Small cell carcinoma of the lung

Cance~

t Reeiews ( 1982} 9, 237..258

cell carcinoma

of the

R o b e r t L. CGq~is Department ~ Aledicb~e, ~r.~'~dical Oncologr, L~'pst~TteA I ~ c a l , ~¢ew ~ r k 13210, L;.S~+I~

7;%1Ea.~t Adams Street,

Introduction Lung cancer is the most common cause o f c a n c e r death in 0ae U~ited Statt~o It accounted Ibr approximately 120,000 dearths i~ t981 (89)~ R a t h e r than being a single entity~ luz~g cancer represents a heterogeneous group of diseases, the histopathologic cl~-~\sification of which i~ presented in Table Io O n a fimcdonal, cIinicdpathohJglc basis lung ca~tcer is divided into two major categories, 0v3se tumors of the small cell ai~apl~stic carcinoma variety (SCAC) and those of the non-small cell type (epidermoid, adcnocar~i~oma a~d large cell anaplastic carcinoma). This broad categorization is mandated by the knowledge that tlae natural history and clinical course o f S C A C d i ~ r s substantially from tum~)~ of the non-small cell variety. For non-small ceil tumors, surgery a n d / o r radiotherapy have remained the pivotal therapeulic modalities. N o sigMficant progre~ has been made in controlling these diseases over the last several decades. On tile other hand, major st6des have been made in the treatment of S C A C over the past I0 years. These advances have resulted from a better u n d e ~ t a n d i n g of the biologic nature of S C A C and the development ofeff~ctive systemic therapy. O v e r the tast decade it has become well established tl~a~ the cornerstone to the eff~cdve treatment of S C A C is the use of aggressive con|binzdons ~)t" chemoO~erapeude agents~

Incidence and etiology Apppoximately 2 0 - 2 5 % of all lung c a n e e ~ are of the S C A C variety (95), thus, accounting for approximately 24,~,0-30,000 cancer-related deaths per year in the United States alone° T h e best established etiologic factor is exposure to carcinogens in cigarette smoke~ T h e risk of developing S C A C is approximately 20-fiMd greater for cigarette smokers than nonsmoke~ (95). O t h e r carcinogens which have been established ws 6sk thctors for developing this d i s e ~ e include exposure to uranium in uranium miners, and pogsibly exposure to t982 Academic P ~

0305/7372182/030237 + 22 S03£~I0 ~7

Inc. (L~Jndon) Limlt~

R. L, COMIS

238

T a b l e I. H i s t o l o g i c a l d a s s i f i e a t l o a s o f lung c a n c e r W H O clarification 1.

IL

Epidermold carcinoma

Small cell a n a f ~ t l c car*i~toma t. Fusiform 2~ Polygonal 3, Lymphocyte-like 4. O~he~ 111~ Adenocarcinoma 1, Bronchogetfic a. Acinar b. Papillary 2, Bronehi~loalveolar IV. Lauge cell carcinoma I. Solid tumo~ wilh muci~ 2. Solid tumo~ with(mr mucin 3. Giant cell 4, Clear ceil

WPL classification 10. 1L 12. 53. 20. 21, 22.

Epidermoid ¢a~inoma VVelldilfcrentiat~! M ~ e r a t e l y differentiated Pf~dy di~rentiated Sm~l cell anap|~s|~c ca~inoma Lymph~yte~llkc (oat cull) |ntermcxliate cell {fusif~rm pol~gon;d~ others)

30. 31, 32. 33. 34. 40.

Adez~arcit~oma Welt diffcrentiated M~.~lerately differentialed P(~r@ d~Te~ntiated Bronchioloalvcolarlpapilla~" Large call ea~inoma (40130} with mucin production (4Oj [6) ~,hl~ str~dficadotx 41. Giant cell 42~ Clear cell

asbestos, nickel and chromates (95). Exposure to uranium and cigarette smoke acLs synergistically, with the risk ofdeveloping l~ng cancer increasing about 67 times when nonsmoking uranium miners are compared to uranium miners who smoke heavily (7).

C~ll ~ or~ein Witbh~ the last 5 years, there have been major advances made in u n d e ~ t a n d i u g the biology of SCAC, These advances have resulted fi'om the development ofshort and |ong-~erm tissue ct~lture techniques. Prior to the development of thcz~e teclmklUeS, circumstantial evidence supported the impression that this disease arose f i r m a Kulchitsky type cell (K-cell) of the amine precu~or uptake and decarboxylase (APUD) system. T h e major Klctors leading to this impression related to the knowledge that S C A C is often associated with clinical syndromes resulting fiwn the autonomo~.~s secretion ofpolypeptide hormones such as A D H and A C T H , and that most SGAC cells can I~ shown to contain electron-dense cytoplasmic granules similar to those seen in other A P U D cells by electron microscopy (91). As a result, the presumed cell oforigin has been, and is still considered to be, the granulated basal lining cell (K-cell) of tl~e bronch{al mucosa. T h e pioneering work of ~nvestigators at the National Cancer Institute (37) and Dartmouth (80) has led to the development of both sllort~ and long-tet'm tissue culture systems which have c o n t i r m ~ the A P U D nature of S C A C cells. Continuous, clonable cell lines have bee~ shown to have initially, and maintain, A P U D characteristic, including high levels ofneuron-specifie enolase, dopadecarboxylase and bon'lbesln; in addition, they exhibit /brmaMehyde-indured fluorescence and electron-dense granules. All of these properties are characteristic ofcells of the A P U D system. O t h e r types o f l u n g cancer rarely' co:hibit a n y of these properties. These systems are also providing a better understanding of growth corJtrol mechanisms involved in this d i s e ~ e (37, 72), an increased ability to clone cells in semi-solid agar systems (37), and a better definition of specific chromosomal abnormalities ass~iated with the malignant process (96)°

SMALL CELL CARGINOMA OF T I l E LUNG

239

Natural historj, clinical biol~g)~ and clinical course

S C A C directs from other lung cancer celt types in two maior ways. First, it is a disseminated disease from Its outset. Work by the Ameriean3uint Committee fbr Staging (74) showed that tbr cell types other thau S C A C lhere was a c l a i r relationship l~:tween the clinical singe of the primary tumor and survival° O n the other hand, when the idet~tical clinical staging system was applied to SCAC no signillcant relationship between clinical stage and survival was apparent. T h e major implications of these data life that the disease is generally disseminated beyond the apparent confi~tes ofcllnical involvement, and that local modalities addressing tile clinically apparent disease will- be unilbrmly ineflk-ctive in controlling the overall dise;~se prc~e~s. A clinical study perlbrmed by the British Medical Rezearch Council p6or to the development of efficctive ~ystemic chen~otherapy verified these two hypotheses (36). In tt~is stttdy, patients who were thought to have potentially resectable disease were randomly allocated to surgical therapy or "'radical radiation '~ thentpy. I~l spite ofllaving such apparently limited diseasc, 98~)~ of the patie1~ts died withi~l the fi~t 5 years from widesprettd metastases (36). A second clinical study is important in defining the virulent, disseminated nature of SCAC. During the 1960s patients studied by the Veterans Administration Lung Cancer Study Group were randomly allocated to treatment with either placebo plus supportive care or cyclophosphamide treatment (I02). Patients in this study were characterized as having "limited" disease (conlined to one hemithorax arid/or the ipsi|aternl suprack~vicular node) or "extc~lslve" disease (disease otltside the limits defined by the "limited" disease category). T h e median survival of placebo treated limited disease group w~s 3.0 months, while the median survival ot'patients with extensive disease was 6 weeks. Secondly, most studies have shown that SCAG is a rapidly prolitLwntivc solid tumor. Kinetic data arc available from both laboratory and clinical studies showing that S C A C has a high 3H-thymidij~e labelling index, calculated growtl~ t?action and volume doubling time, when compared to other types of lung cancer or other h u m a n tumors (86). T h e propensity for rapid growth and e a d y dissemination is reflected in the clinical presentation of the dlse~e. T h e time from lirst symptoms to diagnosis is approximately 3~months, Presenting signs and symptoms relate to both ti~e central location of the primary tumor and its propensity tbr digsemination. Local symptoms and signs include cough, hemoptysis, chest pain, dyspilagia and superior vena cawt syndrome. Symptoms of widespread dissemination include bone pain, abdominal discomibrt and nausea or vomiting from liver involvement, pancytopenias from bone marrow involvement, and headache and other symptoms and signs of central nervous system metastases (23)° These data also can he used to determine an appropriate schema 9or the pretreatment evaluation of patien~ witl~ SCAC. T h e fi~t routine steps include a complete history, physical examination and chest X-ray. T h e required histologic or cytologic diagno~z is generally obtained by fiberoptic broncho~opy. Mediastinoscopy is only required when other diagnostic measures fail or in certain clinical research settings in which therapy will be significantly altered by i ~ result. C o n s i d e f n g the patterns ofspread mentioned above, the additional routine pretreatment evaluation must include radionuc|ide liver, bone and brain scans, and a bone marrow aspirate and biopsy. C~:rtain variations on tiffs basic pretreatment evaluation have evolved; particularly in the clinical researcl~ setdng~ At this point, it a p p e a ~ that the C A T scan is superior to the radionucllde sc-an in detecting brain m e t ~ t ~ e s (53); bilateral bone marrow ~ p i r a t e s and biopsies have been shown to incre~ose the yield of positive studies, when compared to unilateral examinations, by approximately

240

R, L. C O M I S

30% (49), and peritineoscopy a p p e a ~ to be the most sensitive means ofdetecting hepatic metastases, particularly in the presence of abnormal liver fiJnction tests and no apparent abnormality determined by other, non+invasive studie~s (28). Prognosdc

racers

For almost every malignancy there is a set ofprognostic factors which powerfillly intluences the response to treatment and survival. T h e power of these p r o g n ~ t i c fi~eto~ is to a great extent invemsely related to the efl~ctivenes~ of therapy, i+e+as truly eft~etive therapy l~eeomes available, the response to such treatment becomc~s the most important variable relating to sur~,ival. To a significant extent complete r e s ~ n s c to treatment has become the most p o w e ~ l prognostic factor in SCAC+ T h e impact of this variable will be discussed ill the treatment-related section. O t h e r important prognostic factor:s which relate both to response to therapy and sur~¢ival include disease extent a n d l.~:rformance status, Disease exlettl

The most powerful prognostic t~ctor is disease extent. Classically, the staging system employed in SCAC has separated patients into two broad categories+-Iimited a n d extensive disease. Limited disease. As first defined by the VA Lung Group, limited disease represented disease

confined to one hemithorax and[or the ipsilatcral supraelavlcular node. More recently it has been shown that contrataterai hilar, medlastinal and]or supraclavicular nodal involvement does not significantly alter survival or resf~nse to therapy when compared to patien~ with classically defined limited disease (68). T h e prc~seuce ofa pleu~d effusion does not decrease the 2-year disease-free survival rate (64)+ O n the other hand, [hctors such as pleural elTusion or contralateral nodal involvement may significantly atfiwt the therapeutic strategy for combined modality research when employing radiotherapy and/or surgery ~ the local modality ofehoice+ ve disease. T h e initial definition of extensive disease used by the VA Lung G r o u p included disease ou~ide of the confines of one hemithorax and]or the ipsilateraI supraelavicular node. With the redefinition of limited disease, extensive d~ease now encompasses nodal disease more distant than contralateral supraclavicular nodal involvement and visceral disease. T h e power of disease extent as a r~sponse and survival determinant is pre~entc~ in T a b l e 2. peurormanc, slalu+s

Various modifications of the Karnofsky performance scale are in current usage. T h e most prevalent scale which is employed is as follows: 0 ~ a s y m p t o m a t i e ; 1---mildly symptomatic T a b l e 2. E f f e t e o f d l s e a ~ e x t e n t o n ~ s ~ n s e ~ d survival (I2)

Disease extent Limltd ~tcmive

to ~erapy

No. of pafien~

% CR

M~ian surAvat (wee~)

123 331

e3 25

33

51

SMALL CELl. CARCINOMA OF 'FILE IA~NG

241

b u t fully a m b u l a t o r y ; 2---in bed < 5 0 % o f the w a k i n g hot,~; 3 .....in bed > 5 0 % o f the waking h o u r ; a n d 4 - - b e d 6 d d e t L Othe~.x ~.~lien eolhtpse these definitions i n t o "ambulatoD.'==~O~l .......a n d "non-amhttlatot2,f ' status ~2--4. T h e p o w e r of w r r l h r m a n c e $|alus Oil respollse to t h e r a p y a n d tile interl:day b e t w e e n these ptx~gnostic lhctl~t~ it nd diseast. extent a r e presented in Y a h l e 3.

Or&rfactors Age > 70 years has recently been s h o w n to be a negative prognt~iit Ihctor (68)° As well, certain studies h a v e s h o w n that t~males h a v e a higher ol~ieelive rcswmse rate, mediat~ survival a n d 2-year disease-|~ee survival r a t e t h a n males (31,68). Cet taln o t h e r thetm~ have b~:n e v a l u a t e d as tO their impact on response to t h e r a p y a n d survival. T h e ellbet of the pathologic s u b t y p e o f S C A C , i.eo l y m p h o c y t e - l i k e (oat cell) ty!ar a n d the i n l e r n t e d l a t c types including fi,sifi)rm a n d polygonal varieties, has been e v a h l a t e d . Xlt~st studies have not shown a signiticant inlluencc of the c o m m o n i)athologic suhtyf~cs tm disease p a t t e r n at presentation, response t~ Iherapy, m e d i a n o r overall stHvival; ott the ~ t h e r hand+ ;tva, iant with both small a u d lar~4e cell attaplastic e l e m e n t s has been associated with a shorter m e d i a n survival c o m p a r e d to patients with tile CtlllllnOtl cell types t r e a t e d wilh the sitnle therapy (67). As opF~osed to lung c a n c e r o f tile liotl-slllall cell type, there is nt~ clear-tilt evidence that it~tact d e l a y e d twl~'rset~silivity is an i m p ~ r t a n l flit tor (33). ( ) n the o t h e r h a n d , it is possible that ;t m o r e precise dt f i n i t i o , o f s p t x i l i e immm~e detbcts, particuhtr!y relating to T-cell filllCtiOl!, lllily i m p r o v e the prognt~tic l)ower o f the, i|lll)lttl|e evah|i|tioll

()9). Therapy

General primqples O v e r the last d e c a d e , there have been a g r e a t mat,y studies which have c v a h , a t c d va,4ous t r e a t m e n t regimens. F r o | n a fi:w ol'l|lcsestudics, several gctleral thel'apetttie principh~s have been ~ t a b l i s h c d w h i c h relate to the a p p e o p r i a t e use o f a v a i l a b h : t h e r a p e u t i c tnt~datities. T a b l e 3. Effects of d i s e a ~ extent a n d performBnce stKtu~ o n r e s p o n ~ to t h e ~ p y ( ~ )

No+ of patiems

paticms with GR

paficm~ whh GR +~r PR

129

23 (I 8%)

84 (65%ff

t 21 2~.)

12 ( t 0%) 35 (14%) b

79

38 (48%) c

62 (78%)

29 l~

6 (21%y ~ (41%) b

19 ( ~ % ) 81 (75%}*

Exte~ive

Fully ambulator~~ ~ s than fully arnbulato~ Total Fully ambulatory Less than fully ambulato~ Tram ~P < 0.01. ~P < 0.~I. P < 0.05~

56 (46%)* 140 (06 ~ o+*+o)

242

R. L COMIS

Chemotherapy~The advances which have been made over the last decade have resulted from the d~covery of several moderately effective chemotherapeutic agenm. A listing of drugs with established activity is presented in Table 4 (61). In general, o~ective responses to single agents are partial and short-lived, with complete respon~ being extremely unusual. Etoposide (VP- 16) appea~ to be the most active ofthese single drugs (81 ). The discovery of these active drugs ted to combination chemotherapy studi~ which proved that combination chemotherapy is superior to single-agent treatment in inducing both partial and complete objective response (5, 31, 65, 68). A randomized, controllc~ study cornpa~ng tv,,o dose levels of the CCM combination (CCNU, cydophosphamide and methotrexate) showed the advantage of more aggr~:.ssive therapy over a tess aggressive approach (20). Although this and more recent studies (77) have shown a dose~response eflbct, it appears that there is an asymptote to the dove-response c u ~ e for certain regimens ( 13)° For certain drugs, such as methotrexate there is clearly no established dose-res~anse curve ( ~ , 68). Since there is no predictable dose-response c u ~ e for individual drugs or drug combinations, the g e n e ~ l principle which has evolved has been to employ a W e n combination at its maximally tolerated dose, with the m~ority of patients experiencing significant, intense transient myelosuppre~iom Thus, the underlying principles applied in the chemotherapeutic strategy tbr this disease relate to use of intensive combination chemotherapy.

Radiation tl~rapy. During the last decade, certain therapeutic principles have been learned concerning the role of radiation therapy to the primary tumor in treating SCAC. Fi~t, a randomized controlled t~al in limited disease comparo:l the sequence ofradiation therapy ~Jllowed by chemotherapy at relapse to radiation therapy sandwiched between chemotherapy courses. This study showed that the latter approach was a~s~iated with a doubling in median disease-free survival (78). Therefore, irradiation is to be employed as a primary therapeutic modality it must be combined in some manner with effi2ctive, aggressive combination chemotherapy. Secondly, randomized controlled trials have shown that for patients with extensive dise~e, the addition of raxliation therapy to the primary tumor combined with chemotherapy is not supe~or to chemotherapy alone (6). Finally, most controlled trials have shown radiation at the time of initial therapy is capable of significantly decreasing the incidence of clinical CNS relapse ( 13, 68). Unfortunately, most studies have now shown a survival advantage for all patients receiving cranial irradiation compared to the unirradiated groups. Ahhough a survival advantage has not been yet established, it is imperative that CNS irradiation be considered in the design ofpotentially curative programs for limited disease patients or in patien~ obtaining a complete response, independent of stage, ifoverall long-term disease control is the therapeutic objective. Table 4. Single a g e n ~ in s m a l l cell carcinoma (61) Drug Cyd~phosphamlde Ad~amycin Methot rcxate Vincfisfine Et~idc

No~ ofpatients

Resp~:mse(%)

CR (%)

I89 36 73 43 167

52 (28) 1 | (31) 22 (30) 18 (42) 75 (45) 11 (14) 21 (30) 24 ( ~ )

4

CCNU

76

Hexamethy|meiamine HN2

69 55

7

9 4

7 --

SMALL CELL ~XRCINOMA OF TIlE LUNG

243

SurgeEy. The resul~ of tile British Medical Research ( ~ u n e i l Study e~zentially eliminated

s u r g e ~ ~ a p ~ m a r y therapeutic m ~ a i i t y for SCAC. Subsequent to that study, it has been shown that the small minority of patients who pre:4ent with either solitary- pulmonary ncMules, which are subsequently shown to be SCAC on histologlc examination, or intraop~rative Stage I disease have a 5-year survival rate of 30~0~., (48, 99). Morn recently;, ~ w i l | I ~ d i m u ~ e d ~z'low, surgery is I~ing re-explored as a local therapeutic modality combined with aggressive combination chemotherapy (70).

Specific studies relating to disease extent

Ti~e prit|ciples outlined in the previous section Imvc been derived from, and applied to, a large n u m b e r of patients in numd~uSstudies over the last 10 years. An analysis ofselected studies will be presented ~ l o w in o ~ e r to d~:ument the current "state of the art" and ~stablish the tlie~peutic research needs for. the future. Since disease extent is the l i l t ) s t prolbund pretreatment variable effecting comp!et e remission and tile possibility of longterm survival~ the discussion will be divided accordingly. Limited

T h e majo~ty of studies performed in patients with limited disease have empl~wed combined modality approaches including combination chemotherapy, plus radiation therapy directed to the prima D. tumor and draining lymph nodes (I2, 83"): T h e most c o m m o n sequence of combined modality treatment has bee " * ~ate cotnbination chemothet"apy prior to radiation therapy and then administer therapy, prior to resuming c h e m o t h e r a p y - - c o m m o n l y relY:fred to as "sandwich radiotherapy". There has been a wide variation in the total radiation dose delivered in such studies as well as in critical radiation time-dose ~x:lationships (83). It should be noted that a h h o u g h there appears to be a radiation dose-response relationship fi~r local control of the primary ttmmr (17), the optimal total dose and time-
244

R. L. C O M I S Tal~leS.

C-ontroll~ tfi~s

evaluating "~dwich"

~diotherapy

in small ,xtll l u ~ g

eatl¢~r

Regimen l)ru~ ~ CCMV ±

Radlat~on 2 ~ tad/5 days on weeks 7 and 1 |

No, of patients | 34

R~ults

Rel~rence

Nf~difference in

45

objective r ~ s c - ;

CAV ±

1750 tad/5 da)mon days22~' a nd 43

32

CAV~

1750 rad/5 days on days 22 aud 43

65

C~V ~

4f'~4) rad[4~5 ~*eeks

Abbreviations: C = ¢yeloph~phamide; A ~ adrlamycln; V ~ vincdsdt~e~

median surviva! for eomblncd rnodality v~ ehet~othe~py ! | and 14 months r~l~'elively (P < 0~01). No signifieam differs:nee in % Cg, me~Jian re~.~mnse dum~tlonor survival CR rare fi~r eombh~ed m~lality w, chemotherapy 6t3 and 37% r~pecdvely, No di(!i're~ee i~ (IR alter 3 week.sof CAV or m~ian su~*iva|; initial ~-laps~ i~ p6mary site 67% (|9/28) and 3|~b for chemothe~py and combil~d m~a|ity reflectively. C.C ~ cyeloph~ph~mide

plus

~.)

77

34~ 35

C~NU;

a p p e a r c o m p a r a b l e to those o b t a i n e d with c o m b i n e d m o d a t i t y p r o g r a m s using " s a n d w i c h r a d i o t h e r a p y " . T h u s , a l t h o u g h most studies have utilized 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 , the ability o f tlle g e n e r a l l y e m p l o y e d " s a n d w i c h r a d i o d i e r a p y " a p p r o a c h to a u g m e n t the basic chemothe?rapeutic effect is e q u i v o c a l at best. This does not necessarily i m p l y that c o m b i n e d m o d a l i t y t h e r a p y should not be e m p l o y e d in t r e a t i n g limited disease, but r a t h e r t h a t the p r o p e r r a d i a t i o n dose, t i m e - d o s e relationship a n d e d m b i n ~ m o d a l i t y s e q u e n c e has yet to be established. In spite o f the fact t h a t the o p t i m a l m ~ e o f t h e r a p y has not been defined, there is c l e a r e v i d e n c e t h a t the d e v e l o p m e n t o f a g g r ~ s i v e c o m b i n a t i o n c h e m o t h e r a p y has led to a n increase in m e d i a n survival, disease-f~e survival at 2 y e a r - - a n d p r o b a b l e cure. "Fable 6 presents d a t ~ from several studies in w h i c h m e d i a n a n d aaual 2 - y e a r disease-free s u ~ i v a l rates a r e available. P r i o r to the a d v e n t o f c o m b i n a t i o n c h e m o t h e r a p y the m e d i a n sm-¢ivat o f p a t i e n ~ treated with supportive c a r e o r local m o d a l i t i ~ a l o n e r a n g e d from 14-25 weeks. A l t h o u g h not detailed in the table, a s t u d y p e r f o r m e d b y Be 1 a aL (8) c o m p a r e d r a d i a t i o n t h e r a p y a l o n e to r a d i a t i o n t h e ~ p y c o m b i n e d w i t h e y c l o p h o s p h a m i d e . Interesfingly,~ the results o f this s t u d y s h o w e d a m e d i a n surviva| o f 31 weeks w h i c h is i n t e r m e d i a t e b e t w e e n the s u p ~ r t l v e care]local m o d a l i t y r e s u h s a n d w h a t is c u r r e n t l y a n t i c i p a t e d from m o r e a g g r e ~ i v e c h e m o t h e r a p e u t i c rams. C o m p l e t e respor~e rates in e x c ~ of 5 0 ~ a r e o b t a i n e d in m o s t studies w i t h m e d i a n

S M A L L C g L L C A R C I N O M A O F T H E LUNG T a b l e 6.

~ngqerm

sub|vat

Therap¢

in l l m l t ~

Nt~. of patients 3| 187 235

small eeU hag

2.t5

caner

% CR

Median survival (w~)

% ~ 2 yea~ NI~D

Rdrte~c¢

25 40- 65

14 20 25

0 0 <5

97 73 8, ~ 5~

II

4 l, 45

15 19 s 22

63 14 31~

Pilot to rhtmot~a.O' No~e Surgery ~ca! radiatiot~ therapy

Combination thtmotheta~ plus therapy

crx, cent:, MTX. VCR C I ' X , AI)R, VCR CFX, ADR, VCR Cq'X, VCR, CGN U, AI)R, H E X A CFX, ADR, VCR~ H I~XA~ VP- 16. MTX + C pareurn U I ' X , ADR, VGR, CC:NU, M T X , BG(; C I ' X , VCR CFX~ VP-16 ADR, VP-I6 (71"X, ADR, VCR, MTX

l |0

108 24 3t;

4! 81 iFt

5(t Mi

32

94

6,8

25

76

19

89

78

26

76, 91)

16 12 9 12

50 40 33 E~~)

50 13 12 .......

!9 25 I! 17

50 30 30 9

20

70

-~

25

52

19

74

65

16

21

!4

78

54

29

4

()~t~¢b,nati~nchtmothe,~b~"alone CTX~ AI)R~ C C N U , MTX, VGR, BLEO, EM~;TINE (YI'X~ MTX, CGNU~ ADR, VGR, 1~ ~ | ' X , A | ) R , VP-16

adrlamydn; t'IEXA ~ hexamelhy|radamine; G u n ' n ; BLEO ~ bleomycin; Pz ~ p ~ a r b a z h e . b33 6 7 months s~lrvival.

V P- 16 ~ etOl:~idc;

B G G = BadUut

ealmttte

survival times generally greater than I ),ear. Mt~t importantly, a substantial proportion of patients, ranging from ! ! to 29%, remain alivc and discase-fi-ec fbr ~ 2 ),ears. Many patients who survive alive and4i:;ease-frce fnr 2 year.,;, remain disease-free (38). I t has been the policy at the S U N Y Upstate Medical Center, Syracuse to discontinue therapy at 16-28 months after an extensive restaging prozedure (38). O f the 8 patients with limited disease surviving at that time, ! died within 4 months of recurrent disease; I patient devdoped adenocarcinoma of the lung and died at 60 months, and a third patient died at 50 months from widespread prostatic cancer with no demonstrable SCAC at aulopsy. T h e remaining 5 patien~ are alive, disease-free and presumably cured at ~ 7 y e a ~ post,diagnosis, 2.5-5.5 y e a ~ after discontinuing therapy. In spite of these therap-eutic advances, 50% of patients die within the first 12-! 6 months after diagnosis arid 80-90% succumb within the fi~t 2 yea~. An analysis ofrelapse patterns

2~

R+ L Ga'-JMI8

and the problems inherent in tile combined mcMality approach is n e c ~ a ~ in order to determine an appropriate therapeutic research stra~gy ibr the future. The following discu~ion will emphasize the problems and y~tential of the combined modality approach, with either radiation therapy or surgery employed as the p6mary local modallty+ The rensotts figr this emphasis lay in the ~ c t that, at best, the use ofcombination chemotherapy alone has yielded only cquivaient, not superior, therapeutic resul~ when compared to combined modality treatment; the proper sequence, dose and schedule ofradiation therapy comblued with chemotherapy has been poorly explored; and, initial t2dlure in the prlma~, site occurs in about 30+50~ ofn:sponding patients with limited disease (71 )+ Several i~sucs concerning existing results and their impact on combined modality treatment necd to be addre~ed in order to establish the optimal combined modality trcatment+ As mentioned above, and presented in "Fable 5, cont~lled studies, and uncontrolled trials using aggressive combination cher,~otherapy, have not shown that "sandwich radiation" combined with combination chemotherapy is clearly superior to aggres~sive combination chemotherapy alone. Therefore, new modes ofcomhin+xt modatity treatment need to be explored. An obvious alternative to the "sandwich radiation therapy" approach c~uld be to employ simultaneous treatment with both m~aliti~++ The ~ i a t e d thc~rc4ical a d v a n t a ~ , include: the immediate inldation ofmultim~|ality therapy direct~ to tile p f i m a ~ site of bulk dise~e and initial relapse; the immediate initiation of systemic treatment; and. the exploitation ofany important drug[radiation interactions which rnlght t~ccur. A fi.+wstudies have addressed this i~sue+ Greco et aL (43, 76) have presented a series of reports on the use ofsimuhaneous radiation therapy (3000 ntd] ! 0 sessions) combined with cyelophosphamide, adfamycin and vincfistine (CAV)+ The prelin~inary results ofth~s trial indicated an exceptionally high p disease+free su~ival rate (43)+ A more mature analysis has shown a consistent 25~}~,disease+f~e survival rate at 24 months in consecutive series of patient entries (76). Recently, Catane a aL (14) have reanalyscd a consecutive se6es ofpafients+ initially r e p o r t ~ by Johnson el aL (56), treated with a combined modality approach including various simuhaneous or sequential radiation therapy schemes combined CAV. Intensive combined m ~ a l i t y therapy was ~dministered K~r 3~4 months, and no maintenance therapy was employed. In spite ofexcessive toxicity ( 2 4 ~ treatmentrelated mortality) the 2+year sur¢ivai nile was 2 7 ~ , and f9~/, of patients ~re alive and dlsease-free from 33-57 months. Since the groups were small and not chosen at random it is diMcult to be certain of wliich radiotherat~utic program or approach was supe6or to another[ But, there was a trend ~avo6ng the simultaneous administration of CAV and radiotherapy over sequential treatment. Finally, the preliminary r ~ u l ~ of a randomized study have been presented which compared chemotherapy with CCNU, cyclophosphamide and methotrexate (GCM) alternating with vincfistine, adfiamycin and procarbazine (VAP) to CCM c o m b i n ~ with simultaneous radiation therapy rad/15 sessions]3 weeks) with the same alternating C C M - V A P sequence after the completion of radiotherapy (22). These data showed a trend in favor ofsimultaneous treatment. The final results of this study have not been report~+ In addidon to explofng the value of simultaneous intensive therapy Other developing a r e ~ of research include inv~dgating various super fractionation schem~ or the use of radiosensifizo~+ ~q-~e exploration of new radiation therapy approaches may demand a readjustment of chemotherapy programs in order to obt~An an acceptable therapeutic ratio. The toxicitic~ encounte~d in c o m b i n ~ m ~ a l l t y ms relate to the choice of chemotherapeutic agents, the dose and schedule of radiation employed and the timing of the local and systemic modalifies+ Recently, Livingston et aL have reported t h e resul~ of a pilot study

SMALL CELL ~ R C I N O M A

OF THE LUNG

247

which employed radiation therapy, adtiamycin and methotrexate (62). A high incktence of recall stomatitis, eso#lagitis and central nervous system toxicity and profound, licethreatenitlg myelotoxicity tbrced early termination of this combined m ~ a l i t y approach. Feld h ~ extensively reviewt~t the toxicitk~ as~soeiated with the contemporary treatment of SCAC (32). Adfiamyein ham b,~_omeone of the most extensively uscodd r u ~ in tile treatment of SCAC~ In spite of this, there are tbw data whiclt indicate that its use in combination chemotherapy programs is required ~Jr achieving complete t~sponse or long-term survival (Table 6)~ There is substantial clinical and laboratory evidence to indicate that adfiamycin is a radiosensitizer (39, 55, 94). The two major ill-field target organs fi~r which there appeaes to be enhanec-d toxicity art: the esophagus, the lung and tile skill ill the radiation portal. There is a wide range in the incidence of toxicity which appeal~ to be related to tile scheduling ofthe radiation tberapy, with shnu|taneous treatment l~ing more toxic, in most studies, than "sandwich" tyl:.c therapy~ As mentioned above, the study reported by Catat~c a al. (I4) evaluated several dittO:rent sequential or simultaneous radiotherapy programs combined with CAV. Their data indicate that the incidence of severe or lifi:-threatening esophageal wild]or pulmonarT toxldty w;~ related to the duratiotl of sitnuhalR:ous treatnlent, wiOl 3000 rad/3 weeks Ilaviug tile best therapeutic illdex. This study and that reported by Oreco a aL (43, 76) ~'~th indicate then that (.'AV can bc combined with the simuhaneous delivery of 30e~ tad/15 scsslons with acceptable toxicity. Uulbrtunately, there is no clear-cut evidettce that this simultaneous approach, employing a relatively h~w dose of radiation therapy, is superior to t|~e more co~r~,entional "sa~dwlcb" type of approach. It is quite probable that if the clFcctiveness of high dose simultaneous radiation therapy (45G~)-~5500 rad/4~-5 weeks), hyperfractlonation, or radiosensltlzers are so be explored, adriamycitl-containing combinations may yield prohibitive toxicity. An alternative approach is to employ non-ar~thracycline-containingcombinations during the combined modalhy period. As mentioned above, the current NCI study has taken this approach. In addition, a national study is being performed by the Canccrand Acute Leukemia Group B (CALGB). The primary ~ m b i n a t i o n of drugs employed in this study incl~de cyclophospbamide, etoposide and vincristine (CEV) administered e v e ~ 3 weeks. The 3-armed st udy compares (a) simultaneous radiation therapy (5000 rad[5 weeks) plus CEV on day I to (b) 3 cycles of CEV with the same radiation therapy commencing on day 53 to (c) combination chemotherapy alorle. The simultaneous CEV plus radiation therapy program has been shown to yield acceptable toxicity (79). Finally, another approach to be considered is a re-evaluation of the role of surgery in treating selectcM patients with limited disease. T h e results of the British Medical Research Council Study kxi to file abandonment of surgery as a primary therapeutic rncyAality(36). This study was performed prior to the development of effective, aggr~sive combinatio|~ chemotherapy. There are several £actors which demand a reappraisal of the thera[~:utic role of surge~¢ as a p r i m a ~ therapeutic modality. Such facto~ include the high rate of initial Failure in the primary site (Table 7), the potentially protbund and lifi:-threatening toxieiti~ a~sociated with a g g r ~ i v e combination chemotherapy and rad~atiort therapy and, most importantly, the plateau in t h e r a ~ u t i c results which has occurr~l in the last decade. We have recently conducted a ~ibi~lity study which employs surgery ~s the p~mary l ~ a l modality for selected limited disease patien~ (24). The criteria for entry include: (i) ipsilateral disease only, as defined by appropriate radiographlc techniqu~ and medi~tln.

60 {6) 53 (8) 35 (3)

10 15

62 (5j8) ~ (3f5)

77 (10/13} ~o

CR only

PR only

to.3 (9/9)

Chestonly

-

C.h~t + other

Rehrv~paucro(%)

Combin~ m~a!iiy studi~ in which initial r d a ~ is d~c.d~d for r~nding paden~ either ~ a group or stradfi~ by respon~ pa~mmr, bSee Table 8 br drug cede. One pauent devdo~d met~taac d l ~ within ! momh. ~O~ty CR m ~ e d .

8

~1 (7) ~ (20) 32 (9) 77 (10) 6 (r)

17 40 28 13'~ 16

,~ above C~V x 3--25C0rM/IO-CPM C~V × 3-4,%~0~diT0-CAV CAV + va6o~ radiation CV-30,~ rad/i0-4 wee~-3000 rad/!O-CV AC-3iE~)tad/10or 00 rad/30-55-AC-CMV 20C0~/5,-2000 md/5-CCV-AV BVMPz-35 mdlt5-20-BVMPz

67 (24)

36

,AJIpatients

rda~e (No,)

% v&h ch~t

CAV x 3 - 2 ~ r~d/lO-~~eeks1500~d/5-CAV

* C~mbined m~a|,ty treatmen~ programb

No.of paticn~

Table7. C a m ~ ap~ m resting ~ t e d dise~ ~tien&

34, 35

Reference

V

SMALL GELL ~ARC|NOMA OF THE LUNG

249

oscopy; (it) no medical contr~indications to surger¢; (iii) no evidence of severe superior vena cava obstruction; and (iv) a negative m e t ~ t a t i c evaluation. Patients with Stage I~I l disease receive immt.Jiate surgery followed by I year of chemotherapy. Patients with ipsilaterat T 3 and]or N z disease receive preoperative chemotherapy ~llowed by complete surgical resection. T h e current chemotherapy program emplo)~ cyclophospt~amide, adriamycin, vlnerlstine and etoposide (CAVE). Eight of 9 paiients with Stage l - ! I dlsea~: have completed the program and are currently alive at ~13+ months. Eight of 14 (57%) Singe I l l patients have receivt~ tile combined progr~5~, ~vith 5 ot"8 truing alive at 16+ months; the longest disease-£ree su~,ivor is alive at approx~mately 3 yea~. T h e re.suhs ofthis study indicate that this is a feasible approach, which has virtually eliminated local relapse as a major site of IMlure. Further studies are required to establish the role of surgery in selected patients with small cell ca~:inoma. I n summary~ a g g ~ i v e combination chemotherapy in patients with limited SCAC has )qelded a significant increase in median sup¢ival and long-term disease-lYre su~'ival. In spite of these advmlces the majority of patiems die within the fi~st 2 years after diaguosls. Current then-q~eutic research thrusts il~clutte the establist~ment of the optimal combi~ed modality approach employing either radiation therapy or sulNelT, in selected patiellts, as the pNma~. Ic-$ai m~lality. W i t h regard to Ole t;omler approach, the choice aml ayailability ofacdve drugs is a critical lilctor in ~tabtNhiug an acceptable therapet~tic ratio which will allow a thorough exploration of the appropriate radiotherapy/chemotherapy dose and sequence. Finally. since chemotherapy I~mains the c o m e . t o n e of efl;:etlve treatment, it is important that the most etl~ctive d r u ~ ~ :: :.,:~;~..,Idefi~r use in establlshi~g the optimal chemotherapeutic programs, particularty as ne~ ~',,~?possibly more eflhctive agenu~ to be used in combination ar~: discovered. Extem::e disease

Over one-half of the patients with SCAC presem with diseasc beyond the confines ofo~m hemithorax and the ipsilateral or contralateral mediastinal and supraclavicular nodes~ T h e preferred sites ofmetastasls in this group include the liver, bone, bone marrow and braim Unlike limited disease in which the disseminated tumor burden is subclinical, the disseminated tumor burden in e×tensive disease is clinically apparent. In this situation it would be anticipated that combination chemotherapy programs would be somewhat I~ss e~:cu e in inducing complete remission, the prerequisite £or lbng-term d se. se-rue survival, 0~an the same combinations u s ~ in limited disclose; T h e analysis p e r ~ r m ~ by Bunn et aL (12) revealed that the complete response rate was 25% and the mcglian s u ~ i v a l was approximately 8 months prior to 1977 (Table 2). l)uring that p~:riod many patients with extensive disease were treated with combination chemotherapy combined with radiation t h e ~ p y directed to the p r m a r y tumor and draining lymph nodes. As mentioned before, the relatively small study reported by Alexander a aL (6) s h o ' ~ d that radiation therapy to the pHmar~, tumor did not improve the survival ofextensive disease patients. A larger study by the Cancer and Acute Leukemia Group B has confirmed this r ~ u l t (R. Corals, pe~onal communication). T h e combination ofcyclophosphamide, adfiamycin and vincrstine (CAV) has become one of the most commonly used treatment programs (63~ 64). For this regimen, the overall objective respmnse rate is approximately 50%, while the complete r~ponse rate is relatively low a t about 15%. For virtually all con complete r ~ p o n d e ~ is significantly longer than I on:~. T h e

250

R. L C O M I S

T a b l e 8, I n t e n s i v e t h e r a p y f o r e x t e n s i v e d i s e a ~

Response No. of patlen~ % CR (No.) % overall (No.)

Regimen° CCM CCMV High d ~ e C C M

52 53 19

High d~e CCM~VAP ~'XE ~XV~M[CF ~E~BVMPz GAVE~PzlM E~DDP~CAV

42 19 21 12 17 !7

-~

(5/19) 36 (15/42) 52 (I0/|9) 42 (9121) 25 (3112) 47 (8117) 41 (7/17) 25

M~ian survival {months) 2-yearsur~Aval gel~ont~

~ ~ (18/19)

5.9 7~6 8.5

2/19

20

~ 95 (18119) 95 (20121) 11~3~(13112) ~ (15/17) 88 (I5117)

9.3 9.5 |2 9,6

o~ 1119 -~

21 4 42 2 93 87

95

+

|I!O5

-

-

9.0

46

-

0117

"Abbreviations: C ~ cydoph~phamide; CC ~ cyclophosphamlde + CCNU; M = methotrexate; M/CF.~ high d¢~e methotrexate + citrovofin r ~ u e ; V ~ ~ncristine; E = eto~side; B = BCN|J; ~ ~ proca~q~;tzine; I ~ iphospha~ide; DDP ~ ¢is-plminum; O ~ oneo~n. m e d i a n su~-,ival o f extensive disease patients w h o a c h i e v e a c o m p l e t e response is c o m p a r a b l e to t h a t o f limited disease patients a c h i e v i n g c o m p l e t e response. T h e m ~ o r dlfference b e t w e e n limited a n d e x t e n s i v e di i:omplete responders relates to the e x t r e m e s o f the survival c u r v e w h e r e there is m i n i m a l e v i d e n c e for a significant p l a t e a u in extensive disease p a t i e n ~ (63). A m a j o r t h e r a p e u t i c research goal over the last several years has been to increase t h e p r o p o r t i o n o f patients a c h i e v i n g a c o m p l e t e response, as well its to increase the d u r a t i o n o f c o m p l e t e response. The:se a t t e m p t s h a v e t a k e n severa| forms with the most p r e v a l e n t a p p r o a c h ~ h a v i n g been d i r e c t e d to increasing the intensity o f c h e m o t h e r a p y , i n c o r p o r a t i n g etoposlde into the initial c o m b i n a t i o n o f drugs, o r using a sequence o f d r u g combinations. Several c o n t e m p o r a r y studies w h i c h h a v e e m p l o y e d these a p p r o a c h e s a r e p r ~ e n t e d in Table.~ 8 a n d 9. A h h o u g h t h e n u m b e ~ o f patients t r e a t e d in most studic~ are r d a t i v e l y small, this t y p e o f t h e r a p y has yielded an overall respoi~se r a t e o f 950/0 a n d a c o m p l e t e response r a t e r a n g i n g from 25 to 5 3 % . T h e m e d i a n survival o f these extensive disease patients has r a n g e d from 8.5 to 12 m o n t h s . T h e r e is a n occasional 2 - y e a r disease-free survivor. A d e q u a t e 2 - y e a r ~urvival d a t a a ~ available o n 269 patients from the s t u d i ~ presented in T a b l e s 8 a n d 9. S e v e n (2.67%) w e r e alive a n d disease-fro: a t 2 y e a ~ . T h r e e o f b le 9, R ~ d o m _ i z e ~

con~lk~l ~ials es~uating mutually "non*¢ross,~sistant" comb i n a t i o n e h e m o t h e ~ p y in e x t e n s i v e d i ~ a s e

R~mena CAE* ± CMVPz CCM

±AE

No. of ~licw~s :25 23

73 73

% CR (nO.)

Reference

7.5

--

3

30 (?!23) ~

9

--

27

~

9 8~8

1120

Il

--

--

57

6.9

2189

88

Il

18 (2111)

9

22 (2119)

CCM ±VAPz

|I 9

--

I~OCG

89

a S ~ Table 8 for drug code.

2-year suP,4va!

2:8 (7/25)

APzE--MC~C MOCC--APzE

EAM

Md~an surxdva|

--

20 ( ~ ) 40 ( ~ )

10

SMALL GGLL ~RCINOMA OF THE LUNG

251

the programs presented in Table 8 used aggressive chemotherapy combined with intensive support in laminar air-flow rooms. T h e comp|ete response r a t , ~ in these studies by Cohen a aL (20), A b e l o f f a a L (2), and Valdivie~so aal. (93) are 25, 25 and 4 7 ~ , rc~pectivdy. T h e y do not appear superior to other aggressive programs administered with more routine supportive care. T h e study by Sierocki et aL (87) is ofinterest since the induction chemotherapy program was somewhat unusual, consisting of etoposide and eta*platinum, lz~ rcqYactory small cell carcinoma the response to the latter agent h;~ r a n ~ d from 12 to " | 0 ~ with an overall response rate of 2 3 ' ~ in 83 patients (15, 16, 25, 29, 40, 82). Whether the high complete response rate will be sustained remains to be determined, but it is interesting to note that there was some evidence for potentially synergistic toxicity, particularly thrombocytoImnia. T h e pos~ibility of therapeutic synergism with this conlbi|lation of drugs has been suggt~ted from animal studies (85) ms well as clinical trials in testicular cancer (26). As can be seen from Table 8, several studies have employed a combination ofdrugs used in induction tbllowed by a second combination at a fixed point. Often, these combinations, which are presumed to be non-cro~s-resistant, are alternated in a lixed sequence. Mosl studies have reported ttmt the maximal response to thcxT~py is achieved in the first few induction cycles (21,87). Thus, the tEeoretical value of the aherl~ating sequence is dilfieuh to evaluate in uncontrolled trals. O n the other hand, Cohen el aL (22) reported that the complete response rate was increased fi~nn 24~/, (1014.2) to 36% (15142) with a fixed cro~over to V A P (vincristine, adfiamycin and proearbazine) afler induction therapy with high dose C C M . This ahernating approach has been evaluated in a controlhxl, randomized lhshion in 5 studies. T h e resul~ of these trials are summarized in Table 9. Two studies reported a statistically significant difference in ~avor of the ahernating sequence. T h e study reported by Dombernowsky et aL (27) compared continuous GGM to GCM alternating with etol~3slde and adriamycin, Complete response rates were z~ot presented; the overall resWanse rates were equivalent in each group. Also, the median survival was the same fi)r each group. A di~.'rence in survival favo~Sng the ahernating approach was noted tbr the 25th ~ r c e n t i l e , and response duration as significantly increased in the alternating group. T h e study reported by Sikic a aL (88) compared P O G C (procarbazine, or~covin, (]GNU and cyclophosphamide) therapy to EAM (etoposide, adriamycin and methotrexatc) induction followed by alternating cycles of P O C C ~ E A M . A significant difference in favor o f a h e r n a t i n g therapy was reported lbr complete remission as well as median survival. T h e study w ~ designed in a manner which per~nitted a compa~son of the 3 induction cycles of P O C C or EAM. T w e n t y per cent of patien~ achieved complete remission during tttc~e 3 induction cycles tbr each regimen. Thus, the doubling of complete remission is noted in "Fable 9, apparently resulted f ~ m the alternation. O n the other hand, the complete response rate of 4 0 % , median survival of 10 months, and 2-year survival of 2 % is similar to that observed in other studies which employ etopos~de-containing combinations in induction (Table 8). At this p-tint, there is no eonsLstent, conclusive evidence from controlled o r uncontrolled studies indicating that alternating therapy is superior to employing the most active drugs in aggressive combination chemotherapy programs. Recently, certain non-cytotoxic chemotherapy modifiers have been used in an attempt to i n c r e ~ e the objective r~ponse rate or survival in patien~ vcith SCAC. A study reported by Zacka~ki el aL (100) employed chemotherapy with cyclophosphamide, methotrexate and vincfistine (GMV) with or without war£a~n ~ an adjunct. This approach was based upon extensive e x ~ r i m e n t a l data which indicate that anticoagulation decreases the time

252

R, L. ( ~ 9 M I S

m metastases and mthances the chemotherapy eItb.ct in certain animal tumor n;odels ( 10l ) Twenty-five patients were randomized to each arm of the study. T h e complete plus partia response rate was tow in each arm, 28 and 32% respectively. Although there was n< significant difference ill objeciive response rate, there was a gtatistically significant increase ill the time to p ion, | 5 v& 32 weeks (P ~ 0.03) alld incdian survival, 25 vs. 50 weeks (P = 0.026 L for the C M V and C M V + war~lrin groups, res~wtiveiy. Akhongh there are severaI problems with the design, execution and analysis ofthis study, further work is being performed to ae~se~ in a controlled thshioti wlmther the addition of warfitdn will significal)tiy increase the response duration a n d | o r sutx, ival in extensive disuse patients treated with more contemporary aggrewsive c o m b i n a t i o n chemmherapy prt)grams. Another attempt at modifying chemotherapy response has been to use thymosin fraction V (TFV) as an adjunct to chemotherapy with C C M (19). Ill a randomized study pe~gorm~xt by the N C I - V A group patients treated with TFV, 60 m g / m 2 twice >~t.kly, had a statistically significant increase ill median survival when compared it)patients treated with either no T F V or T F V at 20 mg/m 2 twice weekly. Once again, no increase in objective response to chemotherapy was noted to acconm for the increase in m(~llan survival Ahhough these sttidlcs witb warfitdn and TFV arc I~r from conclusive, such stndies represent the it)ilia| attempt to employ certain non-eytotoxic me
SMALL CELl, CARCINOMA OF Till{ LUNG

253

As with limited disease, extensive disea~ patients tend to develop initial relapse in previous sites of bulk disease. As upposed to limiled disease where an intensilication and/or dive~ifieation of therapy directed toward the p 6 m a r y tumor presents an obvious initial and readily testable research strategy, the problem of relapse in disseminated bnlk disease sites presents fi~rmidable problems in developing an apprnpriate therapeutic research strategy lbr all patients. I t has been the tendency during the last decade to design a single treatment program fi)r all extensive disease patients, independent ofpertbrmance starers, tile pattern of metastasis, the n u m b e r of disease sites involved and the quality o f response to initial therapy. This broad strategy may not be appropriate. Rather than treating all groups of patients similarly, it may be more appropriate to design dill}went types of stra|egics ibr dill~:rent sub.~ets of patients. T h e fimndation o f a tailored strategy rests upon the use of a combination of eurremIy available drugs which gives a consistent, substantial complete response rate. Many of the r~2gimens presented in Tables 8 and 9 have not been evaluated in large pa6ent pop~dations. But if40--50~(~ complete response rates can he consistently achieved, the group ofconap!ete~ responders may be at substantial group which should deserve: sepala~te consideration. T h e achievement of complete response is d e p e n d e n t upon several interrelated i]lclo~s including perl}~rmance status, tile site ofh~volvement and the n u m b e r of involved sites+ Tw~ studies have shown that patiems with a single metastatic disease site have a higher response vale and su~-¢ival than patients with multiple siles (5 I~ 54). 1t might be po~ible to g!ve intensive ~onsolidation lher~py wid~ t'idler saldiation d~erapy orintraarlerial chemotherapy in single sites slleh as bone, ~xrtroperitoneal structures or liver, respectively. Patients with hone marrow as the only site of involvement might benefit fi-om intensive antileukemie type therapy. Patients achieving complete response may be the ljcst grol~.p to t~st the t}2asibillty of employing l~erni- or whole-b(~Jy radiodlerapy as an adjunct Io chemotherapy, particularly in patients receiving non-a|~thraeyeline-containing therapy, in addition, the concept of late intensification as used in acute myclogenous leukemia (10) or explo~ ing the relevance of the Norton Simon hypothesis (75) may be best applied in this group. Patients achieving partial res|yonse tend to be those with poor perlbnnance scores and m~dtipte disease sites at presemadon. Although the inidal respo~se to 01erapy may be clinically important and gratifying in individual patients, as a group, such patienu~ have a dramatically short response duration and survival Such patients might represem an important group to study new agents or innovative approaches to therapy as initial treatment.

Summary The last decade has seen the development ofmoderately efl~:ctive therapy for patients with SCAC. When combinations of the most active drugs are employed the majority ofpatients with both limited and extensive disease can be expected to respond to such therapy~ Contemporary aggressive programs have substantially increased the median survival of treated groups; more importantly, a significant minority of patients with limited disease can now be expected to be alive and disease-free at 2 yea~, with a chance for long-term survival. Ahhough 0nly a fizv., patien~ with extensive d i s e ~ e survive for 2 years, a response to treatment is g e n e ~ l l y a~oeiated with significant palliation and increased survival. Thus, the availability ofthe drugs active in this disease provides an opportunity for the m~ority of patients to derive some benefit from treatment.

254

R. l.,, COMIS

C l e a r l y , tile strides w h i c h h a v e b e e n m a d e h a v e b e e n c l i n i c a l l y a n d t h e r a p e u t i c a l l y significant; yet, t h e Ktct r e m a i n s t h a t o n l y a m i n o r i t y o f p a t i e n t s a r e c u r e d o f t h e i r disease. C o n t i n u e d r e s e a r c h is t h e r e f o r e m a n d a t o ~ i f t h e m ~ o r i t y o f p a t i e n t s a r e to be c u r e d ( I 8), O n a clinical r e s e a r c h level, t h e c o m e . t o n e to this r e s e a r c h will be to use t h e m o s t a c t i v e d r u g s in t h e most e t ½ c t i v e m a n n e r while e x p l o r i n g d i l l ~ n t m e a n s o f i n t e g r a t i n g s u c h t h e r a p y into a r e a s o n e d , t a i l o r e d s t r a t e g y for specific g r o u p s o f patients. I n cow,junction w i t h this a p p r o a c h it will b e n e c e s s a r y to e x p l o r e |be t h e a c t i v i t y o f n c w a g e n t s w h i c h Call be successI~tlly c o m b i n e d w i t h tile m o s t a c t i v e e x i s t i n g d r u g s . T i l e d e v e l o p m e n t o f c u r a t i v e t h e r a p y for testis c a n c e r r e s u l t e d t~om s u c h a s t r a t e g y w h i c h c o m b i n e d n e w d r u g d e v e l o p m e n t r e s e a r c h w i t h r e s e a r c h i n v o l v i n g c u r r e n t l y a v a i l a b l e age|its. O n a t n o r e basic level, tile a v a i l a b i l i t y o f n e w biological systems m a y p r o v i d e a b e t t e r u n d e r s t a n d i n g o f g r o w t h c o n t r o l m c c h a n l s m s critical f o r t h e s u s t e n a n c e o f tile m a l i g n a n t process. I f specific gcow~h lhctol~ a r e d i s c o v e r e d , it m a y be l ~ s i b l e to d e s t r o y S C A C cells in a h i g h l y specific m a n n e r . I t is p o ~ i b l e t h a t t h e significant t h e r a p e u t i c a d v a n c e s w h i c h h a v e b e e n m a d e in t h e last d e c a d e will b e f a r s u r p a s s e d b y l~ature r e s e a r c h efforts w h i c h will c o m b i n e d l n l c a | a n d basic k n o w l e d g e in a comprehensiw.~ a t t a c k o n s m a l l cell I t m g c a n c e r .

References I. hheloff, M~ O~, Ettinger, O. S,, Bayliu, S. B~& I |azTa, T. {197G} Xlu,~geme~t ~small call ¢~rch~oma ~f the hmg: Therapy, ~taging and bi~zhemicat marke~ Cancer 3~g: 1394 - 1401. 2. Abe~o~ M~ D., Eltinger, D. S., Khouri, M. IL & Lenh~rd, R. E.,Jr. ] 1~)79) Intotslve induction the~,py for small cell carcinoma of the lung. Canea Treat. Rep. 63:51 $)524. 3~ Aisner, J** Whitacre, M . Van Eden, D. A~ I~sterhay, R. J, & Wie~ik, P. 1L {1980)Alten~ating noacr~sresistam combination chemotherapy for small cell ca~i~oma ofthe lung. Pr~-. Am. A s ~ . Canter Res. 21: 45:L •L Aisner~ J. & *~Vicrnik, IL }L (19~d] Chemotherapy versus chemoimm~nodleraoy in small cell us* dilfi:reutiated earrnoma of the lung. tTanea4~ 2543-~2549. 5. Ai|~zrto, P.~ Brum~cr~K. W**Marts, G.. Obrccht,J~ P. & Sonntag, R. W. (1976) Treatment ofbronchogenic carciBoma witli simultaneous or se.qtte~xtialco~nl~,~atlot~chctt-,otherap¥, including Inethntrcxate~ cyciopbos#amide, pr~arbazine and vinc~tine. Cancer 3B: 2208~2216. 6. Alexander, M,~ Glatstein, E J . , G o . o n , D. S, & DanielsJ. R. (1977) C~mbined modality teen|meat fi~roat cell carcinoma of the lung: a randomized study. Cancer TreaL Rep. 6|: 1-6. 7. Archer~ V. IL, Giliam, J. 1). & Waggoner, J. K.. (1976) R~s#rato~ dis~:~e mortallty among t|raninln minet~. AmL ~V.17. Aead. Sci. 271: 28@~293, 8 Bergsagel, D. I:.., Jenkin s, R. D. T., Pringle~ J~ E, White, D, M., Fetterly, J. C. M., K l a t c h , D. J~ & McOermot~ R. S. R. (1972) Lung cance~ clinical trial of radiotherapy alone ve~u~ radiotherapy #us cyelophosphamMc~ Canger 30:621-6~7. 9. Bitran, J. (1978) Cnmbint~ mc'~lallty therapy for small call carcinoma of the lung. Paper presented at the V¢orld ~onCeres~ceot~ Lusxg C~r~ccr, Hi|ton Head, S.C. 10, ~ l e y , G. P., Freireich, ILJ., Gehan, E. McCrc~ie, K. B., Rod~iguez, V., Gutterman,J. & B u ~ , M. A. (1976) I~te intensification the~py for acute leukemia in remis.sion; chemotherapy and immut~othe~py. ,7. Am, Ated. Assoc. 2-35: 1021-1025, 11+ Bender, ~ E+, Selawry, O. S+, Charyulu, K+ N+, Ng+A, & Bagwell, S. {1981) A controlled clinical trial t~ting two ~tentiMly n o n - c r ~ resistant chemotherapeutic reglme~-~in smMl cell ~-~reinotna. Cheat 79: 327-335. 12. Bunn, P. A., ~ h e n , M. H., Ihdc, D, C., Foxsieck,B.;E., Matthews~ M.J. & Minna~J. D. (1977) Advances in small cell b~ndlc-genic carcinoma. Ca~er TreaL Rep. 6I: 333-342. 13. Btmn, P. A., Jr, Lichter, A~ S., Olatstein~ E. & Minna, J. D. (1981) R~ults of r*z~entstudi~ in small call hronchogenlecarcinoma and prospec~ for future studio. In (Gr~.~o,F. A., Oldham, R~ K. & Bunn, P. A.Jr, ~.~s) Small Cell ~ g Cancer. New York: G ~ n e and Stratton, pp. 4!3-446. 14, Catane, g., Lichter, A., ~ e , Y . J . Brertdn~ H. D,, ~hwade, J. G. & Glats~ia, ~. (t981) Small cell lung cancer. Analysis of f ~ a t m e n t facto~ eontributlng ~o prolonged snpeivM. G'aneer48: 193~-1943, 15. Cavalli, F., Goldhirsch, A.~ Siegcnthaler, P., Kaplan, S. & Bier, M~ ( i ~ O ) Ph~e |l study with cis-

SMALL G~LL (~,R(HNOMA OF TltE LUNG

255

dichlor~tiammine platinum (11) in small veil anaphl~tic brmwh~enie carcinoma. ~ r . ~. Cancer I& 617~621.

16. C~valli, F., Jnngi~ %'. F., Sonntag, R, W . t'qi~n, N. l. & Holland, J. F. (1979) Ph~e 11 trial ofcisdlchlor,~diammine platinum (l I) in advanced malignant lymphoma and ~,ntaUcell hmg cancer: prdhuinary resule~. Cantel 7)eat. Rep. 6 3 : 1 5 ~ 1603, 17. C:hoi, H. & Gar~:y,R. W. (1978) Small cell anal)l~tle carcinoma ofthe luug. Ganxrr 37: 2658. 18, (~hen, XI. H. (1980) Small cell lung cancer: r{~trained optimism, lnL 3, Radial On¢oL Biol. P~rs. 6: 1119,,.1120, 19~ C:ohen, M. II., Chretlen, IL B. lhde, D C . F~i~'k~ B, IL, Makueh, R., Bunn, IL A., Johnstou, A. V., Shaekl~ey~S. E., Mat*hews, M,J., lapson, S, D., Kcnady, D~ bL & M h m a J . O. ( 19791Thymt~in fraedo~ V attd intettsi~.~cmllhlnatkm chemotherap% Prolonging the sttrviwd of patients with small ceil lung cancer. 3. Am, ~lltd. Aa'~o¢.241~ 1813=t815. 20. C~hen, M. H., Creaven, P. L, l:ossieck, B. E., Bender, 1,. E. Setaw~2¢~O. S,,Johnstou, A, V,, ~Yillia~, (i, L. & AllnuaJ. D. (1977) intensive chemotherapy ofsmall cell br~meh¢~genlccarcinoma. Ca~tr "l%'¢at.R-ep~61~ 349.~354. 21. C4~hen,2,d. I1,, lhde, D~ C., Buun, IL A.,Jr, F<~ie~k, B. E.Jr, Matlhews~ M.J., Shaekney, S~ E.Johnston. l~arly, A., Makuek, R. & M i n n a J . D. (1979) Cyclic alternating comlfinatlon dicmodtcrapy for small cell hronchogenie carci,oma. ¢~M~urr Treat. Rep. 63~ 163--170. 22. (~)hel|, XI. H., Lichter, A. S.~ Bu||n, P. A., Glatsteiu, E.J., lhde, I). C,~ I:osai~a:k,IL E.~ ~latthews, M J . & Minna,J. D. (1980) Glic:motherapy*radiatlon therapy (CI\ RT) versus chem~the~q~y (CTF)ill llmhed smMI cell hmg cancer (SCLC). Pr~-. Am. Assn. Canter Real 21: 448. 23. Chdtcn, NL H. & Mat*hews, M.J. (1978} SmMI cell br~mchngenie citrciuoma. A distinct elinicopathotoglc entity. Semin. Or..oL$: 23¢ ,243. 24. Gomis, R., Meyer, J.~ Gi~tsberg, S., I ~ I L B.~ DiFino, S., "l]nsley, R & Gullo, J~ (198t) F.flbctiven~-sof coulbination chenmtherapy (CT|I) |)Ills adjtlvant surgc~ in small cfll anapktstic hmg cancer (S~XLC), P~oc. Am. A~. Clin. OmoL 22: 50~. 25. Dejagcr, R+, [d.mgeval, E. & K|~ste~ky, J. (1980) High d~,. cLsplatln with llnld and mamlito| dinrcsis h~ advanced lung cancer: A #tase I 1 clinical trial of the EORT~ hmg cancc¢ working party (BeMium). Ganctt "l'reaL Rep. 64: 1341-1346, 26. Dhafir, R. A., Eiahorn, L. H~ & Wiliams, S. (1981) The effect ~ etol~ide (VP-16) used alone or iu combination on die survival of patients with refractory tt~tlcular cancer. Pro¢...in,. S~. Clim OncoL 22~ 464~ 27. Dom~rnowzky, P, Hansen, it. H., Sorel~en, S. & Osterlind, K. (1979) Sequential versus non-sequential comMnation chemotherapy using 6 drugs in advanced small ~11 carcinoma (SMAC). A contparativc trial including 146 patients. Pr~. Am. A ~ , Cancer Re~. 20: 277. 28. E~am~rnowsky, P , Hi~di , F.~ Ha~en, H. }t~ & Hainau, B. (1978) Peftoneoscopy in the staging r£ 190 patients with small cell anaplasfic carcinoma of the l~ng with sFmcial refi:rence to snbtyping. CMnu~41: 2"008-~2012. 29~ l)oml:~:rno~ky, IL, ~rctLson, S., Aisner,J. & Hanson, H, H. (1979) Cis-dichlorodiammine platinum (11) in small cell anaplastic bronchogenic ca~inoma ~ a ph~e II study. Cancer 7,C'eaL Rtp, 63". 543545. 30. ~ g a n , R~ T~, Care, D, T~ Lee~ R~ E.~ F~,tak~ S., Rnbln, J. & C o l ~ D. T. (1977) Phase: 11 studi~ of Fq31ychcmotherapyregimens in small cell lung cancer. Cancer Treat. l&p. 61:93--95 31. I~monson,J. H.~ Lagak~, S. W., Selawp/, O. S., Pcrlia, C. P., BennettJ. i . , Mu~ia~ F. M., ~Vampler, G,, Br~ovsky, H. S.~ Horton, J , ()MskyJ., Mar~our, E. G , Grecch, R., Stoihaeh, L., Greel~pan, I L i . , Levitt, M,~ Israel, L , Ezdinli, E. & Car~mne~ P. (1976) Cyclo#l~sphamide plus GGNU compar~ to cyclophosphamide alone in the treatment ofsmall cell and adenocarcinoma of the lung. Can,re ~_l-real.Rep. ~ : 925--932. 32. Feld, R. ( 198 }) Complicatioe6 in the treatment c-17smallcelt carcinoma of the lung. Ca~'er T~ent. Re~.g'. 5--26. 33. F o r b ~ J . T., Green, F. A. & Oldham, R. K. (1@1) Immunoblology ofsmall cell ca~inoma, rln (G~C~~, F. A., Oldham, R. K. & Bnnn, P. A . Jr, Ms) Small Cell Lung Cam~. New York: Grane and Strut,on, pp. 327-352~ 34. Fox, R. M,, Tattersall, M. H. N, & *¢¢~s~ R, L. (1981) Radiation therapy ~ an adjuvant in small cell lung cancer treated by combination chemotherapy: A ~ndomized study~ Pr~. Am. Sere. Clin~ OmoL 22."5"02. 35. Fox, R . i . , R L., B ~ i e , C. N. & Tatte~Ml, M. H. (1980) A randomized study: starlit cell anapl~tic lung cancer treated by combination chemotherapy and adjuvant radiotherapy, int~ .7. Radial. O~oL BioL Phys, 6: 1083-~10~ 36. Fox, W. & Seadding,J. G. (1973) Medical R~eareh t~unci! comparative thai ofsurgery and radiotherapy for the primary treatment ofsmaU celled or oat call carcinoma of the brondms. Ten year f~low-up, t ~ e e t it: 63~35.

256

R. L, C O M I S

37 Gazdar. A. F . (~rt~ey, D. N . gun, ell,I~.K . Sink's,H. L . l~aylln, S. B:. Bunn, P. A . Guccion.J. Go & Mhma, J~ D, (1980) |~tabl~hmenl ofcomlnuo~, clonable cultures ofsmMl cell carcinoma of the |ung which have amine prccu~or nplake and dcearlmxylatlon pr~>~r~ie~s~Cancer Res. 40: 3502~3~7, 38. Giz~Dcrg, S . J . Cmmis, R. L. & Gottlicb, A.J~ (1979) ~ m g term su~ivo~hip in small cell anaph~tie lung carcinoma. Cancer 7~¢aL Rep. ~3: 1347~1349, 39. Greco~ 1:. A., Brercton, H. I). Kent, H., Zimbl~ o~IL, ,Mcmll, J, &.!uhv~n, R. E (1976) Adriamych~ and enhanc~l radiation reacdon in normal ~ p h a g u s and skin. Ann. Intern. Ated. 85: 29@298. 40. Greco, F. A~, PSnhor~l~ L. H., Hande, K. R. & Oldham, R. K. (1979) Phase II s/udic~ i~ rcsistam smMl call lung cancer. Prec, Am. A~soc. Cancer Res. 2 ~ 28. 4L Grco), F. A . Einhor~, L. H . Richardson, R. L. & Oldhanl, R. K. (1978) Small cell lung cancer. Progr~s and ~rsW2ctive. Sere|n, O~d, 5: 323~335. 42~ (}~co, F, A,, Harde~ K. R . Richardson~ R~ L. & Oldham, R, K. (1980) High d ~ e mcthot~xate in combination chemotherapy for smMl cell lung cancer. Rec~t Resn/t~ Cancer Res. 7 4 : 5 0 55. 43. Gr~co, F. A. Rid~ardson, R. L., Sht~lman, S. F., Stro~p, S. & Oldham, g . K. (I978} The~qW ofoat ceil caminoma gffthe lung: complete remissions, acceptable complicatlt~rL~and improved survival lit, Afed..7, 2: ~ . Hat,de, K, R . Old|tam, R. K . Fee, R. L , Richardson, g. L. & Gr~o, F. A. (1981) A randomized trial of | l i # dose (HD) vs. low dose (LD} nlethotrexate (MTX) in the tr~tment ofcxter~sive stage smMI re|| lung cancer. Proc. tim. Soc. Clio. OneeL 22: 505. 45. Hansen~ }L H . |)om|~crl~ov;.ky, P., Halogen,H. S. & l(orlh, M. (1979) Chemotherapy venus chcmotheralry #igs radiothcrgtpy ill ~giouM small cell carcinoma of the lu|~g ~-a randontizgxl trial P~o¢. elm. As~e¢. C'at~xer ICes. 20."277~ 46. Hal>sen, H~ H.~ l)omhcrnowsky~ P., Ha~s,:n~ M. & Hir~ch~F. (1978) Chemotherapy ofadvan~cd small cell anapl~tic carcinoma: superiority ofa lbur drug combination to a |here drug comMon>ion, Ann. l n u ~ . ,Sled. ~ : 177~181. 47. Hansen, H, H.~ Dom|~rno~ky, IL~ Her~ch~F. & Rygaard~J. (1977~) |n|eusive combination chemothc~lpy plus Mcalized or exteusbee r~d6c~therapy in SlaM| cell anapl~stlc brouchogcnic carcinoma (SMAG). A randomized trial. Pr~. ~|m. Soc. Ctin. OmeL 18: 350, 48. Hig#ns~ C. A,, Shidds, T. 1V, & Kcehn, R.J. (1975) The solhaD~ pulmonary nodule. Ten year fi~lluwup(ff Veterans Adm{nistvatior~--,A,mcdi%rcc, coo~rative study. Arch. Surg. 110: 570~575. 49. Hirsch~ Fo R,, Hansen, H. H. & Hainau, B. (1979) Bilateral l~one marrow examinations in small call a n a # ~ t i c carcinoma of the lung, Aeta Pathol. 3lierobioL Seand, A 87: 59~62. 50. Holoyc, P, Y., Samuel>, M. L,, Lanzotti, V. J., Smith~ "lL & Barkley, H. T. (1977) f~mbination chemotherapy and radiotherapy for small cell carcinoma, 3. Am. 3led. Asaoc. ~ 7 : 1221-,01224. 51. ihde, D. C., Makuch, R. W . ~ h e n , M~ H., Bunn, P. A., Mat>hews, M.J. & Minna,J. D. (1979) Prognos|ic imMication~ ofsit~ of nlet:~ta~ in patients with sma|l cell carchloma o f the lung (SGCL} 6 y e n intelL~ive chemotherapy. Pr~-. Am. A~s~c. Career Res. 20= 264. 52 ls~el, L., DiPicrre, A & Choffe|~ C. (|977) Immun~hemotherapy in 34 c ~ , ; of 6mt cell carcinoma of>he |ung with 19 corn#ere e ~ t ~ s . Cancer Treat. Rep. 61~ 343-347. 53~ JaoM,.,% L.. Kinkel, W. R. & Vincent, R. G. (1977} "Silent" brain met~tases f~om |ung carcinoma determined by computerized tomogra#y. Arc,~.~uroL 34:6 54. Jacohs, S. A., Sandky, M.J. & Stoller, R. G. (I980) A eompar~on ofsurvivM in subse~ o f p a t i ~ with extend>lyesmall c~ll ca~inoma of the |ung (SCC). Proe. Am~ Ass~. Cancer Re>. 21: 455. 55. Joh~on, R. ~., Brercton, H, D. & l<-en%C. H. (1976) Smal~ cell c a ~ n o m a of>he lung: at~mpt to r e m ~ y ca~es o f p ~ t thera~ude failure. Lancet it: 1. 55. Johnston, R. E,, Brercton, H. D. & It.era, C. H. ( t 9 ~ ) Total therapy forsmal| ceil ca~inoma of the lung. Ann. Tl~ora¢. Surg. 25:510-515. 57. Kant, R, C . ollar, M. R. & Bieler~ D. D. (1979} Alternating drag c~mbinatio~ in small cell b~nchogenic carcinoma (SCBC): A randomized triM. Pr~. Am, As>at. C ~ n ~ R~. 20: 406. 58. ~.it~g, A~ H., B e ~ , R,J, & Newman, C. R. (1975) eat ofsmaU call carcinoma of the bronchus. L a ~ t i: 129~i 32, 59. ~e~ R~ ~., Care, D. T~ &Childs, D~ S. (1976) ( ~ m ofsplit cour~ radiation therapy and continuous ~diation therapy for unresectaMe broneh~enie ~ n c ~ a : 5 year ~UltS. Am. ~. L Ra~ T~. ~ . Aeed. 126:1 tE--122, 60. ~ i U , M., Meikle, A., M u ~ y , N: & ~,/ei~erman, B. (1978) Oat cell carcinoma ofthe lung~ CNS metastas~ in s#te of prophylactic brain irradiatt0~q/Ca~,~er.~'tat. Rep. 62." 131-133. 6 I. Livingston, R. B. (1978) Treatment ofstrmll cell c~rci~oma: EVolution and future direction. Semin. Oi~eL 5: 29~30&

SMALL CELL CARCINOMA OF THt{ L,UNG

257

62. LivingSton, R. B. ~ w ~ 3,, t t a ~ , C. & lleilbn~tl, L. (| 979) Un~×pcct~l ~oxicity of ¢omNm~ ln~alh~ therapy tbr ~mall c¢ l ..a~irmma of Ihe lung. A Sunthwest Oncohx~y Gr~,ap study, int~.7. Radial. On,d, BioL Phy~ 5: 1637-,~I~L 63. Livingston~ R. B. Xt~re, % N., Heilbruti, L . Botlomley, R . Lehane~ D., Rivkin, S. E. & T|ligpen, % (1978) Small cell carci)lOlna tff lhe hltlg: combined chemotherapy and radlation: a ~aih~'est Oncolo~W Group Study A~n. l~tt¢~. Attd~ g~: 194~,t99~ (~. Livlng~ton~ R. B., Trautb. (LJ. & Oreenstreel, R. L. (1981)Sma|l cell rarcil~nla: clinical manlf~tatiims and behavior with t~alment, in (Greeo~ F. A., Oldlmnl, R. K. & Btmn, P. A.,Jr, eds) Small Ctll Lnng C~nr~ New York: Grm~e and 8{fattou, t~). ~ 8 5 ~ 1 , 65. Lowenbraan, S~. lartolucci, A , SmaHey, R~ V . Lynn, M , Kraal, S.~ Durant,.t.R. & ThcSoutheit.~tern ~ t l c e r Study Group (1979) The sul~riofiW ofcorablnatitm chelatorherapy {wee single areal chemmherapy in small cell lung cancel Cantle 44:41~413. 6@ X|a.~n, iL A . Richter, M. it., Catalano, R. IL & (:re~e|h R. [l. (198l) Up|)er hemitu~y radlntlou (UI|BI) and I~al eh¢~{ irradiatM~ (LOll ~ co~tsolldation follo~vi~gr~u)~se to high denseinduction chemotherapy l~arsmMI cell l~ng ear,aroma {*$CL(~) ~a pilot study. Pro~-..din. ~ . Clin. OntM. 22: 498. 6~. Mattlw~vs, ~t, J. & Gazdar, A. F. (198l) Small cell earclntnnll iff tile hnlg and its v~fian~: A ctinlcopathoh~c ¢orrclatlon, In (McGttire, B'. & [jvlngstot~, R, B,, eds) Lung Cagtr. ¢ld~nce~ i~ I~¢scatdi~ml Tteatmt~L q'he H~gue: Martinns-Nifl=o~ I)P- 283° 330~ ~ . Mau~r, L. }t.~ TuHoch, M . XN~xs, R. B.) Biota, J,, Leone, L , Gildewell, O. & Pajak, "|L F. (1980) A randomize~ combined m ~ a l h y trim in stnali cell carcitloma d the lung, C~r~er 45: 30,-39, 69. McMahon~ L. A., H erman~ T. S., Manning, M. R. & Dean)J. C. (1979) Patler~ ofrelapse in pa~ten~ with small cell car~cinomaof the |ung treated with adHamycin cyclophosphantlde chemotherapy It|td radiation therapy. C~)~rr Treat, RZp. 63: 359.o362~ 70. ieyer~ J. A., C~mis, R. L.) Gir~si~rg, S . J . ikirL% P. M., Burke, W. A. & Parker) F. B. (1979~ S~21ectlve s ~ i e a l resectio~ in sr~all (tell carcinoma of the |nng~ .7- Threat. Surg. ~ : ~43 248~ ?l~ Mira)J. G~ & Livili~ton~ R. B. (l.qSO) l{valuatio~tand radii)therapy iln#icalh)r~,~t~fchest relaw~ patten~ h~ $)na|~ ceil it)tlg eaFci|lolrla treated ~t|~ radiotherapy~ chemot|terapy: study of 34 e e ~ attd rx:viewof t|u~ literature. Cancer 46." 2557-~565~ 72. M ~ y , T. 'i,V., Pert, C. IL, Gazdar, A. F,, CLarncy,O. N. & MintlaJ. D~ (1981) High level ofintraeelhdar ~ a m ~ i n characterize hm~an smMi cell ~areinoma. Se/t~ce21'l: 1246. 1248. 7~. Mountain, C. F. (1978) Clinical biology c4 smMl celt lung cancer: Kelagonship to .~urgjcal therapy. Strain. OmaL 5~ 272-27D. 74. Mountain, C. F . ~trr, iX T. & Anderson, W~A. l). (1974) A s~tem for the eliniea| staging oftung cancer, Am. ~. Rot~tgtnaL 120: 1 ~ 1 3 8 . 75. Norton, L. & Simon, R~ (t977) Tumor size, sensitivity to therapy and d~ign of treatment sehedult~. CMncet 7>eat. Rep. 61: 1307~-1317. 76. Oldham, R~ K. & Greoa, F. A. (1980) Small cell lung cancer: a curab|c d l v 2 ~ . Canter . Pha~aeoL 4: 173o,177. 77. Oldham~ R. K~, G ~ o , F. A., Ehlhorn, L. IL) Per~, C., Birch, R . F/~ter, iM. & Krau~, S. (1981) P~liminar~ r~uhs uf a randomized trim to evaauatc the role of radiotherapy in the eomMned modality therapy of limited stage small cell lung cancer. Pr~. Am. Sot. CIin. Or.d. ~ : 505. 78. Perez, C. A., K r a ~ ) S . Bartolueci, A. A., Du~ant, J. R., Lowenbraun~ S., Sa|tee~ M. M.) St~lra~li, J., Kellermeyer, R., F. & The S~uthea~tern C~anccrStud~ Group (1981)Tboradc anti elective brain irradiation with concomitant ordeiayed muhiagent chemotherapyin the management ofiocaiiz~ small cell carcinoma of the ban~: A randomized Dr¢~pectivestudy by the Southeastern ~ n c e r Stud)' Group. Can~' 47: 2~7-24 i 3. 79. Perry, M. t.~, ~ t o n , W~ L., Confis, R. L , Spaulding, M. B. e a s y , R. W. & Maurer, L. H. (1981) Simultaneo~ ~diadon therapy and chemothe~py in limited small cell cancer of the lung: a #lot study, Pte~. Am~ Soc. CID~. OrxoL ~2: ~ 3 . 80, Petted#ll, O. S., S o ~ n ~ n , G..D. & Wu~ter-Hil|~ D. H~ (19&9) lsMadon and g ~ w t h chamcteristh~ of contlnuom cell Hnes from small ceil carcinoma of the lung. Ca~er 45: ~ - . 9 1 8 . 81. Radi~, P. P.~ Bvua, P-~A.)Jr & |hdc, I3. C. (1979) T h e r a ~ u t l c tdal$ wi{h V P - ~ I 3 arid VM 26: Active agen~ in small cell lung cancer, non HodgMn's lymphoma and other malignantly. Caeca Trt~t. Rip. 63: 123| ~-1239. ~. t, F. P., gi~% B. L, Darting J, R. & Rosenbloom, B. E. (19B0)Phi: 11 e~luafion ofei~iam~ mlnedlehMr~platlnum (DDP) in emaR ceil carcinoma of the lung (BCC}. Peat. Am. Sac; Cgin, Oa~oL~1: 449. 83. Salazar, O. M, & Cx~cb, R, H. (I977) Thcstateoftheart: Towar~defintng thcro/eofradMtion therapyin the management o f s m ~ ceil lung canape. Int. ft. ~ d a t . OmoL BiaL Phys. ~ 1103-1117~

258

R. L COMIS

~. Sala~,~r,O. M., Creech, R. H . Rubln, P., ncnnett,J., M ~ n , ~. A. Young,JJ.. Sc~rantino, C, W. & ~talano, R. B, (I 980) HMfbe~ly and 2ocMch~t i~diation ~ cop~Iidation following r~pon~ to standa~ induction chemotherapy for dimemlnatcd small cell hmg cancer: an E~tern ~mF~rativc Oneology Croup pilot rcport~ lnt~J. .~adial. OmoL Biol. Phys, 6," 2093~1|02.

85. Scha~l, F. M, Jr, Trader, M, W . l~zter, W. R. Cor~tt, T~ H. & Gfiswald, D. E (2979) Dichlon~Jiammine platinum (l l): Combination chemotherapy and cr~-r~istancc smdi~ with tamo~ in mice. C~nter Treat. Rep. 63: 2459~1473. 86. Schakney, S. E~, St~us, M.J. & Bunn, P. A.,Jr (1981) The growth cha~acte~sti~ of sinai2cell carcinoma of the lung. In (Greta, A. F., OIdham, R. K. & Bunn, P. A.,Jr, c~) S~all Cell Lung ~ e r . New York: Come and Stratton, pp. 225 ~234. 87. Sier~ki, J. S,, Hilafis, B. So, H a # n , S., Martini, N., Barton, D. Gol~y, R. B~ & Witty, R. E. (1979) Cisdiam mlncdlchloroplatlnum (1! } and VP- 1~213: an active ind uetion regimen for small cell carelnoma of the lunff C~'~ter 7~eat. Rep. 63: 1593~159L 88. Sikie, B. I., Daniels, J. R., Chak, L., Alexander, M., Kohler, M. & Caner, S~ K. (2982) venus POCC-VAM the~py for small cell tung cancer. In (Pr~taykn, A, W., C ~ k e , S. T., Baker, L. H., ~aner, S. K. & Schein~ P. S., eds) Nitrosoureas: CurrentStal~ and 2~to . New York: Academic Pre~ pp. 221~231. 89. Silverberg, E. S. (2~2) ~mccr statistics, 2981. Ca 31~ 13-28. 90. St~'e,~, ~., Einhorn, L. & Rohn, R. (2979) Treatmem ~ffllmltcd small cell 2m~gca~er. Pra~. Am. A.is~. Cancer R¢$~201 43~,

91. Tiehler, A. S. (1978) Small cell carcinoma of the hmg: cellular origin and relationship to other neop2~wa. ."~in. On~l. 5: 2~252. 92. Urt~un, R,, Belch, A., ttiggi~, E., Saunde~, W~& MaeKimam, S. (1980) Whole ~ t y i~adlatioo ~small cell carcinoma of the lung com~tr~ to three d~g chemotherapy. P~u. Am. Asm. Canter Rts. 21:45 l. 93. VMdivieso, M., Cahanill~, F., Barkley, H~T., Mountain, C~ F. & BMey, G. P. (t980) Intet~ive induction chemotherapy of extensive small cell bronchogenlc carcinoma in protected enrichment--p~phylactle antiMotic unil:s.A p~limina~ ~ r t . lot. ft. Radial. Oe~wl.aioL I~hys:6: 1087-q002. ~ . Warring, W. G., Byficld,J. E., Lagasse, L. D., Lee, Y. D, JuillaM, G.,Jacobs, M. & Smith, M. L~ 0974) Combination adfiamy6n and radiation therapy in gynecologic cancer,. Oncol. 2: 5t8~526~ 95. Veei~, W~ (198!) Small cell o~inoma ofthe lung. Epldemiology and etiol%~. In (Greco, E A., Oldham, R. K. & Buno, P. A,Jr, c~s) Small Cell ~ g g Cancer. New York: Grm~ and Stratton, pp. I~35. 96. Whang-Peng, J,, Bunn, P. A,,Jr, Kao-Shan, E., ~e, E., Minna, J. & Gazdar, A. (198!) Non random chromosomal abnormalitk~ (3P) in continuous cultur~ ofsmall ~I1 luug cancer. Pr~. Am. Asso~. C'as~erRes. 22: 45. 9L Wolf, j., Patna, M.E., t, B. & D'~:~po, l'L (1966} ~ontroUcd study of survival of patien~ with clinically i n o ~ b l e lung cancer treated with radiation tllerapy. Am, ~7. Med. 40: 3~-367. 98. W ~ R. L., Tatteesall, M. H. N. & Fox~ R. M. (1981) Hemii~dy irradiation in " ~ o r progn(~is" small cell lung cancer. Plot. Am. Sac. Clio. OmoL 22: 502. 99. Wright, P~, Schutman, S., Dav~, S., Ande~n~ S., ltammar, S. Hil2, ~ , ~ , W. & Thorning, D, (1981) Une×pcct~ly t~avomblesuPelval without intemive ~mhinadon chemotherapy in patien~ with smMl cell lung cancer, lqu. Am. Sac. Clio. Onc~L22: 493. 200. ~charski, L R., HetuJer~n, W. G., Rickl~, F. R. Fo~an, W. B., ~nld2, C . j , Forcier, R.J., Edwards, R., Headley, E., Kim, S-H. O'Donnell, J. R., O'~dl, R., To~y~, K. & Kwaan, H. C. (1981) E ~ t of warfarin on survival in small cell ca~inoma ofthe lung. Veterar~ Adminlst~tion Study No, 75. ~7.Am. Meg. d~ac, 2~: 832-835~ 202. Zacharski, L. P.., Henderson, W. G. RicMes, E R. Forman, W. B., ~rnell, C.J. Foreler, R.J,, Harrower, H. W. & Johmon, R. O. (2979) Rationale and ~pefimentM design for the VA cc~perative study of a n t i ~ t # a t i o n (warfarin) in the treatment of cancer. Caexer44: 732~74L 102. Zelen, M. (1973) Keynote addr~s on bio~tat~fi= and data ~trievaL ~n~er C,~met~. Rep. 4: 31-42.