c u r a t e at i n t r a v e n o u s d o s e s b e t w e e n 500 mg/sq m a n d 1.2 m g / s q m given at 3or 4 - w e e k intervals. Since t h e a d v e n t of b o n e m a r r o w t r a n s p l a n t a t i o n to salvage irreversible b o n e m a r r o w toxicity a n d the availability of intensive s u p p o r t w i t h b l o o d p r o d u c t s a n d antibiotics, a n u m b e r of investigators have e x p l o r e d t h e d o s e - r e s p o n s e curve of c y c l o p h o s p h a m i d e . Cun-ently t h e h i g h e s t d o s e s e x p l o r e d have b e e n u p to 200 mg/kg, i.e., a b o u t a t e n f o l d i n c r e a s e over t h e s t a n d a r d dose. At this d o s e (160 to 200 mg/kg) S o u h a m i has r e p o r t e d r e s p o n s e rates of u p to 80% to 85% (60% to 70% c o m p l e t e r e s p o n s e rates) in p a t i e n t s w i t h o u t p r e v i o u s t r e a t m e n t , lza In a d d i t i o n to the i m p r o v e d r e s p o n s e rate to this d r u g as a single agent, toxicity h a s b e e n less t h a n initially p r e d i c t e d . Initially t h e r e w a s c o n c e r n t h a t in this o l d e r p o p u l a t i o n h i g h d o s e s of d r u g s w i t h t h e i r a c c o m p a n y i n g toxicity w o u l d b e p o o r l y tolerated. N u m e r o u s investigators have n o w s h o w n that, in fact, this p a t i e n t p o p u l a t i o n tolerates t r e a t m e n t well a n d b o n e m a r r o w r e c o v e r y is u s u a l l y c o m p l e t e w i t h i n 2 to 3 weeks. In fact several g r o u p s have n o w s h o w n t h a t m a r r o w r e c o v e r y a n d toxicity are i d e n tical w i t h a n d w i t h o u t a u t o l o g o u s t r a n s p l a n t a t i o n . 124-128 Doses of cyc l o p h o s p h a m i d e of u p to 200 mg/kg a p p e a r to n o t be b o n e m a r r o w ablative b u t r e s u l t o n l y in p r o l o n g e d m y e l o s u p p r e s s i o n . With a p p r o p r i a t e s u p p o r t i v e m e a s u r e s s u c h as platelet a n d r e d cell t r a n s f u s i o n s a n d t h e aggressive u s e of antibiotics d u r i n g t h e l e u k o p e n i c p h a s e , c y c l o p h o s p h a m i d e in d o s e s of 150 to 200 mg/kg c a n b e given to this p o p u l a t i o n , w i t h a t r e a t m e n t - r e l a t e d d e a t h rate of less t h a n 5%. However, a l t h o u g h h i g h - d o s e c y c l o p h o s p h a m i d e yields i m p r o v e d res p o n s e rates, it is u n c l e a r w h e t h e r t h e s e r e s p o n s e s will t r a n s l a t e into p r o l o n g e d survival. A n u m b e r of o n g o i n g trials are s t u d y i n g t h e m o s t effective w a y (if any) to integrate h i g h - d o s e c y e l o p h o s p h a m i d e into s t a n d a r d i z e d t r e a t m e n t r e g i m e n s . T h e n i t r o s o u r e a s c m ~ n u s t i n e (BCNU) a n d l o m u s t i n e (CCNU) are also active agents in small cell l u n g c a n c e r . As single a g e n t s t h e i r r e s p o n s e rates are a p p r o x i m a t e l y 20% to 30% .122 However, t h e i r tend e n c y to c a u s e c u m u l a t i v e p r o l o n g e d m y e l o s u p p r e s s i o n w i t h p r o l o n g e d a d m i n i s t r a t i o n has m a d e t h e m less f r e q u e n t l y u s e d agents. B e c a u s e it was t h o u g h t t h a t BCNU's dose-limiting toxicity was m y e l o s u p p r e s s i o n , d o s e e s c a l a t i o n s of u p to 800 to 1,200 m g / m 2 have b e e n a t t e m p t e d . 129-132 Significant n o n m a r r o w toxicity, i n c l u d i n g hep a t i c v e n o - o c c l u s i v e disease, a n d p u l m o n a r y toxicity o c c u r r e d at t h e s e d o s e escalations, w h i c h w e r e o n l y t h r e e to f o u r t i m e s the stand a r d dose. In a d d i t i o n to t h e s e serious n o n - b o n e m a r r o w toxicities it h a s b e e n difficult to d e t e r m i n e w h e t h e r t h e r e is t r u l y a significant d o s e - r e s p o n s e r e l a t i o n s h i p for this a g e n t since in m o s t s t u d i e s of

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h i g h - d o s e BCNU this a g e n t h a s b e e n a d m i n i s t e r e d in c o m b i n a t i o n w i t h o t h e r active agents. M e l p h a l a n , c h l o r a m b u c i l , busulfan, t h i o t e p a , a n d n i t r o g e n m u s t a r d are o t h e r alkylating agents active against small cell l u n g cancer. T h e r e are limited d a t a c o m p a r i n g t h e m to c y c l o p h o s p h a m i d e , a n d it is u n c l e a r w h e t h e r o n e has a n a d v a n t a g e over a n o t h e r . Cross-res i s t a n c e is s h a r e d a m o n g t h e s e a g e n t s (i.e., if a t u m o r a c q u i r e s clinical r e s i s t a n c e to o n e agent, it is u s u a l l y r e s i s t a n t to t h e others). However, S k i p p e r a n d Schabel et al. have s u g g e s t e d a t h e r a p e u t i c synergistic i n t e r a c t i o n w h e n a n u m b e r of alkylating agents are u s e d in c o m b i n a t i o n . 133'134 T h e clinical significance of this finding was exa m i n e d in a SWOG trial c o m p a r i n g a c o m b i n a t i o n of t h r e e alkylating agents, BCNU, t h i o t e p a , a n d c y c l o p h o s p h a m i d e , along w i t h vincristine to a s t a n d a r d d r u g c o m b i n a t i o n c o n s i s t i n g of vincristine, d o x o r u b i c i n (Adriamycin), a n d c y c l o p h o s p h a m i d e in p a t i e n t s w i t h previo u s l y u n t r e a t e d extensive stage small cell l u n g cancer. 135 Both t h e m a j o r a n d m i n o r r e s p o n s e rate as well as smvival w e r e similar in b o t h g r o u p s . H e n c e , it is unlikely t h a t t h e s e a n i m a l studies a n d t h e in vitro cell line findings have clinical r e l e v a n c e in the t r e a t m e n t of small cell l u n g cancel-. T h e v i n c a alkaloids are a g r o u p of n a t u r a l p r o d u c t s w i t h i m p o r t a n t a n t i t u m o r activity in small cell l u n g cancer. Both vincristine a n d vinb]astine have activity as single agents. 122 Vincristine is the a g e n t u s e d in the m a j o r i t y of clinical trials since it h a s m i n o r b o n e m a r r o w toxicity a n d c o m b i n e s well w i t h t h e o t h e r d r u g s u s e d to treat this disease t h a t c a u s e significant m y e l o s u p p r e s s i o n . This agent h a s b e e n s h o w n to b e of value w h e n a d d e d to c o m b i n a t i o n s of o t h e r d r u g s .136 B e c a u s e of m i n o r h e m a t o l o g i c toxicity a n d clear activity t h e vinca alkaloids, e s p e c i a l l y vincristine, are p r o b a b l y as a class the m o s t freq u e n t l y a d m i n i s t e r e d d r u g s in the t r e a t m e n t of small cell l u n g cancer. One m a j o r c o m p l i c a t i o n w i t h t h e s e agents, however, is t h e i r p o tential for severe n e u r o t o x i c i t y . With this class of agents p a t i e n t s w i t h small cell l u n g c a n c e r a p p e a r to have m o r e severe n e u r o t o x i c i t y t h a n o n e w o u l d e x p e c t in a similarly a g e d p a t i e n t p o p u l a t i o n . T h e r e a s o n for this a p p a r e n t i n c r e a s e in sensitivity to t h e vinca alkaloids m a y relate to n e u r o l o g i c a l p a r a n e o p l a s t i c s y n d r o m e s , b o t h clinically e v i d e n t a n d subclinical, w h i c h f r e q u e n t l y a c c o m p a n y small cell l u n g c a n c e r . In addition, this p a t i e n t p o p u l a t i o n is u s u a l l y e l d e r l y (older t h a n 65 years) a n d has a h i s t o r y of b o t h t o b a c c o a n d e t h a n o l abuse. T h e s e factors in a d d i t i o n to a n u n d e r l y i n g p o o r or b o r d e r l i n e n u tritional status p r o b a b l y explain t h e f r e q u e n t o c c u r r e n c e of t h e m o d e r a t e to severe n e u r o p a t h y t h a t o c c u r s after vinca alkaloid treatment. Of t h e available a n t i n e o p l a s t i c antibiotics, d o x o r u b i c i n (Adriamycin) is t h e m a j o r d r u g t h a t has h a d extensive p h a s e II evaluation. DM, D e c e m b e r 1989

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R e s p o n s e r a t e s w i t h s t a n d a r d d o s e s of 40 to 60 m g / s q m e v e r y 3 w e e k s r a n g e f r o m 30% to 40% .122 B e c a u s e of severe d o s e - l i m i t i n g m u c o s a l toxicity at d o s e s ~ 1 0 0 m g / s q m, significant d o s e e s c a l a t i o n s h a v e n o t b e e n a t t e m p t e d . B e c a u s e of t h e m i n i m a l d o s e e s c a l a t i o n s t h a t c a n b e a c h i e v e d it is u n c l e a r w h e t h e r t h e r e is a d o s e - r e s p o n s e c u r v e to A d r i a m y c i n a b o v e t h e s t a n d a r d d o s e u s e d in c o m b i n a t i o n c h e m o t h e r a p y . T h e u s e of c o n t i n u o u s i n f u s i o n o r w e e k l y d o s a g e s as a m e t h o d to a v o i d m u c o s a l (as well as cardiac) toxicity h a s n o t y e t b e e n e v a l u a t e d in this d i s e a s e .

CURRENT THERAPEUTIC APPROACHES Over t h e p a s t 10 y e a r s t h e r e h a v e b e e n a m u l t i t u d e of s t u d i e s rep o r t e d e x a m i n i n g t h e c o m b i n a t i o n c h e m o t h e r a p y in t h e t r e a t m e n t of s m a l l cell l u n g c a n c e r . T h i s s e c t i o n will f o c u s o n s t u d i e s d o n e w i t h i n t h e SWOG o v e r t h e p a s t 10 y e a r s a n d will h i g h l i g h t o t h e r s t u d i e s t h a t h a v e t r i e d to a n s w e r t h e q u e s t o n of t h e u s e f l l l n e s s of specific drugs, t h e i r specific doses, a n d t h e o p t i m a l i n t e g r a t i o n of c h e m o t h e r a p y w i t h o t h e r t h e r a p e u t i c m o d a l i t i e s . T h e SWOG e x p e r i e n c e will b e u s e d as a m o d e l of o u r d e v e l o p m e n t a l t h i n k i n g of t h e t r e a t m e n t of s m a l l cell l u n g c a n c e r . T h e first t h e m e to a d d r e s s in a d i s c u s s i o n of c u r r e n t t h e r a p e u t i c s t r a t e g y is h o w to i m p r o v e t h e r e s u l t s f r o m c h e m o t h e r a p y s i n c e m o s t p a t i e n t s w i t h s m a l l cell ] u n g c a n c e r will die b e c a u s e of w i d e l y disseminated disease.

Maintenance C h e m o t h e r a p y In this c o n t e x t m a i n t e n a n c e c h e m o t h e r a p y m e a n s t h e u s e of rep e a t e d c o u r s e s of t r e a t m e n t , u s u a l l y at l o w e r d r u g d o s e s , after t h e i n d u c t i o n p e r i o d is c o m p l e t e d a n d t h e p a t i e n t h a s a c h i e v e d r e m i s sion. T h e d r u g s a d m i n i s t e r e d are e i t h e r t h e s a m e o n e s u s e d d u r i n g i n d u c t i o n or are a d d i t i o n a l d r u g s n o t u s e d d u r i n g i n d u c t i o n . Over t h e p a s t d e c a d e a n u m b e r of r a n d o m i z e d trials h a v e s t u d i e d t h e u s e of m a i n t e n a n c e c h e m o t h e r a p y in s m a l l cell l u n g c a n c e r . M a u r e r a n d c o w o r k e r s r e p o r t e d , in a s t u d y b y t h e C a n c e r a n d L e u k e m i a G r o u p B (CALGB), t h a t t h e r e w a s s o m e survival b e n e f i t for p a t i e n t s w i t h limited-stage disease who received continued maintenance therapy. 1~ T h e r e w a s , h o w e v e r , n o significant effect o n t i m e to d i s e a s e p r o g r e s s i o n . In 1984, W o o d s r e p o r t e d a n A u s t r a l i a n trial t h a t failed to s h o w a n y b e n e f i t for m a i n t e n a n c e w i t h CAV ( c y c l o p h o s p h a m i d e , A d r i a m y c i n , a n d vincristine) after i n d u c t i o n t h e r a p y w i t h c i s p l a t i n a n d e t o p o s i d e (VP-16). 138 C u l l e n r e c e n t l y r e p o r t e d a British trial t h a t d e m o n s t r a t e d significant b u t m o d e s t effects o n d i s e a s e - f r e e a n d overall survival, c o n f i n e d h o w e v e r , to p a t i e n t s w i t h e x t e n s i v e - s t a g e d i s e a s e . 139 Splinter a n d McVie c o m p a r e CAE ( c y c l o p h o s p h a m i d e , Adr i a m y c i n , a n d e t o p o s i d e [VP-16]) for 5 vs. 12 c o u r s e s in a s t u d y for 804

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the EORTC. T h e m o s t r e c e n t u p d a t e of this s t u d y fails to d e m o n strate a n y significant d i f f e r e n c e b e t w e e n 5 a n d 12 c o u r s e s (personal c o m m u n i c a t i o n , 1987)) 4° T h e r e r e m a i n s n o c o n s i s t e n t e v i d e n c e of benefit f r o m m a i n t e n a n c e c h e m o t h e r a p y . T o d a y , it is g e n e r a l l y n o t a p a r t of m o s t treatm e n t "programs.

The Use of Alternating Drug Regimens T h e t h e o r e t i c a l u s e of a l t e r n a t i n g n o n - c r o s s - r e s i s t a n t d r u g c o m b i n a t i o n s was p u t f o r t h b y Goldie a n d C o l d m a n . 141 This h y p o t h e s i s p r o j e c t s t h a t t h e d e v e l o p m e n t of d r u g - r e s i s t a n t t u m o r cells can b e m i n i m i z e d b y t h e r a p i d alteration of equally effective n o n - c r o s s - r e = sistant c o m b i n a t i o n s of drugs. By p r e v e n t i n g the e m e r g e n c e of drugr e s i s t a n t c l o n e s b o t h r e s p o n s e rates a n d t h e p e r c e n t a g e of p a t i e n t s achieving p r o l o n g e d r e m i s s i o n s w o u l d b e i n c r e a s e d . Small cell l u n g c a n c e r has b e e n a p o p u l a r t u m o r type to test this c o n c e p t b e c a u s e of the large n u m b e r of active d r u g s a n d d r u g c o m b i n a t i o n s . However, t h e issue of t r u e n o n - c r o s s - r e s i s t a n c e of m a n y c o m b i n a t i o n s has n e v e r b e e n fully d o c u m e n t e d . T h e m o s t p o p u l a r r e g i m e n t e s t e d as a n "alternative" to t h e c o m m o n l y u s e d VAC (vincristine, Adriam y c i n , a n d c y c l o p h o s p h a m i d e ) is cisplatin p l u s VP-16. Several rand o m i z e d trials have t e s t e d this c o n c e p t of alteration of t w o - d r u g c o m b i n a t i o n s w i t h VP-16/cis-diamine d i c h l o r p l a t i n u m (CDDP)as o n e of t h e c o m b i n a t i o n s . Feld et al. r e p o r t e d t h e results of a C a n a d i a n trial in limited-stage disease t h a t d i d not s h o w a n a d v a n t a g e for CAV a l t e r n a t e d w i t h cisplatin/VP-16 as c o m p a r e d w i t h t h e s i m p l e a d m i n istration of r e p e a t e d c o u r s e s of CAV a l o n e ) 42 G o o d m a n a n d Blasko r e p o r t e d a similar, negative result last yem- in a s t u d y f r o m t h e SWOG in w h i c h a l t e r a t i o n of cisplatin-VP-16 w i t h CAV w a s n o t s u p e r i o r to r e p e a t e d a d m i n i s t r a t i o n of a c o m b i n a t i o n of CAV p l u s e t o p o s i d e (EVAC) .143 Evans r e p o r t e d a C a n a d i a n trial in 1986 w i t h a d e s i g n v e r y similar to t h a t r e p o r t e d b y Feld a n d associates b u t e x a m i n e d p a t i e n t s w i t h e x t e n s i v e - r a t h e r t h a n limited-stage disease: t h e y o b s e r v e d a significant b e n e f i t for the a l t e r n a t i n g a p p r o a c h o n disease-free b u t not o n overall survival. T M Finally, Boni et al. p r e s e n t e d t h e results of a rand o m i z e d trial that actually d e m o n s t r a t e d s u p e r i o r i t y for the rep e a t e d a d m i n i s t r a t i o n of cisplatin/VP-16 w h e n c o m p a r e d w i t h a p r o g r a m in w h i c h this r e g i m e n was r o t a t e d w i t h p r o g r a m s e m p l o y i n g o t h e r d r u g s ) 45 T h e r e is n o c o n s i s t e n t e v i d e n c e of benefit to d a t e f r o m t h e u s e of a l t e r n a t i n g d r u g c o m b i n a t i o n s . However, a d d i t i o n a l s t u d i e s a p p e a r w a n ' a n t e d since it is possible that, b y altering t h e timing of c h e s t i r r a d i a t i o n in limited d i s e a s e or t h e s e q u e n c e a n d t i m i n g of the c o m b i n a t i o n s e m p l o y e d , b e t t e r results m a y y e t b e a c h i e v e d w i t h the regi m e n s p r e s e n t l y available. DM, D e c e m b e r 1989

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Anticoagulant and Antiplatelet Drugs A n u m b e r of r a n d o m i z e d trials h a v e s t u d i e d t h e u s e of a n t i c o a g u l a n t o r a n t i p l a t e l e t d r u g s a d d e d to " c y t o t o x i c " c h e m o t h e r a p y . T h e s e s t u d i e s are b a s e d o n t h e h y p o t h e s i s t h a t c o n c u r r e n t inhibit i o n of t h e m e t a s t a t i c p r o c e s s m i g h t r e s u l t a n d b e s y n e r g i s t i c w i t h t h e effects of c h e m o t h e r a p y . T h e r e w a s a n early, small negative trial r e p o r t e d b y S t a n f o r d 146 f r o m Britain a n d a n early, s m a l l positive trial b y Z a c h a r s k i a n d c o l l e a g u e s 147 f r o m t h e U n i t e d States, b o t h involving t h e a d d i t i o n of w a r f a r i n ( C o u m a d i n ) to s t a n d a r d c h e m o t h e r a p y . T h e trial of Z a c h a r s k i et al. l e d to a large, c o o p e r a t i v e g r o u p s t u d y in t h e U n i t e d States t h a t w a s r e p o r t e d b y C h a h i n i a n et al. 148 R e c e n t l y u p d a t e d r e s u l t s of t h a t trial l e d to t h e s a m e c o n c l u s i o n as r e p o r t e d t h e n : t h a t t h e a d d i t i o n of w a r f a r i n to a c o m b i n a t i o n called MACC ( n l e t h o t r e x a t e , A d r i a m y c i n , CCNU, a n d c y c l o p h o s p h a m i d e ) r e s u l t e d in h i g h e r r e s p o n s e r a t e s a n d a n early effect o n survival in p a t i e n t s w i t h e x t e n s i v e - s t a g e d i s e a s e . By 1 y e a r , this survival effect h a d disa p p e a r e d . Dr. C h a h i n i a n ' s g r o u p , t h e CALGB, is n o w e x p l o r i n g t h e a d d i t i o n of w a r f a r i n in a r a n d o m i z e d trial for p a t i e n t s w i t h l i m i t e d stage d i s e a s e . Finally, L e b e a u et al. 149 f r o m F r a n c e r e p o r t e d last y e a r a r a n d o m i z e d trial in w h i c h CCA ( c y c l o p h o s p h a m i d e , CCNU, a n d A d r i a m y c i n ) p l u s VP-16 w a s t e s t e d w i t h or w i t h o u t t h e a d d i t i o n of a s p i r i n as a n a n t i p l a t e l e t drug. No b e n e f i t f r o m t h e u s e of a s p i r i n could be demonstrated. It s e e m s t e n t a t i v e l y a p p r o p r i a t e to c o n c l u d e that, in t h e a b s e n c e of a c o n s i s t e n t , p e r s i s t e n t survival effect, t h e toxicity of w a r f a r i n addition is n o t w a r r a n t e d . (There h a v e b e e n h e m o r r h a g i c e p i s o d e s , occ a s i o n a l l y fatal, r e p o r t e d in "all series.) A s p i r i n a d d i t i o n a p p e a r s to b e of n o benefit. I n t e r e s t is n o w shifting to t h e u s e of o t h e r n o n c y t o toxic " a d j u v a n t s " w i t h a different r a t i o n a l e s u c h as p h o s p h o d i e s t e r ase i n h i b i t o r s a n d c a l c i u m a n t a g o n i s t s .

New Agents and Combination In r e v i e w i n g t h e t o p i c of n e w a g e n t s let u s c o n s i d e r t h e r a n d o m i z e d trials e v a l u a t i n g t h e i n c o r p o r a t i o n of VP-16 (the m o s t active n e w a g e n t i d e n t i f i e d in this d i s e a s e in t h e p a s t d e c a d e ) into t h e s t a n d a r d r e g i m e n s . A trial r e p o r t e d b y M e s s e i h et al.150 s h o w e d a h i g h e r res p o n s e rate b u t n o survival benefit. I n a trial r e p o r t e d b y L o w e n b r a u n a n d a s s o c i a t e s 151 for t h e S o u t h e a s t e r n G r o u p (United States), CAV w a s i n t e n t i o n a l l y given at e q u i t o x i c d o s e s to c o m p a r e t h e c o m b i n a t i o n of CAV p l u s VP-16; again, n o b e n e f i t w a s s e e n w h e n VP-16 was added. T h e r e h a v e also b e e n a n u m b e r of r a n d o m i z e d trials t h a t involve n e w d r u g c o m b i n a t i o n s . T h e SWOG (Livingston) d e s i g n e d a r e g i m e n of c o m b i n e d alkylating a g e n t s t h a t w a s b a s e d o n p e r s u a s i v e p r e c l i n ical e v i d e n c e of s y n e r g i s m for s u c h a n a p p r o a c h in a v a r i e t y of anim a l m o d e l s y s t e m s . H o w e v e r , this BTOC (BCNU, vineristine, t h i o t e p a , 806

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c y c l o p h o s p h a m i d e ) r e gi m en s h o w e d no advantage over s t a n d a r d CAV. T M Alberto e t a ] . 152 from Switzerland was unable to d e m o n s t r a t e a benefit from seven drugs given at once as c o m p a r e d with a m o r e s t a n d a r d f o u r - d r u g program. Recently, O'Bryan 15a in the SWOG, looking at the c o m b i n a t i o n of cisplatin-VP-16 in the salvage setting (after patients h a d d e v e l o p e d disease progression), was able to s h o w a statistically significant survival benefit from this regimen when, comp a r e d in a r a n d o m i z e d fashion to BTOC, in fully a m b u l a t o r y patients. Th es e results also a p p e a r s upe r i or to any of o u r previous results with "salvage" c h e m o t h e r a p y in the SWOG. In conclusion, the simple addition of an active n e w agent (VP-16) has not r e s u l t e d in a useful overall impact on survival. However, the c o m b i n a t i o n of eisplatin plus VP-16 has b e e n identified as the first "salvage" r eg imen with effects on survival, t hus implying a clinically m e a s u r a b l e degree of n o n - c r o s s - r e s i s t a n c e . Of the available n e w e r agents, carboplatin is u n d e r evaluation as a potentially m o r e efficacious agent t h a n cisplatinY 4'155 Early results s h o w similar r e s p o n s e rates for cisplatin alone or in c o m b i n a t i o n with a different toxicity s p e c i m e n (more hematologic, less renal). After m a n y years of use, primarily in pediatric tumor, a n o t h e r p o d o p h y l l o t o x i n derivative, teniposide (VM-26), has recent l y b e e n s t u d i e d in adults with small cell lung cancer. In previously unt r e a t e d patients, this agent has s h o w n an impressive r e s p o n s e rate. 156 Ultimately VM-26 m a y prove to be an even m o r e active agent t h a n VP-16 is. Investigation of com bi na t i ons utilizing VM-26 as well as d o se escalation studies a p p e a r w ar r ant ed. CDDP a n d a n u m b e r of the n e w e r synthetic p l a t i n u m analogues (carboplatin, iproplatin) have also s h o w n activity in small cell lung cancer. Although initial p h a s e II studies of the p a r e n t drug, CDDP, in previously treated patients s h o w e d u n im pr es s i ve activity, 157 a p h a s e II st udy of carboplatin in previously u n t r e a t e d patients d o c u m e n t e d clinically relevant activity. 158 This p o int bears stressing since m a n y drugs p r o v e d inactive in small cell lung c a n c e r have b e e n t e s t ed only in patients relapsing after t r e a t m e n t with multiple agents. Small cell lung c a n c e r like m a n y o t h e r t u m o r s can acquire multiagent drug resistance. W h e n evaluating p h a s e I-II studies one n e e d s to carefully c o n s i d e r the p a tien t p o p u lati on, previously u n t r e a t e d or extensive pri or treatgiant. Both of the n e w e r p l a t i n u m analogues c a r b o p l a t i n u m a n d iproplatin have s h o w n activity in small cell lung cancer. It is u n c l e a r at this time w h e t h e r their t h e r a p e u t i c ratio is s u p e r i o r to that of the p a r e n t

cis-platinum. Dose Intensification A n o t h e r h y p o t h e s i s e x a m i n e d has b e e n dose escalation. This is b a s e d on the " d o s e - r e s p o n s e " hypothesis, w h i c h can be stated simDM, D e c e m b e r 1989

807

ply as "more is better," within the limits of patient tolerance. A small, early trial r e p o r t e d by C o h e n et al. 159 from the NCI (United States) ind i c a t ed an advantage for the escalation of drug doses in the CMC c o m b i n a t i o n ( c y c l o p h o s p h a m i d e , methotrexate, CCNU). This led to a large, confirmatory trial by the Eastern Cooperative Oncology Group that was r e p o r t e d by Vogl a n d Mheta 16° in w h i c h a statistically significant i mp act o n survival in patients with limited disease was d e m o n strated from escalation of the agent Cytoxan (cyclophosphamide). A s e c o n d a p p r o a c h to dose escalation involves its use after the i n d u c tion period, or "late intensification". In 1984 by using a late intensification p r o g r a m identical to that u s e d for induction, the S W O G 161 r e p o r t e d a survival benefit for late intensification in patients with extensive-stage disease w h o h a d achieved a c o m p l e t e remission with their initial therapy. T he S o u t h e a s t e r n Group r e p o r t e d significant survival benefit from late intensification in patients with limitedstage disease w h e n t h e y u s e d a different r e gim en (cisplatin-VP-16) from that e n l p l o y e d for i n d u c t i o n (CAV). 162'163 All of t hese r a n d o m ized trials involved relatively modest i n c r e m e n t s in drug dosage, possible on an o u t p a t i e n t t h e r a p y basis. A f u r t h e r extension of the d o s e - r e s p o n s e c o n c e p t is exemplified in certain n o n r a n d o m i z e d , p h a s e II trials in w h i c h Cytoxan alone was given in doses that n e c e s s i t a t e d an inpatient approach, b o t h for d r u g administration a n d for s u b s e q u e n t supportive c a r e . 164'165 Res p o n s e rates have r a n g e d from 70% to 88%, with c o m p l e t e r e s p o n s e rates r e p o r t e d by Souham i (1985) from England of 44% to 50% with the highest doses. *za It s h o u l d be n o t e d that autologous b o n e marro w transfusion s u p por t , although it was u s e d in one of these trials, is n o w k n o w n to be u n n e c e s s a r y for full a n d rapid hem at ol ogi c recovery after doses as high as 200 mg/kg given over a p e r i o d of 4 days. In 1986, the Vanderbilt g r o u p r e p o r t e d an a p p r o a c h that probabl y r e p r e s e n t s the ultimate possible intensity for an i n d u c t i o n c h e m o t h e r a p y r eg imen without t he use of autologous m a r r o w s u p p o r t J 66 T h e y gave Cytoxan at 50 mg/kg/day for 2 days a n d VP-16 at 400 rag/ sq m / d a y for 3 days. After two cycles of this "maximal" induction, patients received f o ur cycles of " s t a nda r d" CAV. This st udy was confined to patients with extensive-stage disease, and the r e s p o n s e rates are the highest y et r e p o r t e d in that setting: 16 of 18 r e s p o n d e d , with 12 of 18 c o m p l e t e r e s pons e s . However, the m e d i a n d u r a t i o n of the r e s p o n s e s was only 8 m o n t h s . This r e p r e s e n t s a very m o d e s t imp r o v e m e n t over the e x p e c t e d results with m o r e s t a n d a r d doses and suggests that simply intensifying i n d u c t i o n will not lead to a m aj or i m p r o v e m e n t in the o u t c o m e of patients with extensive disease. One may, however, gain a substantial advantage from the use of ultrahigh-dose "late intensification," especially in the setting of limited-stage disease. An interesting trial along these lines was r e p o r t e d by H u mb let a n d coworkers. 1Gr After initial i n d u c t i o n with s t a n d a r d 808

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d o s e s of CAV p l u s m e t h o t r e x a t e f o l l o w e d b y cisplatin-VP-16, res p o n d i n g p a t i e n t s w e r e r a n d o m i z e d to a d d i t i o n a l t h e r a p y at stand a r d d o s e s o r to t h e following late intensification p r o g r a m : Cytoxan, 1.5 m g / s q m / d a y for 4 days, f o l l o w e d b y the infusion of stored, autologous bone marrow. T h e , results of that trial d e m o n s t r a t e d t h a t disease-free survival, m e a s u r e d f r o m the t i m e of randomization, was s u p e r i o r for late intensification. T h e overall survival in p a t i e n t s w i t h limited-stage disease was also s u p e r i o r for late i n t e n s i f i c a t i o n b u t did n o t r e a c h statistical significance. Impressively, 7 of 11 l i m i t e d - d i s e a s e partial r e s p o n d e r s p r i o r to r a n d o m i z a t i o n c o n v e r t e d to c o m p l e t e r e s p o n s e s after intensification, a r e s u l t a l m o s t u n i q u e for t h e use of d e l a y e d c h e m o t h e r a p y . However, m o s t of the p a t i e n t s e n t e r e d in this trial later r e l a p s e d , e s p e c i a l l y at t h e p r i m a r y t u m o r site. It is i m p o r t a n t to n o t e that no local t h e r a p y s u c h as r a d i a t i o n o r s u r g e r y was e m p l o y e d in t h e trial. T h e s e c o n c l u s i o n s a b o u t d o s e r e s p o n s e s e e m tentatively justified: (1) beneficial effects are evident for c y c l o p h o s p h a m i d e at m o d e r a t e i n c r e m e n t s in l i m i t e d - s t a g e disease; (2) "late intensification" is effective a n d will b e c o m e a c o m m o n a p p r o a c h - - i t is u n c e r t a i n w h e t h e r a d m i n i s t r a t i o n of a " n o n - c r o s s - r e s i s t a n t " r e g i m e n is better; a n d (3) a p p r o a c h e s r e q u i r i n g i n p a t i e n t s u p p o r t i v e care, w i t h or w i t h o u t inf u s i o n of the a u t o l o g o u s m a r r o w , r e m a i n e x p e r i m e n t a l . C o m b i n e d Modalities T h e s e c o n d t h e m e t h a t i n f l u e n c e s c u r r e n t t h e r a p e u t i c strategy in this disease is t h e u s e of t h e c o m b i n e d modalities. We c a n first review t h e results of r a n d o m i z e d trials in w h i c h c h e m o t h e r a p y a l o n e was c o m p a r e d w i t h c h e m o t h e r a p y w i t h t h e a d d i t i o n of c h e s t irrad i a t i o n for p a t i e n t s w i t h limited disease. In a trial r e p o r t e d b y Perez 16~ for the S o u t h e a s t e r n Group, a tripartite, "split" c o u r s e of c h e s b i r r a d i a t i o n " s a n d w i c h e d " b e t w e e n cycles of c h e m o t h e r a p y p r o d u c e d a significant i m p a c t o n disease-free sureival b u t a m a r g i n a l effect o n overall smvival. T h e CALGB c o m p a r e d CEV (Cytoxan, etoposide, a n d vincristine) a l o n e to CEV f o l l o w e d b y irradiation a n d to t h e simultaneous c o m b i n a t i o n of CEV a n d irradiation. ~G9In 1984, prel i m i n a r y analysis d i d n o t s h o w a difference, b u t t h e final analysis of this s t u d y d o s e d e m o n s t r a t e s a survival a d v a n t a g e for the c o m b i n e d m o d a l i t y a p p r o a c h e s o v e r c h e m o t h e r a p y alone. S o u h a m i 17° failed to d e m o n s t r a t e s u c h an a d v a n t a g e for a sequential, c o m b i n e d m o d a l i t y a p p r o a c h vs. c h e m o t h e r a p y a l o n e w i t h AV-CM (Adriamycin-vincrist i n e / C y t o x a n - m e t h o t r e x a t e ) . Initially, Greco a n d colleagues 162 c o u l d n o t d e m o n s t r a t e a n effect f r o m t h e c o n c u r r e n t a d d i t i o n of a short, s p l i t - c o u r s e r a d i o t h e r a p y p r o g r a m to CAV i n d u c t i o n . However, t h e m o s t r e c e n t available f o l l o w - u p o n this trial n o w a p p e a r s to d e m o n s t r a t e a survival effect f r o m the c o m b i n e d a p p r o a c h (Greco A, perDM, D e c e l n b e r 1989

809

s o n a l c o m m u n i c a t i o n , 1987). Finally, Kies et al. 171 f r o m the SWOG c o m p a r e d CAV a l o n e w i t h CAV f o l l o w e d b y c h e s t i r r a d i a t i o n in p a t i e n t s w h o h a d a c h i e v e d a n initial c o m p l e t e r e s p o n s e to i n d u c t i o n c h e m o t h e r a p y . T h e SWOG c o u l d d e m o n s t r a t e n o b e n e f i c i a l effect f r o m sequenced c o m b i n e d m o d a l i t i e s . T h i s l e d u s to a b a n d o n t h e " t r a d i t i o n a l " s e q u e n t i a l a p p r o a c h in t h e SWOG. T h e r e s u l t s r e p o r t e d b y G l a t s t e i n a n d c o l l e a g u e s 172 w i t h concurrent c o m b i n e d m o d a l i t i e s s t i m u l a t e d u s to initiate a g r o u p w i d e , p h a s e II trial, r e p o r t e d elsew h e r e . 173 P a t i e n t s w i t h l i m i t e d d i s e a s e r e c e i v e d c o n c u r r e n t c i s p l a t i n / VP-16 p l u s v i n c r i s t i n e a n d c o n t i n u o u s , f r a c t i o n e d c h e s t i r r a d i a t i o n to a total d o s e of 4,500 cGy in 5 w e e k s (180 cGy p e r fraction) as well as elective, w h o l e - b r a i n i r r a d i a t i o n . After 3 i n d u c t i o n cycles, chemo-t h e r a p y w a s c o n t i n u e d w i t h o t h e r active d r u g s a c c o r d i n g to a n alt e r n a t i n g s c h e m e . T h e r e s u l t s of t h a t trial, in t h e m o s t r e c e n t a c t u arial p r o j e c t i o n , d e m o n s t r a t e d 40% of all p a t i e n t s entered to b e alive at 2 y e a r s a n d s h o w a n a p p a r e n t survival p l a t e a u at 35%. T h i s exc e e d s t h e r e s u l t s of o u r t w o p r e v i o u s s t u d i e s , w i t h 20% survival at 2 y e a r s a n d a p l a t e a u at 10%. To s u m m a r i z e , of six r e c e n t r a n d o m i z e d trials, f o u r d e m o n s t r a t e d b e n e f i t f r o m a d d e d c h e s t i r r a d i a t i o n , a n d this i n c l u d e s t h r e e of t h r e e with concurrent chemoradiotherapy. In addition, the most recently c o m p l e t e d SWOG trial, a l t h o u g h n o n r a n d o m i z e d , involves large n u m b e r s of p a t i e n t s a n d s e e m s to s h o w a survival a d v a n t a g e for t h e c o n c u r r e n t u s e of c h e s t a n d b r a i n i r r a d i a t i o n w i t h c i s p l a t i n a n d VP16. W h a t a b o u t the u s e of s u r g e r y in a c o m b i n e d m o d a l i t y a p p r o a c h ? F o r p a t i e n t s w i t h T N M stages I a n d II s m a l l cell l u n g c a n c e r , u n c o n t r o l l e d d a t a s u g g e s t t h a t initial surgical r e s e c t i o n f o l l o w e d b y c h e m o t h e r a p y w i t h or w i t h o u t b r a i n i r r a d i a t i o n p r o d u c e s r e s u l t s s u p e r i o r to a " h i s t o r i c a l c o n t r o l " of s u r g e r y o r r a d i a t i o n alone. U n f o r t u n a t e l y , this p r e s e n t a t i o n is rare; at m o s t , o n l y 5% to 10% of p a t i e n t s w i t h s m a l l cell c a r c i n o m a will p r e s e n t w i t h stage I or II disease. T h u s , a n i n t e r n a t i o n a l c o n t r o l l e d trial will b e n e c e s s a r y to a n s w e r t h e r a p e u t i c q u e s t i o n s in t h e s e p a t i e n t s . T h e role of a d j u n c t i v e c h e s t i r r a d i a t i o n in t h e s e p a t i e n t s d e s e r v e s e v a l u a t i o n . F o r p a t i e n t s w i t h stage III dise a s e (limited), t h e s e o b s e r v a t i o n s a b o u t t h e role of c y t o r e d u c t i v e surg e r y are p e r t i n e n t : (1) o n e r a n d o m i z e d trial of its value, s p o n s o r e d b y t h e L u n g C a n c e r S t u d y G r o u p , is in p r o g r e s s ; (2) uncontrolled e x p e r i e n c e s u g g e s t s little or n o b e n e f i t to p a t i e n t s w i t h Nz a n d p o s sible b e n e f i t for s t a g e T3NoN0 at p r e s e n t a t i o n ; a n d (3) n o n - s m a l l cell h i s t o l o g y a n d benign h i s t o l o g y are c o m m o n f i n d i n g s in c h e m o t h e r a p y r e s p o n d e r s s u b j e c t e d to r e s e c t i o n s ) ~4'175 S o m e n e w d e v e l o p m e n t s are w o r t h y of m e n t i o n . T h e p r o s p e c t i v e u s e of in vitro p r e d i c t i v e a s s a y to select a g e n t s for initial or s u b s e q u e n t t h e r a p y is a f o c u s of c o n t i n u e d i n v e s t i g a t i o n in s e l e c t e d instit u t i o n s . 1~4'175 C h e m o p o t e n t i a t i o n ( " m a k i n g old d r u g s b e t t e r " ) , i s ,a 810

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t o p i c of g r e a t c u r r e n t i n t e r e s t a n d m a y involve electron-affinic " s e n sitizers" s u c h as SR-2508, m o d u l a t o r s of d r u g r e s i s t a n c e s u c h as calm o d u l i n a n t a g o n i s t s , or t h e u s e of a n e w a n d p o t e n t i a l l y b e t t e r s c h e d u l e s u c h as t h e d i v i d e d - d o s e c i s p l a t i n r e p o r t e d b y o u r G e r m a n c o l l e a g u e s . 176 T h e s e i n v e s t i g a t o r s r e c e n t l y r e p o r t e d the r e s u l t s of a s c h e d u l e in w h i c h c i s p l a t i n w a s given at 50 m g / s q m o n d a y s 1 a n d 7 a n d VP-16 at 170 m g / s q m o n d a y s 3, 4, a n d 5 every 3 to 4 w e e k s for a total of f o u r to six i n d u c t i o n cycles. Complete r e s p o n s e s to this p r o g r a m w e r e r e p o r t e d in 57%, (27/47) i n c l u d i n g 51% of p a t i e n t s w i t h e x t e n s i v e - s t a g e d i s e a s e (19/37), w i t h m e d i a n r e m i s s i o n d u r a t i o n s of a y e a r . This s c h e d u l e was, h o w e v e r , a s s o c i a t e d w i t h a h i g h i n c i d e n c e of p o t e n t i a l l y l i f e - t h r e a t e n i n g m y e l o s u p p r e s s i o n (25%) t h a t w a s p r i m a r i l y r e l a t e d to l e u k o p e n i a . T h e u s e of biologics h a s b e e n a t o p i c u n d e r i n t e n s i v e investigation o v e r t h e p a s t f e w y e a r s . U n f o r t u n a t e l y t h e r e is little p u b l i s h e d o n t h e u s e of t h e s e a g e n t s in s m a l l cell l u n g c a n c e r . As in t h e c a s e of m a n y t u m o r t y p e s t h e u s e of t h e biologics r e m a i n s o n e of i n t e n s e p o t e n t i a l a n d interest. M o n o c l o n a l a n t i b o d i e s h a v e m a n y p o t e n t i a l u s e s for t h e r a p y , e i t h e r a l o n e as in t h e c u r r e n t NCI (United States) trial of b o m b e s i n , or c o n j u g a t e d to p o t e n t i a l " w a r h e a d s " s u c h as i m m u n o toxins, r a d i o e m i t t e r s , o r c h e m o t h e r a p y d r u g s f f 7 Finally, t h e biologic r e s p o n s e m o d i f i e r s are of interest. F o r e x a m p l e , in vitro e x p o s u r e of c u l t u r e d s m a l l cell l u n g c a n c e r cells to i n t e r f e r o n s m a y m o d u l a t e a n t i g e n i c i t y a n d p o t e n t i a l l y r e s u l t in the a u g m e n t a t i o n of a h o s t i m m u n e r e s p o n s e , 178 a n d interleukin-2, a l o n e or c o m b i n e d w i t h inf u s e d effector ceils, m a y b e d i r e c t l y c y t o t o x i c S 9 CLINICAL M A N A G E M E N T

T h e m a n a g e m e n t of a p a t i e n t w i t h s m a l l cell l u n g c a n c e r is a p r o cess t h a t is u n d e r g o i n g c o n t i n u a l c h a n g e a n d r e f i n e m e n t . Currently, t h e r e is n o t h e r a p y t h a t is c u r a t i v e for t h e m a j o r i t y of p a t i e n t s . H o w ever, g a i n s h a v e b e e n m a d e in a c h i e v i n g m a j o r t u m o r r e g r e s s i o n s , a n d t h e m a j o r i t y of p a t i e n t s h a v e t h e n a t u r a l h i s t o r y of t h e i r d i s e a s e g r e a t l y m o d i f i e d b y t r e a t m e n t . Single i n s t i t u t i o n s a n d t h e c o o p e r a tive g r o u p s c o n t i n u e to e x p l o r e n e w t h e r a p e u t i c m o d a l i t i e s in a n effort to c o n t i n u e t h e t h e r a p e u t i c a d v a n c e s m a d e o v e r t h e last 10 y e a r s . To f u r t h e r the r e s u l t s of clinical r e s e a r c h , p h y s i c i a n s s h o u l d c o n s i d e r s u g g e s t i n g to t h e i r p a t i e n t s t h a t t h e y p a r t i c i p a t e in o n g o i n g clinical trials d e s i g n e d to a n s w e r q u e s t i o n s a b o u t t h e o p t i m a l m a n a g e m e n t of this disease. H o w e v e r , w i t h o u r c u r r e n t k n o w l e d g e , a n u m b e r of g e n e r a l i z a t i o n s c a n b e m a d e a b o u t t h e m a n a g e m e n t of this d i s e a s e . W h e n a p p r o a c h i n g a p a t i e n t w i t h n e w l y d i a g n o s e d s m a l l cell l u n g c a n c e r t h e goal is a t h e r a p e u t i c p l a n t h a t will alleviate s y m p t o m s a n d i n c r e a s e survival (with a c h a n c e of p r o l o n g e d d i s e a s e - f r e e surDM, D e c e m b e r 1989

811

vival) at a c o s t of m i n i m a l toxicity. An a d d i t i o n a l goal is to e v a l u a t e t h e p a t i e n t so t h a t o n e is able to give t h e p a t i e n t a n d t h e i r f a m i l y a r e a s o n a b l e e s t i m a t e of p r o g n o s i s . T h e initial s t e p in this e v a l u a t i o n s h o u l d b e a t h o r o u g h r e v i e w of the p a t h o l o g y r e p o r t . If t h e s p e c i m e n is a d e q u a t e a n d t h e p a t h o l o g i s t is c o n f i d e n t of t h e diagnosis, a rev i e w of t h e p a t h o l o g i c a l s p e c i m e n is p r o b a b l y n o t w a r r a n t e d . H o w ever, if the s p e c i m e n is i n a d e q u a t e or t h e d i a g n o s i s u n c l e a r , e s p e cially o n a s m a l l b r o n c h i a l b i o p s y s p e c i m e n or a s p u t u m cytological e v a l u a t i o n , a p a t h o l o g i c a l r e v i e w of this s p e c i m e n or a r e p e a t b i o p s y should be considered. This point should be emphasized since a c h a n g e in t h e h i s t o l o g i c a l d i a g n o s i s will d r a m a t i c a l l y alter b o t h t h e therapeutic approach and prognosis. Since survival a n d c h o i c e of o p t i m a l t r e a t m e n t m o d a l i t i e s are rel a t e d to t h e e x t e n t of d i s e a s e a n d to s o m e d e g r e e t h e sites of m e t a s tases, staging b e c o m e s t h e s e c o n d s t e p after p a t h o l o g i c a l c o n f i r m a t i o n of t h e d i a g n o s i s . A t h o r o u g h p h y s i c a l e x a m i n a t i o n i n c l u d i n g n e u r o l o g i c a l e v a l u a t i o n c a n i n d i c a t e e v i d e n c e of p o s s i b l e m e t a s t a t i c i n v o l v e m e n t ) 8° If a t h o r o u g h n e u r o l o g i c a l e x a m i n a t i o n h a s n o r m a l findings, it is less likely t h a t t h e s e are large p a r e n c h y m a l b r a i n m e t a s t a s e s . H o w e v e r , a b r a i n CT s c a n is u s u a l l y w a r r a n t e d s i n c e t h e i n c i d e n c e of a s y m p t o m a t i c b r a i n m e t a s t a s e s d e t e c t a b l e b y r a d i o n u clide s c a n s is a p p r o x i m a t e l y 4% to 10% .181'~sz T h e p r e s e n c e o r abs e n c e of s m a l l - v o f u m e i n t r a - a b d o m i n a l d i s e a s e c a n n o t b e easily evalu a t e d b y p h y s i c a l e x a m i n a t i o n . B e c a u s e of this, i n t r a - a b d o m i n a l e v a l u a t i o n u s u a l l y i n c l u d e s s c r e e n i n g liver f u n c t i o n s t u d i e s a n d a n a b d o m i n a l CT scan. It is d e b a t a b l e w h e t h e r a n a b d o m i n a l CT s c a n is n e c e s s a r y in a n a s y m p t o m a t i c p a t i e n t w i t h n o r m a l liver c h e m i s tries s i n c e a l t h o u g h t h e f i n d i n g of s m a l l - v o l u m e i n t r a - a b d o m i n a l dise a s e m a y u p g r a d e a p a t i e n t to " e x t e n s i v e d i s e a s e ''181'lSa-ls5 it m a y n o t i n d i c a t e a p r o g n o s i s s i m i l a r to o t h e r p a t i e n t s w i t h b u l k y " e x t e n s i v e d i s e a s e . " In e v a l u a t i n g t h e liver if e i t h e r CT s c a n o r liver f u n c t i o n t e s t s are s u g g e s t i v e of m e t a s t a s e s b u t t h e y are n o t c o n f i r m a t o r y , a p e r c u t a n e o u s liver b i o p s y is w a r r a n t e d s i n c e t h e p r e s e n c e of liver m e t a s t a s e s will n o t o n l y i n f l u e n c e p r o g n o s i s b u t will also affect t h e t h e r a p e u t i c a p p r o a c h . Since b o n e m a r r o w i n v o l v e m e n t is a l m o s t alw a y s a s y m p t o m a t i c a n d s i n c e 4% to 10% of p a t i e n t s h a v e t h e b o n e m a r r o w as t h e o n l y site of m e t a s t a t i c disease, u n i l a t e r a l b o n e m a r r o w b i o p s y a n d a s p i r a t i o n is w a r r a n t e d o n all p a t i e n t s . In p a t i e n t s w i t h o b v i o u s m e t a s t a t i c d i s e a s e t h e v a l u e of a b o n e m a r r o w a s s e s s m e n t is q u e s t i o n a b l e . A l t h o u g h it c a n give a d d i t i o n a l e v i d e n c e of t h e e x t e n t of d i s e a s e a n d is a n e a s y site for r e p e a t p a t h o l o g i c a l confirm a t i o n of r e m i s s i o n status, h o w e v e r , w i t h t h e p r e s e n c e of k n o w n m e t a s t a s i s , p o s i t i v e b o n e m a r r o w i n v o l v e m e n t will n o t n e c e s s a r i l y c h a n g e t h e p r o g n o s i s or t r e a t m e n t p l a n . B o n e s c a n s are sensitive i n d i c a t o r s of c o r t i c a l b o n e i n v o l v e m e n t a n d f r e q u e n t l y p i c k u p a s y m p t o m a t i c i n v o l v e m e n t . Skeletal s u r v e y s are u s u a l l y n o t w a r 812

DM, D e c e m b e r

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r a n t e d u n l e s s s y m p t o m s suggest i n v o l v e m e n t or are u s e d to c o n f i r m positive b o n e s c a n findings. If after a c o m p l e t e e v a l u a t i o n t h e r e is n o e v i d e n c e of i n t r a - a b d o m inal o r b o n e m a r r o w / b o n e disease, a c l o s e r e v a l u a t i o n of t h e c h e s t is w a r r a n t e d . Over t h e p a s t 5 y e a r s t h e role of s u r g e r y in p a t i e n t s w i t h small c e l l l u n g c a n c e r h a s b e e n r e e v a l u a t e d . 186-189 Surgical series have r e p e a t e d l y p o i n t e d o u t t h a t a m o n g surgical series t h e r e are alw a y s a n u m b e r of l o n g - t e r m survivors, f r e q u e n t l y h i g h e r t h a n in t h e n o n s u r g i c a l series. Given the fact that c h e m o t h e r a p y / r a d i o t h e r a p y o n l y m a r g i n a l l y c o n t r o l s bulk disease in t h e chest, it has b e e n p r o p o s e d t h a t small cell l u n g c a n c e r p a t i e n t s w i t h disease limited to the c h e s t u n d e r g o a surgical restriction. This m a y p r o v i d e i m p r o v e d local control. In spite of m a n y r e c e n t trials q u e s t i o n i n g t h e role of s u r g e r y it is still u n c l e a r w h e t h e r surgical r e s e c t i o n is w a r r a n t e d o r is of a n y value in p a t i e n t s w i t h small cell l u n g cancer. One of t h e p r o b l e m s in p l a n n i n g clinical trials a n d evaluating the results of t r e a t m e n t arises in t h e fact t h a t p a t i e n t s w h o are c o n s i d e r e d to b e surgically resectable, i.e., have negative m e d i a s t i n a l l y m p h n o d e s , o r have small t u m o r s also t e n d to d o well w i t h s t a n d a r d t r e a t m e n t (i.e., c h e m o t h e r a p y a n d r a d i o t h e r a p y ) . This results in a bias for t h e surgical series. It is u n c l e a r w h e t h e r t h e s e p a t i e n t s , w h o have a relatively l o w t u m o r v o l u m e , have a n i m p r o v e d p r o g n o s i s w h e n t r e a t e d surgically over t h o s e p a t i e n t s w i t h i d e n t i c a l t u m o r v o l u m e s b u t w h o are t r e a t e d o n l y w i t h m o r e t r a d i t i o n a l t h e r a p y . In spite of t h e s e u n a n s w e r e d q u e s t i o n s , it is clear t h a t the m a j o r i t y of p a t i e n t s w i t h small cell l u n g c a n c e r will n o t benefit f r o m surgery. A m o r e f r e q u e n t r e a s o n for the close e v a l u a t i o n of t h e e x t e n t of disease in the c h e s t is to d e t e r m i n e the a p p r o p r i a t e r a d i a t i o n treatm e n t portals. T h e e x t e n t a n d role c h e s t r a d i o t h e r a p y plays in t h e t r e a t m e n t of small cell l u n g c a n c e r r e m a i n s u n c l e a r . As p r e v i o u s l y d i s c u s s e d , o n e of the goals of staging is to d e t e ~ n i n e the e x t e n t of disease a n d h e n c e t r e a t m e n t o p t i o n s a n d p r o g n o s i s . It is o n the iss u e of t h e u s e of r a d i o t h e r a p y w h e r e the e x t e n t of disease d e t e r m i n e s t h e t r e a t m e n t o p t i o n s . If t h e p a t i e n t is f o u n d to have disease o u t s i d e t h e chest, i.e., m e t a s t a t i c o r g a n involvement, r a d i o t h e r a p y is u s u a l l y n o t a d m i n i s t e r e d since p a t i e n t s w i t h m e t a s t a t i c disease u s u ally r e l a p s e in t h e site of p r e v i o u s m e t a s t a s e s , even if t h e y o b t a i n a c o m p l e t e r e m i s s i o n . T h e c a u s e of d e a t h in t h e s e p a t i e n t s is u s u a l l y b e c a u s e of w i d e s p r e a d m e t a s t a t i c i n v o l v e m e n t a n d n o t f r o m disease in the chest. H e n c e , in p a t i e n t s w i t h extensive disease it is unlikely t h a t r a d i o t h e r a p y a i m e d at c o n t r o l l i n g the p r i m a r y t u m o r l e s i o n will r e s u l t in i n c r e a s e d survival. H e n c e at the t i m e of p r e s e n t a t i o n if a p a t i e n t is f o u n d to have disease o u t s i d e t h e chest, t r e a t m e n t is prim a r i l y a i m e d at the s y s t e m i c disease, a n d t h e p a t i e n t u s u a l l y receives c h e m o t h e r a p y alone. In t h e setting of l i m i t e d disease, t h e u s e of r a d i o t h e r a p y is m o r e DM, D e c e m b e r 1 9 8 9

Sl3

debatable. In patients receiving c h e m o t h e r a p y for limited small cell lung cancer, it is f o u n d that a ppr oxi m a t e l y 40% to 60% of patients relapse in the site of the p r i m a r y l e s i o n f f ° This is frequently the initial site of relapse. C h e m o t h e r a p y appear s to be able to s o m e w h a t control micr o s co p ic metastatic disease that is p r e s e n t in patients with limited disease, or at least initially. It is in this group of patients that r a d i o t h e r a p y has a potential advantage, that is, i m p r o v e d local control for the site of bulk disease. The use of r a d i o t h e r a p y in patients with small cell lung c a n c e r has b e e n e x a m i n e d in a n u m b e r of clinical trials a n d is a topic of c u r r e n t d e b a t e J 91 Although t her e is an i n c r e a s e d c o m p l e t e r e s p o n s e rate along with a d e c r e a s e d i n c i d e n c e of relapse in the chest, t here has b e e n no clear survival advantage for patients receiving c h e m o t h e r a p y plus r a d i o t h e r a p y as o p p o s e d to c h e m o t h e r a p y alone. 17~ Recently the c o n c u r r e n t us e of c h e m o t h e r a p y a n d r a d i o t h e r a p y as initial t r e a t m e n t has b e e n reevaluated. This a p p r o a c h utilizes chem o t h e r a p e u t i c agents c o n c u r r e n t with radiotherapy, t h e r e b y taking advantage of their synergistic interaction. As discussed, these early studies h a d suggested a r e s p o n s e rate hi gher t h a n that with c h e m o t h e r a p y alone or th e " s a ndw i ch" a p p r o a c h (chemotherapy-x-rayc h e m o t h e r a p y ) ; however, toxicity was substantial. However, the int r o d u c t i o n of the c o m b i n a t i o n of VP-16 a n d cisplatin, w h i c h are synergistic with each o t h e r as well as with radiotherapy, has m a d e conc u r r e n t t h e r a p y less toxic. T he results of the c o m b i n a t i o n of VP-16/ CDDP a n d chest r a d i o t h e r a p y a p p e a r to be i m p r o v e d over historical results. An increase in local control a n d disease-free smwival a p p e a r s to be longer t h a n with m o r e s t a n d a r d treatment. F u r t h e r follow-up a n d confirmation of t hes e trials will be necessary, but it appears that c o n c u r r e n t t h e r a p y with VP-16/CDDP a n d r a d i o t h e r a p y m a y be the p r e f e r r e d initial t r e a t m e n t for patients with limited disease. CONCLUSION

In su mmar y , these c u r r e n t l y a p p e a r to be the m o s t prom i si ng strategies in small cell lung c a n c e r for r a n d o m i z e d trials: (1) for c h e m o t h e r a p y , the u s e of dos e escalation for alkylating agents, with e m p h a s i s o n "late intensification"; (2) for c o m b i n e d modalities, the c o n t i n u e d exploration of s i m u l t a n e o u s chest irradiation a n d c h e m o therapy, with e m p h a s i s on specific c h e m o t h e r a p y regimens a n d variations in radiation fractionation schemes. Our o wn c u r r e n t direction in limited disease is s h o w n by a currently active pilot s t u d y in the SWOG. It involves c o n c u r r e n t chest irradiation, brain irradiation, a n d two cycles of cisplatin-VP-16 for i n d u c t i o n followed by two cycles of consolidation c h e m o t h e r a p y using active, b u t nonalkylator drugs a n d a final course of high-dose Cytoxan (50 mg/kg/day for 3 days) as late intensification. We h a v e 814

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demonstrated feasibility for this approach a n d h o p e t o c o m p a r e it soon with the same program without ]ate intensification in a randomized trial. REFERENCES

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