The nitrosoureas: carmustine (BCNU) and lomustine (CCNU)

C~tr Treat~ a ~

(1982) 9, 313-330

The ~trosoureas:

~

~,e

R a y m o n d B. W e i s s * ~ d

Bri~

(B

) and lomustlne

E IsseH~

*Cancer Therapy Eva Program, Diw~ion of Cancer Trea#nent, .Vational Cancer Institute, and the Uniformed University oafthe Health Sciences, , ~.4a~land; and the Reed Army ~ Center, , D.C., and t of State Un of )~.,.o Tork-Upstate l Center, and Bristol L~boratoffes, Syxacuse, J~a~ York, U.&A.

Introduction

Carmustine or B~-~U (BicNU R, Bristol Laboratori~, Syracuse, New York) was in~oduced into clinical trials in the United States in 1964 and was approved by the U.S. Food and Drug Administration in March I977 for the treatment of brain tumors, H ~ g k i n ' s disease and other l y m p h o m ~ , and myeloma. L o m ~ d n e or CCNU (Cc~NU x, Bristol Laboratori~), a carmustine analog, was approved for marketing in A u g h t 1976 for ~ e in brain tumors and Hodgkin's disease. When both d r u ~ were initially evaluated in clinical trials, there w ~ great enthusi~m because of their unique lipid solubility, lack of crossr~sistance with other alkylating agents, and apparent lack o f sefio~ toxidty other than vomiting and myelosuppr~sion. Since thei r marketing 5 and 6 yea~ ago, dvely, this enthusiasm has been tern~red somewhat by the t~ct that their andtumor acdvity in man is mo~dest and offset by often prolonged cumulative m y e l ~ u p p r ~ i o n and a ~ t e n d M for Hfefllreatening pulmonary and renM toxi~ty. W e ~view and update herein the pertinent chem~try, pharmacokineti~, clinical emcacy and toxi~des of flie-~ two chemotherapeutic agen~ with emphasis on data published in the past 5 yea~. Historical dev The discovery and development of the nitrosourca compounds re.suited from the National Cancer Institute (NCI) anticanccr drug development program, p m provides an organized means of scrcefiing c o m ~ u n d s for antitumor activity in animal tumo~ and Repent ~ u ~ s to: P.aym~nd B, Weir, M.D.. Seclion of M~ic~l Onc~lG~, W~t~:r R ~ d A ~ y ~mcr, '~V~hington,D.C. 2~12, U.S.A. 0305-)372~

13 + |8 $05.00~

i~ |~2 Ac~de.~ic ~

315

lnc, (London)

Medical

314

R.B. WEISS AND B. F. ISSELL

h u m a n tumor x e n o ~ a f t s (25). Once significant a n d t u m o r activity is demonstrated by a n y substance, NCI-supported laboratoH~ s y n t h ~ z e analogs of the agent to submit to the animal tumor s c r ~ n in hopes ofdiscox~e~ng other active substance.

T h e Southern R e s e a ~ h Institute began synthesizing rational analogs, and t h e first one, Imethyl- !-nitro~urea, w ~ active against L 1210 routine leukemia~ A more notable fact was that it w ~ active against intracerebrally implanted LI210 leukemia, suggesting that the drug wa.s able to cro~ the b l o ~ - b ~ i n barrier. This fact encouraged the synthesis offiarGher N-nitroso a n a l o g . C a ~ u s t i n e , the 23rd analog synthesized, had marked antitumor acdvity in the animal tumor screen and w ~ selected for clinical t h a i (78). A n o t h e r analog, lomusdne ( C C N U ) , w ~ later introduced into clinical thai a|~er it was found t~ have greater effect than c a ~ u s d n e agMnst intracerebrally implanted L I 210 leukemia (78). T h e t ~ k ofsearching for rueful analogs continues at the Southern Research Ins tute add has resulted in the introduction of three other n i t ~ s o u r e ~ ( ~ m u s d n e or m e t h y l - C C N U , chlorozot~=in and P C N U ) into clinical trial. Also, Japanese r e s e a ~ h e ~ synthesized a water~ and lipid-~luble nitrosourea designated A C N U in |974, and clinical trials with this agent are being conducted in J a p a n (76). O t h e r J a p a n ~ e i n v ~ t i g a t o ~ have initiated clinical tridls with two water-soluble nitrosourea~s designated G A N U and M C N U (67). ~ c a u s e all of these n i t r o s o u ~ remain inv~stigationai, they will not be d i s c u s s ~ here.

~emlst~ T h e structures o f c a ~ u s t i n e and lomusfine are compared in Figure 1. M¢'ork conducted at the Southern Research Institute on structure-activity relationships h ~ shown that the his 2-hal0ethyl and cyclohexyl configurations of these compounds are e~entiaI for m a x i m u m anfitumo~ activity (G4). Numerous molecular variations in these two a g e n ~ have proved inactive (64). ~ t h a g e n ~ are Hpid*soluble and have low m M ~ u I a r weight, two c h a r a e t e ~ s t i ~ t h a t facilitate their" entry i n t o the brain. Studies with ~h~e two drugs in intrace:~brally implanted and s p o n ~ n e o u s animal brain t u m o ~ have demonstrated a consistent and high 1~3NU:

1,3-Bis(2~hior~hyt)-l-nitro~urea O C|-CH2--CH2-N-C--NH-CH2~CH2-C| ! NO

CCNU:

1.(2.chloroethy{).3¢yclohexyl.%nitrosourea .

NO

.

.

.

.

~

~gu~t L The ¢h~'mi~ structu~ of~rm~tlne (BCNU) and I ~ d n ¢

(C~U).

~ R M U ~ I N E #~D LOMUSTINE

315

level o f a n d t u m o r acdvity (10, 60, 78, 89). In some animal brain tumors, lomustine h ~ had an effect superior to that ofcarmustine (60). Among the available cancer chemotherapeutic a g e n t , t h e e nitrosoureas are unique in their high efficacy in intracranial animal tumors. Thus, interest in them h ~ f o c u s ~ on their use in h u m a n b-rain t u m o r .

Mechanism of action T h e cytostatic properties of the nitrosourea~s m a y he a ~ to i n ~ b i t o ~ effecu on DNA, F-ANA and protein syn . Some e x ~ m e n t s indLcate that the DNA synthes~ inhibition m a y result from interfe~nce wAth ourine ribonucleodde synthesis (103). Both drugs d e c o r a t e to yield chlomethyl moieties that can alkylate reacdve sites on nucleoproteins~ thus interfering with and R N A synthesis and D N A repair. T h e bifuncfional alkylafing a g e n t , such ~ mechlorethamlne~ require two reactive sites to produce their antitumor acdon through cross-linking of double-stranded DNA. T h e nitrosourea-s are monofunctional, hut they also apparently can produce cross-linking by a different mechanism. K o h n (48) h ~ shown that D N A c~oss-linMng d ~ occur and that Lhe reacdon a p p ~ r s to proceed in two steps: chloret~ylation o f a nueleophilic site on one strand and displacement o f a chloride ion on the other s t a n d . T h e ~ u l t is an ethyl bridge between the strands that preven~ unwinding of the D N A double h e l ~ , a lethal effect. O t h e r inv~tigamrs have m a d e similar obse~ations (54). A further molecular effect of these drugs is cadi3amoylafion of nucl rein lysine

carbamoyladon plays, at best, a minor part in either anfiturnor activity or n o d a l dssue boxidty. T h e high alkylafing activity of carmusfine v e ~ likely contributes m at least one of i ~ ~ i c effect, interstitial pnem~nonifis (I02). P u l m o n a w toxiciw can occur with mo~t of the biF~nctional alkylafing a g e n t . Alveolar lining cells are p r o b a b l y injured by che~tothe uric a g e n ~ through D N A ~ k y l a d o n , in a mariner similar to the D N A injury from free radicals Chat in o r radiation lung toxicity (102).

Pha~acokmedcs

~d

metabolism

These aighly reactive, and their chemical and b cal half-Hves are short. In as ] 5 rain after administration of either agent, no parent d r a g can be detect~ R a p i d degradation occurs and parent d ~ g is not excreted. Degradation products can b e detected in the urine up to 72 h after a d m i n ~ t ~ d o n , and biliar] excretion also s i g n i f i ~ n t (68). B ~ d u s e of this rapid de-~adadon , the nitrosoureas' is probably produced by one of the metabolites, ~ t h e r than the parent compotind. As suggested by their a~dvity t a n i m a l brMn ~umors ( l 0, 60, 78, 89), ~t~h agents and in animals and man (24, 88). Drug tministration at concentrations 15-3 c i ~ are ~ole to ~ n e t r a t e b ~ n fi~u, activity against a~Jmal b r a i n turn( hrmn tumors.

316

R. B. W E I S S A N D

B. F. ISSELL

Admmstration

and doses

C a ~ u s f i n e must be administered intravenously, because in t ~ f i n g oral usage it was found that a high percentage of patien~ had vomiting severe enough to preclude intake of adequate drug d ~ (52). Lomusfine is completdy absorbed orally and is well tolerated by this route. A rea~sonably tolerated dose o f c a r m ~ t i n e was d e t e ~ i n e d in the initial clinical trial to be 250 mg/m z of body surface area in a single dose, repeated at 6-week intervals (23). Other doses used have been 2 ~ - 2 2 5 mg/m 2 ofbody surl~ce area. Because the m ~ o r dete_rrninant ofdose is the myeLotoxicity of~daedrug, some dose individualization is necessaE¢ depending on the degree of marrow compromise by prior treatment or eoncurreht use of other d r u ~ . Most cUnicians have dected to administer the total dose over 2 or 3 days to diminish the em~is effect. The lomusfine dose is 1 ~ than c a ~ u s f i n e and varies from 100 to 130 mg/m z of body surface area, again d e ~ n d i n g on the marrow e.

Clinical activity Braz~ lumors

Malignant g l i o m ~ of the brain are uniformly lethal. When some of the earlier clinical trials witlh c a ~ u s t i n e and lomusfine demonstra~d antitumor effect in human gliomas (3% 93), there was great hope that t h e e two d r u ~ would prove highly beneficial in an otherwise hopel~s disease. Both nitrosoure~ appear to be usethl in the treatment of gliornas, but their impact is more m ~ e s t than ori~nally anticipated. In order to evaluate the emc~cy o f c a ~ u s t i n e in malignant gliomas, the NGI supported a randomized trial conducted by d~e Brain T u m o r Study Group. Three treatment modes ( c a ~ u s f i n e alone; 5 rad whole brain irradiation alone; or both treatmen~ together) were randomly c o m p a r ~ to a c o n t ~ l group receiving ~ t available supportive ~ r e (94). There were 222 evaluabIe patien~ in the study population. Survival w ~ m ~ the end point ofevaluation because of the difficulty in ing tumor changes in the brain in respor~e to treatment. Among the adequately treated patients, there was a highly significant improvement in median survivM compared to ~ e control group for t h e e patien~ receiving either the irradiation alone or the combined treatments (94). T h e combined treatment w ~ only slightly better than irradiation alone and the advantage was not statisfic~ally significant. C a ~ u s t i n e alone provided only a small impact on survival. Despite a 2.5.fold inCre~e in median survival b y use o f c a ~ u s t i n e plus irradiation, there was no " p l a t e a u " on the survival curve, i.e. there were no cures. A subsequent t~al by the Brain T u m o r Study Group randomly compared semustine, irTadiadon and carmusdne plus irradiation. This study, involving 358 evaluable p a t i e n t , confirmed the favorable survival effect of the latter treatment combination (95). T h e fi~t study (94) showed a median survival of 40 for carmustine plus irradiation; the second trial (95) showed a median survival of 51 weeks for this same treatment. Offurther interest, the second trial contained a ~ e a t e r number o f " l o n g - t e ~ suP~ivo~' (i.e. alive at l8 months) in the g ~ u p ~ceiving carmusdne 'plus irradiation than in the group receiving irradiation alone (95). Based on the resul~ of t h ~ e clinical t~als, ~ r m u s t i n e in conjunction with whole brain i r r a d i a t o n ~ now w i d d y ~ for treatment of malignant gliom~. Aldlough not curable

C,A.RMUSTINE AND LOMUSTINE

317

. . -~d'l . t b ~. combined t ~ a ~ e n ~ mea "mngful s u p r"a 1 prolongadon and p ~ i a d o n of neuro o~c defici~ ~ n be ac~eved. i n the t~als conducted by the Brain T u m o r Study Group. no attempt was made to control the dining ofadn~Anistradon of the two treaLmen~. ~ e ¢armusdne might be ~ven several days ~ £ o ~ or du ~ ng the fi~t 3 days of the irradiation, depending on individual circumstances. One can speculate d~at the changes in cerebrov~cular ~ e a b i l i t y p~duced by i~adiadon may influence the di~dsion o f c a ~ u s d n e into the tumor~ and t h ~ the Xmlng of ~ e two treatmen~ may have beating on their antitumor effecL Some laborato~ work with animal m ~ e l s sugges~ that treatment dming is vec¢ important (9, 104), but other work provides c o n t ~ d i c t o ~ data on this ~ i n t and thus there ~ no clear-cut ~m'e relationship ( 6 2 ) . Clinical trials testing the effect of dining of t h e e two treatmen~ are n e c ~ a ~ to clarify this p ~ b l e m . The Brain T u m o r Study Group h ~ specified in a recendy initiated thai that c a ~ u s f i n e will be a d m i ~ t e ~ d 16 h before irradiation, but no ~andomiz~J c o m p a ~ o n of"t r e a ~ e n t dining is being done. Lornustine has had similar emcaey in brMn tumo~ in uncontrolled studi~ (34). Two small ~andomiz~ tdals, involving 41 paden~ (98) and 63 paden~ (75), compared ~ r e e d i ~ n t treatmen~ in malignant gho ~ , i ~ d i a d o n alone vs~ lomustine alone vs. ~ t h modalities administered simultan~usly. In bodh trials (75, 98) the lomusdne-Mone ~ o u p s had shorter i n d i a . I s to recurrence and shorter s u ~ v a L The study conducted by Weir a a L (98) showed that the combined treatment group had a longer dine to tumor progre~ion than the group treated only with irradiation. The other study (75) did not demor~trate any advantage for the combined treatment over irradiation alone. A E u r o ~ a n study (33) t e s t ~ the value of lomusdne administered after completion of irradiation c o m p a ~ d to i r ~ d i a d o n fi~t and then iomusdne later when tumor p r o ~ i o n occurred~ In ~sence, this w ~ a trial of irradiation alone vs. ~quendM irradiation and |omusdne or tnl~al treatment ofglioma. T h e ~ w ~ no difference in the dine to progression ~eeveen the two treatment. T h ~ result ~ p ~ i b l y due to the fact that the eft:cot Of the nit~sourea may be apparent only when the drug is a d ~ n i s t e ~ simu|tan~usly witih radiation. Tt~e~ w ~ an overall su~ival advantage for the p a d e n ~ who received irradiation fi~t and then lomustine later when p r o g r ~ i o n ~curred, p ~ u m a b l y because the salvage t r ~ t m e u t with lomustine had a henefi~al, e~_~ct. A larger randomized study in I02 evaluable paden~ of irradiation alone vs. irradiation plus carmustine, or irradiation plus lomustine, was conducted by a group in Milan (87). There was an improvement in sup¢iv~ at !2 months for both groups ofpatient.s recei',dng a nitrosourea and lrrao!ation ore that of the group receiving only irradladono T h e ~ w ~ l~o su~tantial diffe~nee in sur~¢ivalat 12 months between the two nitrosourea-treated g r o u ~ . Although there is ~ m e inconsistency in the resul~ of vadous studio, it seems that lomusdne with ir~dlation pro*v~dessome therapeutic advantage over irradiation alone. Lomustine appears ~ u i v a l e n t to c a ~ u s t i n e in this r*'dpect.

Hod#in's Both n i t ~ s o u ~ are acdve in Hedgkin's di~ase and other lymphomr~s (39, 51; 56, 1 ~ ) . M a t importantly, they are active in p. uen~ whose dLsease ~ r~.,istant to the Conventional alky atmg a g e n t . Furthermore, the substitution of lomusfine for mechlorethamine may provide a toxic ty advantage in t h e inidal combinadon ehemothe~py of advanced The ~ancer and Leukemia Group B h ~ conducted a series ofclinieal studie~ evaluating

318

R. B. WEISS AND B. I~', ISSELL

• e reladve emcacy of nitt~soure~ in Hodgkin's dise~e. A r a n d o m i z ~ c o m p ~ v o n of c a ~ u s t i n e and lomusdne in previously treated H ~ g k i n ' s showed a 28% response rate for ~ u s d n e and a 60% response rate for |omus~ne (39). A subsequent study comparing lomusfine with semusfine c o n f i ~ e d ~ a t lomustine is the most active of the nitrosoureas tested in th~ disease (56). The ~ d r u g re#men containing mechlorethamine, vincfisdne, procarbafine and prednisone (MOPP) has become widely accepted ~ the initial chemotherapy of advanced H ~ # i n ' s disease (26). Of i 98 patien~ treated with MOPP in an NCI study, 54.6% were disease-fi-ee at 5 year~ (26). The Cancer and Leukemia Group B randomly compared the MOPP re#men with a s i ~ l a r one substituting carmustine for mechiorethamine (65). The percentage ofcomplete rerrdssions and the remission durations attained were identical. The c a ~ u s d n e re#men produced 1 ~ severe myelo~uppre~ion and 1 ~ frequent gastroint~dnal side effects than did the mechlorethamine regimen (65). This same cooperative group t~ted other substitutions in the MOPP regimen ~ - ~ - ~ MOPP. Lomu~sfine v¢~ substituted fiJr mechlorethamine and vinblastine for vincrisdne (21). "~Ghe lomusfine-vinMastine substituted regimen produced a higher complete remission rate than did MOPP and a l ~ longer remis~on duration and sur'~vaI (21). G~trointestinal effec~ and neuroto~ci~ were less for the I o m u s d n e - v l n b l ~ n e substitution than ~ t h MOPP. In another cooperative group study, adding carmnstine as a 5th drug to a 4-drug regimen did not confer any rerpHssion or su~ival advantage over MOPP

(29). Although the rate ofdisease cure achieved with the I~OPP regimen (26) remains the standard for comparison, ~ e results of d-iese cooperative group studies show that nitr~ourea substitutions for mechlorethamine a ~ e~cacious and can offer some advantages with less short-term toxicity and greater ease of administration (e.g. oral lomusfine vs. intravenous mechlorethamine). In individual patients, t h e treatment flexibility provided by ~ese alternative regimens m a y b e usefial. Lomusdne h ~ also been used in comMnation regimens as therapy for patients who fail inidal e h e m o ~ e ~ p y . A group of inv~figato~ at Stanford (74) ed the B-CAVe regimen (bieomycin, lomusdne, doxorubicin and vinblasdne) for padents who relaF~d during or after MOPP chemotherapy. Seventeen ~ 22 padents (77%) had responses of which one-hMfwere complete responses. However, the contribution that lomusdne made to tP~s treatment cannot be determined.

Carmustine and lomusfine have p r ~ u c e d useful remi~ons in patien~ with non-Hodgkdn's l y m p h o m ~ who have relapsed from o t h e r chemoth (51, 56). However, these r e m ~ i o m have ~ e n generally of sho~ du~fion, V e ~ few studies have been done using either drug in combination with other known effective d r u ~ as initial chemotherapy. The S o u t h ~ t e r n Cancer Study Group randomly compared a combination of" cyclophc~phamide, ~ncristine and p r e d n ~ n e with and wifllout ~ u s t i n e to determine ifcarmmdne a d d ~ any" benefit to a active r e , men for n o n - H ~ g k i n ' s lymphoma~s (28); Only- in those paden~ with difl~.tsehisfi~:ydc lymphoma w ~ any- enhancement ofthe com#ete r~sponse r a ~ and survival noted as a re,suit of the addition ofcarmusdne. Most other regimens include doxorubicin to produce long survivals in this l ~ p h o m a tyrr~ (46). An im t question is whether a 4
~ R M U ~ I N E AND LOMUSTINE

$19

but would be le~ toxic b e ~ d ~ there would ~ no risk ofdoxorubicin cardiomyopathy. T h e Southeastern Cancer Study G r o u p ~ c e n t l y conducted a r a n d o m i z ~ thai of 2 such 4-drug combinations, and p r e l i m i n a ~ r ~ u l ~ suggest that the c a ~ t l n e r e , m e n is inferior, p r ~ u c i n g fewer complete r e m ~ i o n s (35). Lomusdne has been litde used in combination r e ~ m e n s for non-Hc
treatment widl myeloma (i,eo th

: n h a n c ~ the s u ~ i v a t for some patients with or otherxvise p ~ r - ~ s k disease). However, the

320

R~ B. ~,-¥EISS AND ]3. F. !SSELL

addidon of car-musdne to m u l d d r u g regimens doe~s not confer a clear advantage, particularly when only low dos~ can be used because of marrow s u p p r ~ *0 n. ~ m u s t i n e plus prednisone has ~ e n ~ n d o m l y c o m p a r ~ to car.,nustine plus prednisone by Cornwall et aL (22) for the initial treatment of myeloma. There w ~ little difference between fine two nitrosoureas in t e ~ s of objective response ~ t e or d u ~ t i o n . C a ~ u s f i n e alone h ~ been used in patien~ who fail initi~ melphalan-prednisone therapy, but the response razes were low (77). When a comb~natlon o f c a r m u s d n e and d o x o ~ b i c i n was u s ~ by Alber~ a al. (4) in a series of 13 melphalan-resistant patients, 7 r e s p o n d S . This pilot study £ ~ e d the basis for a larger study by the Southwest Oncolo~.¢ Group in which vincrisdne and prednisone were added to the above two drugs. Thirty-nine of I51 (25%) pafien~ responded, but only 2 o f these responders had disease that was init~l~, refractory to m d p h a l a n (I 2). When carmusfine was used in c-o~_binafion wiffn cyclophosphamide and pr..~dnisone in 42 pafien~ after prior treatment with melphalan in another study, only 7 responded (50). These data do not enable us to detem~ine whether there ~ a lack ofcross-reslstance between the bifunctional alkylating agent.s and the nitrosoureast but suggest that if there is, it is relatively infrequent. It does seem that some patien~ who initially respond to melphalan and then relapse, may r ~ p o n d to thrther chemotherapy containing a nitrosourea.

Small-cell lung cancer

Although used in many invesfigafional therapies, the role of the nit~soureas in small-ccll lung cancer is not yet established. ~oth earmustine and lomustine have modest activity as single agents in advanced disease (13, 99), W h e n lomustine was used in combination with cyclophosphamide, there was some evidence of increased a n d t u m o r effect over that achieved with cyclophosphamide alone (31). Some improvement of response rate was also obtained by the addition of lomusdne to a 2-drug combination of methotrexate and cyclophosphamide (40). In small-cell tung cancer complete remissions are the only responses p ~ d i n g improved survival, and cornbination chemotherapy is more effective than single dr~ags in producing

overall r ~ u l ~ of these combination regimens are a n a l y z e , there is little difference a m o n g them lay any parameter (14). Use of a 3- or 4-drug regimen containing lomustine is effective treatment, but a multidrug combination without lomustine is cqually effective. Central nervous system involvement in small-cell bronchogenic carcinoma is common (99). Studies in which brain irradiation was part of ~ e initial treatment p have shown a markedly reduced frequency of relapse of tumor in the brain (99). ~ c a u s e of the ease oflomustine diffusion into the brain, it was hoped that use of this agent as part of the systemic tr-~tment would also reduce the frequency of relapse of tumor in the brain, thus obviating the need for irxadiation. Unfortunately, the incidence of brain metastases has been unaffected by the use oflomustine (5, 66)_ Although there is no evidence ~ a t c a ~ u s t i n e is int~crior to lomustine in small-cell lung carcinoma, c a ~ u s t i n e has never achieved widespread use. O n l y one reported study with a small n u m b e r o f p a d e n ~ incorporated carmusfine in a combination regimen with 6 other drugs(1). There is no way to determine whether carmusfine m a d e a contribution to the treatment results.

~RMUSTINE

AND L O M U S T I N E

321

Non-small-cell lung cancer

T h e nitrosoureas have low activi W in the other types of lung cancer (adenG~arcinoma, squamous carcinoma, and large-cell undifferentiated carcinoma). C a ~ u s d n e and Iomustine have produced only a few objective responses when used singly (3, 30). Lomustine has been incorporated into multidrug combinations for treatment of the non~ small-cell hlstotogic types, but only I, a 4-drug combination, a p p ~ r e d to provide meaninga~ul benefit in response rate and s u ~ i v a l prolonga~on (I8). However, other investlgato~ have b ~ n unable to confirm these favorable resul~ using the same four-drug r e , men (92). At present, ~ e of 6hese two nitrosoureas in non-small
The nitrosoureas have been widely u s ~ in the treatment ofgastrointesfinal cance~, but their mle in 6hese t u m o ~ is not established. T h e activity ofcarmusfine and lomustine single agents in advanced Upper gastrointestinal tract cancer is low, with g ~ t r i c cancer r ~ p o n d i n g in 1 ~ than 20% o f p a t i e n ~ and pancreatic cancer rarely responding (61, 63). T h e combination of carmusdne and 5-fluorouracil in gastNc cancer was supeHor in nse rate and sur~eival compared to either d r u g alone in a randomized study (49). However, because of the ease of oral administration and equivalent activqtv ofsemustine, tMs drug has been substituted for carmusdne in most studies, and c a ~ u s f i n e is now litde used in combination therapy o f g ~ t r i c cancer. Such studies have not yet defined a role for semustine~ and other drug combinations, not containing a nitrosou~a, m a y be m o ~ active in this disease (55). In advanced colorectal cancer, carmusfine, Iomustine and semustine have low r~ponse ~ t ~ as single agents, vau¢ing from 9 to 18% (61). T h e addition of semustine to 5fluorouracil in a randomized comparison with 5-flourouracil alone resulted in a r e s ~ n s e advantage for the Combination, but no surAval a d v a n t a g e was demonstrated (8). Semustine in compa~son with lomustlne, each with 5-fluorouracil, is being e v a l u a t ~ in an ongoing tNal, but apart from this, there has been little i n t e r ~ t in p u ~ u i n g fiarther s t u d i ~ with lomustine or carmusfine in a n y stage of this disease.

Carmustine and lomustine both have some activity as single ggents in metastatic melanoma, but respons~ occur in only 1 5 2 0 % of treated patients, are rarely complete r e s p o n d , and are ofshort d u ~ t i o n (2, 97). These results have been obtai ned only when the nitrosourea is used as the initial chemotherapy~ and a patient who has had prior chemotherapy very rarely r~ponds to a nitrosourea (2). Dacarbazine, the most commonly used drug in melanoma, has similar limited activity. It h ~ been combined with eanntLstine or lomustine in an attempt to increase the response r a t ~ of any of the d r u ~ used Nngly. Despite using these di, ug combinations and escalating doses to the ~ i n t ofseve~z toxicity, there was no significant improvement in the response rates, response durations or overall survivals for either nitrosourea-dazarbazine combination in a large number o f p a t i e n ~ studied by Hill et aL (44). ik~leKelvey et aL (58) also did not find any increased effect by adding c a ~ u s t i n e to dacarbazine over t h a t ofdacarbazine alone.

322

R, B. W E I S S A N D

B. F, !S~ELL

In breast carcinoma, there have been instane~ ofshort-duration responses among patien~ w i ~ advanced disease (86). However, both n i ~ o s o u r e ~ (particularly !omus~ne) are inferior to the other ~tablished dr~ags useful in breast carcinoma (86). There have been repor~ of significant c a ~ u s f i n e activity in Ewing's sarcoma and K a p ~ i ' s sarcoma (72, 9!). Since these early yeports, there have been no confirmatory studio, but anfitumor activity was demonstrated in ~ t h series of these rare eance~ involving 12 and 20 patients, r~pectively (72, 91). The Gynecologic Oncology Group has tested lomusfine in patien~ with a variety of gqcnecolo~c malignanci~. Lomustine had no meaning,Pal effect on cance~ a ~ i n g in the o v a l , cervix, uterus, vagina or vulva (69, 70). Two series of small numbers of patien~ have been r e ~ r t e d using carmustine in advanced ovarian cardnorna (36~ 47)~ In neither study was there any notable effect of the carmusfine in either previot~ly treated or unt~aved p a t i e n t . Lomusfine and c a ~ u s t i n e have both been tested in acute leukemia treatment (43, 45). Although some anfileukemic effect was achieved, neither drug has provided any advantage over other effective therz.py, and neither has any role in leukemia treatment.

BOn~ ~rP,ar~r0w

The nitrosoureas as a drug clam have the unique property of a lengthy delay in marrow supprCmion. The nadir of white b l ~ cell coun~ occurs at 3-4 weeks after administration; the nadir ofplateIet counts is 4-5 weeks. Both cell counm return to normal 6 7 weeks after drug administration. With p r o l o n g ~ use, the time to marrow recovery is progressively longer (up to 10-! 2 weeks). This delayed myelosuppression has been f a t ~ t o some patients ,~n many reported studies, and it has never b ~ n adequately explained. There have been two recent repor~ o f d r u g interactions that can accentuate nitrosourea marrow supp n. Selker et aL (84) noted that when patients were giver, cimetidine with earmustine, there were inordinate decreas~ in blood counts after the first carmustine dose. A single case r~port (•07) s ts a similar drug interaction with accentuated m yelosuppression b e ~ e e n th~ophylline and lomustine. Laboratory experiments with carmustine and theophylline have demonstrated that the two drugs together will depr~s vchite blood counts more than carmustine alone (27). Neither cimetidine nor theophylline should be used in patients receiving eifitaer nitrosourea. Second malignancies in the form of acute leukemia are well known to occur from prolonged therapy with a va6ety of alkylating a g e n t . A single case of acute leukemia developing in a patient who received both carmustine and lomustine has been reported (20). This patient also received an unusually high dose of tenip-~ide, so the nitrosoureas cannot be implicated soldy in the evolution of the leukemia. Two other nitrosoureas, semustine (20, 7I) and streptozocin (38), have been associated specifically with the development of acute leukemia. Thus, it would not be surprising if carmustine and lomustine a l ~ could W e rise to such a problem when treatment is unusually prolonged.

toxicity ~in the form of fibrosing a|veoli~s and intcrs~fia| pneumonitis due to c a ~ 0 s t i n e has been reported with increasing frequency (102)~ Over 75

A usuallylife-threatening

~RMUSTINE h~-ID LOMUSTINE

323

cas~ have now been r e c ~ e d , and it is no longer an isolated problem. T w o series, totalling 140 p a t i e n t , have established that if tom! drug doses are high enough, pulmonary toxi~ty will occur in 2 ~ 3 0 ~ o f p a t l e n ~ recei~ng c a ~ u s t i n e (7, 83). From a review ofpublished case repor~ and these two studies, it appears that when the cunaulatlve drug dose reaches 1200-1400 mg/na z of body surface area, the risk of pulmonary toxicity is high and approaches 50% (7, 83, I02). Because this toxicity is generally lethal, careful monitoring for pulnaonary dysfiancdon is indicated and unless individual circunastances dictate other.vise, carnaustine should be stopped when drug doses have r e a c h ~ I200 mg/na 2. Patien~ with u n d e r l i n g lung disease, previous thoracic irradiation, or heavy exposure to o ~ e r pulmonary toxic d r u ~ appear to be more suscep~ble to c a ~ u s t i n e - i n d u c e d p u l m o n a ~ toxicity-; they should be observed e~s~cially closely for this complication (102). In contrast to the high prevalence of this problem with carmusdne, instances of pulmonary toxicity have not been recorded for lomustine. This may be due to any or all of the fi311owing:the lower total drug dose received by most patien~ on Iomustine, the fact that lomustine h ~ l~s alkylafing activity than carnaustine, or because of a lower lomustine distribution to the hangs (I 02). Renal

Renal toxicity was noted in the preclinica[ toxicological studies with both drugs (16, 80). Lomustine, in particular, caused fatal chronic ~ t e ~ t i a l nephritis in m o n k e ~ (80). In the earliest clinical trial o f c a ~ u s f i n e , 10% ofthe pafien~ had u n e x p l a i n ~ elevations of BUN, but there were no severe renal problems (23). In the r e ~ r t s ofnumerous subsequent t6als with these drugs, the investigato~ specifically stated that no instances of significant renal toxicity occurred. Thus, ~ n a I problems were believed not to be of major importance with either drug. Three recent e-~e rep~r~ of lomustne-induced renal failure now contradict this impression (11, 37, 85). These patien~ received high cumulative doses of lomus~ne [3320 mg (I I), 2300 mg (85) and 3360 mg (37)]. Schacht et aL (79) r e p o r t ~ 6 patien~ who manif~t-~ renal dysfiJncdon from carnaustlne. AII6 patien~ had at least 6 courses o f d r u g in 1 year. T h e total carnaustine dos~ ranged from 1 5 ~ to 2800 nag. Two parents, both of whom had carnaustine and, later, semusdne developed uremia. Only ! patient who received carmustine alone had more than mil~ renal dysfianc~on. Schacht et aL (79) also obse~ed ~ n a l toxicity in 11 patien~ t ~ a t e d with the inv~figational nitrosourea analog, senausU*ne (methyl-CCNU). This reF<)rt and o t h e ~ (101) suggest that semusfine is more nephrotoxic than either carmustine or lomustine. Any patient receiving t h e e d r u ~ over an extended time should be o dosely for renal dysfunction. Neph city can occur insidiously and m a y be i~eve~ible, reqni~ng dialysis. Gastrointestinal

Both carmustine and lomustine cause nausea and vomiting that usually occur l~or 2 h after adnainistration, I~ting le~ than 24 h. Sometimes. this vonaidng can be ~pecially severe as shown by the fact that prolonged retching from nitrosoureas has been r e ~ r t e d to cause vertebral compression fracture and tear of the esopha tric mucosa ( 3 2 , 105). Premeditation with phenothlaz~nes will prevent or ameliorate vonaiting in most eases. The ~i ureas are rapidly metabolized, a n d it islikely that vomiting is pro_dticed by the .action of metabolites on brain-stem v o m i t i n g ceniers. However, this subject has received no investigatiouM attention, a n d i t is not known how the vomiting is naediat~d. It

324

R. B. WEI~S AND B. F. ISSELL

is, however, known that it is not due to a l ~ a l ga~stdc irritant effect in the c ~ e of oral lomustine, because it o c e u ~ after fi~ll d r a g absorption and metabolism. Neuro

A recently recognized encephalopathy h~_s been ~ c f i b e d to carmustine (15, 42). I n the mild cases, occurring when moderate d r u g doses are u ~ d , transient focal neurological deficits a nd headaches have been seen ~ 2 ) . A more serious, and fatal, eneephalopattw has occurred when extraordinarily high carmustine doses have been used invesfigationaUy with autologous marrow transplant. B u y e r el aL (15) reported 4 patients who were found at autopsy to have cerebral white m a t t e r necrosis after receiving a single dose of 1200 Visual problems, varying from blurred vision and d i # o p i a to b|indnes,, have ~ e n observed (53, 59, 90). Some of these symptoms have been ~:~ociated with retinal exudates and hemorrhages. Some p a d e n u with these problems received brain irradiation and]or had brain tumor, so ~ r h a p s the nitrosourea treatment cannot be implicated as the single c a u ~ f i v e factor (53). leIinor m

toxicitTes

Some minor and nonqife-threatening t o x i ~ t i ~ from carmustine a ~ conjuncfival flushing d u n*ng intravenous administration, local venous irritation and mild, reversible liver dysfune~on (23, 96). Several i s o l a t ~ instances of rash have occurred (42, 51). N o c ~ e s of ttrticaria or serious anaphylaxis h a v e been reported (100). A few cases of gynecomasfia apparently solely related to carmustine have been observed (52, 82). The'breast swelling subsided in these pafien~ after drug discontinuation.

usions The ni t ~ o u r e a c l ~ of chemotherapeutic a g e n ~ provided promise of new possibilitie's to treat certain cance~. H a v e they lived up to this promise? T h e answer.is affirmative, but qualified. T h e lipid-solubility ofcarmustine and lomustine allows entry into brain t u m o r , and ~ e s e two drugs favorably affect the course o f h u m a n brain tumors, but only in association with whole brain irradiation. As sole therapy ~ e y provide no sur¢ival benefit. In combination with radiation, they seem to enhance the survival benefit accorded by irradiation. Unfortunately, the s u ~ i v a l after diagnosis of malignant glioma remains relativelyshort, and the nitrosoureas do not provide any curative effect. As far ~ other tumors are concerned, these nitrosoureas are definitely useful, but in each case there are other active agents no less effective. T h e two drugs may be used as substitutes for other d r u b in combination regimens, when there are concerns about specific side effects or means of administration. ~ o t h e r question worth asking is: Is there any difference between these drugs in their zntitumor activity? This question is dimcult to answer in all situations. Carmustine has been studied in greater numbers of patients with brain gliomas. O n l y o n e randomized study in these cancers has compared lomustine and carmusfine, each given with irradiation, a n d there was no difference. Lomustine was found to be d~e more active d r a g for Hodgkin's disease. I f a nitrosourea is to be used in this dise~e, it should be lomustine

CARMUSTIN~

AND

LOMUSTINE

325

T a b l e I. T o = i e i 6 e s o f ~ r m u s ~ n e

Major and/or common Namea and vomi~ng Mydosuppre~ion ~uMly d d a ¥ ~ ~uMly cumula~ve |ntersddal pneumonitis and fibrosLs Nausea and vomiting

Minor and/or ~ Renal d y~tqJ~tion Encephalopathy Visual distur~nce C-:mjunc6~1 flushing Loe~ veno~ imtatlon Gyne~m~a Acute leukemia

Table 2. Toxicitle$ o f IomuStlne .....

:J,,,tt,,,,

Mzjor andlor c o m m o n

Myd~uppression usu~ly delayed ~uMly cumulative Na~ea and vomidng

Major and ~t~

R~

Ren~ dysfunction and failure

Acute leukemia

incorporated into a "MOPP-like" combinadon regimen. There seems to be little difference bet-~en the two d~a~ in myeloma. ~ e ~ ~ no reliable information c o m p a t n g ~ e two d r u ~ in small-cell lung carcinoma; lomusdne is the 6he widely used. When one of the~e nitrosoureas is used in melanoma, it is usually ~ u s t i n e , but carm~fine is not known to be definitely°superior. Despite uncertain differences in the anfitumor effec~ of these d r u ~ , there are deafly some toxicity differenc~ (Tables I and 2). Lomustine can be admAn~tered o~Ily and thus the inconvenience and local irritant effect of c a ~ u s t i n e is obviated. To date, there have been no repor~ of p u l m o n a ~ toxicity with lomusdne, whe~as it is a common problem with long-duration c a ~ u s t i n e use. Other uncommon c a ~ u s t i n e - r e l a t ~ problems are encephalopathy and gynecom~da. Lomusdne seems capable of prc~ucing severe nephrotoxicity with prolonged use, but n~ther drug appea~ to have the nephroto~c potenfal ated with the prolonged use ofsemustine. ~,re can summa~ze by, stadng that ~ yea~ after markefng~ t h e e two drugs have a uniquely usefiM role only in p r i m a ~ brain g l i o m ~ . For o ~ e r cancers, they comdtute reasonable substitut~ £or other d r u ~ . New, sometimes life-~reatening, toxicity h ~ been recognized that should make physieiar~ wary of e x t e n d ~ ad~drJ.stradon of either draag,

Acknowl~gement The autho~ thank Dr Vincent T. DeVita, J r for review of the manuscript.

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25. DcVita, V. T., Oliverlo, V.T., Muggia, F. M . VVie~ik, P~W . Ziegler, J . Goldin~ A . Rubin, D., Henr~ey,J. & Schepar~, $. (1979) The drag development and diP~c~ t r i ~ programs of the Division ~ Cancer Treatment, Nadona! Canc~ Ir~tituteo Canee Clin. Tn~ls 2: 195-216. 26. DeVita, V. T., Simon, g. M., Hubbm~ct, S. M., ,Young, R. C . Beraxxt, C. ~V., Moxley, J. H., Fret, E., ~ne, P. P. & Candlos, G: P, (1980) Curability of advanced Hodgkin's d ~ a s e ~ t h chemothe~py. ~ng-tcrm follow-up of MOPP-lreated ~ f i e n ~ at the Natlontd ~ n c e r lr~dlUte, dn_~. latin. Attd. 9"2: 587-595. 27. DeYV~, ~V. D. & Balhlna, S~ H~ (1980) S~nerg~stic antileukemic effect of theuphylline and 1,3-bls(2chlo~:thyl)-l-nhr~oure~. Can~r lies. 40: 2202~2208. 28. Durant, J. R., Gums, g.. A., Bartolucci, A . A . , , R. F. (1977) BCNU ~ t h and ~ t h o u t c ~.phamlde, -Ancristine, and predn~ne {COP) and cycl~acfve therapy in non*H~gkln*s lyre#urea. Cal*~tr Treat. Rcp. 61: 1085~1096. ~ . Durant, J. g., Gums, R. A., Vcl~-Garcia, ~ , Bartducci, A., ~¥ir'~hafter, D. & Dare;man, R. (1978) BCNU, vdban, cyclophos~aamides p r ~ r b a z l n e , and p ~ n i s o n e (BCVPP) in a d v a n c ~ H~gkin's d ~ c ~ . Car~xer42:2101-2110. 30. ~ g a n , R~ T., ~arr, D~ T . Cole~, D. T., Din~, D. E. & i/Ate, R. g. (|974) Rand study comparing CCNU (NSC-7g0$7} and methyl-CCNU (NSG-95441} in ad~nct.M bronch~enle ~ n o m a . C~m¢~ Rap. 58: 913-918. 3 I. Edmo~on,J. H . Lagakos, S. W., Selaw~, O. S- et aL for the ~ t e m ~ r a a v e Ontology Group (! 976) Cyeloph~phamlde and CCNO in the treatment ofino~rable smMl cell carcinoma and a d e n ~ r c i n o m a of the lung~ Cancer ~%toL Rtp. 6~ 925-cJ32. 32, Enck, g. E. (1977) Mallory-%Vei~ lesion following cancer chemotherapy. ~ r ~ t t |Jr 927-928. 33, E.O.R.T.C. Brain Tumor Group (1978) ~tTcctofCC~./Uonsurvlvalrateofo~ecdvercmissionandduration of free interval in padcn~ ~ t h malignant h ~ n giinma~.fin~ evaluation. ~'ur. ,7. C ~ t r 14: 851~56. 34. Fewer, D., Wilson, C. B., Boldrcy, F,. B. & Enot, J. K. (1972) Phase I1 study of l.{2-chlor~th#}-3cydoh~yl-l-nitrosourea ( ~ N U ; NS~79037} in the t~atment o r b = i n tumor. C ~ , r RJp. 56: 421~27. 35. Gains, R. A., B~tolucci, A. A. & Durant,J. R. {1981) Ph~e II1 tfiMofCHOP vs BCOP in diffuse b&sdocydc lymphoma (DHL). P ~ . Am. Su. CWn. OncoL 22: 518. 36. G~Jfrey, T. E., King, A. & Ren~chler, R. {1973) l~3-bis{~h|or~th#)-i-nitrosourea: elt'c~c~on a d ~ n c ~ ovadan carcinoma. Am, if. 06~;ttt. 115: 57~577, 37. Goupil, A., Baglin, A.~ Clavel, B., Verger, C. & Fritel, D. (1980) Insuffisance r~nMe chronique aprds traitemnet par le CCNU. JVouv. Prt,se ,~td. ~ $069-~70. 38. Green, M. R., Anderson, g. E. (1981) Acute myelogenous leukemM follo~ng p~longed strept~otocin the~py. Carder 47: 16-5-.165, 39. Ha~en, H~ H., Se|awry, O. S . Pajak, T. F . Spurt, C. L., Falk~on, G . B~nuer, K.~ Cuttner,J., Ni~en, N. 1 &Holland, J. F. ( I ~ 1 ) ~ e su~rloHty of C ~ / U in the treatment ofadvanced H~gkin~s d~ase: C~ncer and Leukemia Group B study. C ~ ' ~ ~7: ~ 1 8 . 40. Ha~en, H. H.~ S d a s ~ , O. S., Simon, g.s ~ r r , D. T., van ~Vyk, C. E., Tucker, g. D. & Sealey, R. (1976) C~mMnation chemoth~apy of advanced lung caner. A ~ndomlzcxl triM. Ca~tr 38: ~R0|-2207, 41. Harley, J. B., Pajak, T. F., i c l n w r e , O. R., Koehwat S . ~ r , M. R.) Coleman, i . & Cutmer, J. (I979) lmFn-oved survival ofincre~ed-risk mye|oma patien~ on combined triple*aklylafing-agem thera~y: a study of the ~ G B . B t ~ 54: t 3~~. 42, Har~, son, D, T. & Neim~n, P. E. (1977) Primary t~'~atment ofdissemlnated HodgkJn's d~ease with BCJCU alone and in combination ~ t h ~ n c ~ d n e , p fine, and p r e d ~ n e . ~ Treat, Rap. 61: 789-795. 43, Hayes, D. M. & ~llison, R. R. (1969) Production Of remission in bl~tic # ~ e f f chronic m ~ l ~ y t i c leukemia (CML) and acute myelocydc leuke~a (#.NIL) by a~Mnosyl cyt~ine (A~*C) # ~ I,$ b:. (2-chlorcmthyl)~l-nltrosourea (BCNU), Blood 3~ 8 ~ (A~tract). 44, Hill, C . J , i e t t e r , G, E., Kremen~, E. T., Fletcher~ W. S, Golomb, F, M., Ramirez, G . Grage, T. B. & Mo~.s, S, E. (1979) DTIC and combination thera~¢ for melanoma, lI. ~ a d n g s c h ~ u l ~ of DTIC with B C N U ~ CCNU, and v l n ~ n e . Ce~xtr Tr*ot. P.,p. 63: 198~1992, 45. Holland,J. F . Glldewell, O . ~ n , R. R . Carey, R;.W., S ~ w a r ~ , J . , XVMIace,J. Hoagland, C , Wiernlk, P., Ral, K,, Bekcsl, G. & Cuttner, J. (1976) Acute mycl~>aic ieukemla, d r ~ . lnt~n. 3gtd. I36: 1377~138L 46. Jones, S. E., Orozeai P. N.fMetz, E, N., Haul, A., Stephens, g . ~ , Morrison, F. S.~ B u f l ~ , J . J . Byrne, G: l~., M ~ n , T. E,, Fisher, R., Ha~klm~ C~ L. & Cohman~ C. A. (1979)Sut~rlorlty of adriamye~n~eont~nJng combination chemotherapy in the treatmem ~ d i l ~ l~aphow~. A ~uthwe~t Oncolo~ G ~ u p study. Cancer 49." 417~25. 47, Jo , E, O., MMka~dan, G. D., "¢dcbh, M . J . & Hahn, P~G. (1973) Pilot study evaluating 1,3-bis

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(2-chlor-~h#)-l-~t~ur~ in the ~re~mcnt ~ a d v a n ~ ovarian carcinoma. A~. ,7. Obsta. q~,tcd. 116: 769-770. 48. Kohn, K, W. (1977) I~t crc~,-linking of DNA by l,~bis(2-Cnlorcvethyl)-l-nltr~urea and other l-(2-chlomNethyl)-l*~tmsourea~. Career ~s. 37: 1450,-14~ 49~ K-ovacbJ. S~ Mocrte|~ C. G . Sehutt, .A~J., Hahn~ R~ G. & Reitemeler, R~J~ (1974) A controlled study of combined 1,3-bls(2-chlor'~thyl)-l-nitr~ourea and 5-fluomuracll therapy for advanced gastric and pan~eatic cancer. Cam~ 33t 563~567. 50. Kyle, R. A~ Gaitani, S., Sdigm~n, B. R . Blom, J./'~/clntyre, O. R., Pajak, T. F. & Holland,J. F. (1979) Multi#e myeloma r ~ t a n t to reel#alan: treatment with ~¢clo#osphamtde, predni~ne, and B~ffU. ~,~cer Treat. Rtp. 63: I265-1269. 51. L~ner, H. E. for the ~uthe~siern Cancer Chemotherapy ivc Study Group ( ! 9 ~ ) BCNU (l ~3-bis(2~h|oroeth# )- l-nitr~oorca. Effec~ on advanced Hodgkin's disease and other a~ Career 22~ 451~56o 52. ~ n e r , H~ E. & Vog/er, ~V. R~ (~974)Toxldtystudy ofBCNU (NS~409962) gb.-enorally. Gane~ Rap. 58:407~41 i. 53. Louie, A. C . Tu~sl, A~ T,t M u ~ a , F. i . & Bona, V. H. (!978) Letter to the cxiitor..4lttL Ptdlau. OncoL 5: 245-247, 54. Lmwn,J. 'W.~ icLaughlln, L. ~ . & Chang, Y.-M. (1978) Mechamsm ofaction of 2 - h a l ~ t h y l n i t r o s o u ~ on DNA and i~ relation to t~eir andleukemic p~perties. Bioerg. Chem~ 7:97-1 I0~ 55. Macdonald, J. S** ~hein, P. S., W ~ l l ~ , P. V., Smythe, T., Veno, W., Hath, D . Smith, F., ]~imn, M~, Gi~|brecht, C~, Brunet, R. & La~rde, C. (1980) 5*Fluorouracil, doxorubi¢in, a ~ mltomycin (FAM) combination cheroot:herapy for advanced ~a~tric cancer. A ~ . Int,r~. ,el,d. 93: 533~536. 56. Mauricc, P., G , 0 . , Jacquillat, C., S~lver, R.~ ~ r c y , R . Ten Pas, A . CMm~, C., Bunfingham, R. A., Nis.scn, N. L & Holland, J. F. (1978) Compaf~on ~ m e t h y l CCNU and CCNU in patients with advanced f o ~ s ofH~gkin~s d~e~e, lymph~arcoma a ~ reticulum cell sarcoma. G~_etr 41: 16~-1663. 57. Mclntyre, O~ R., Pajak, T., Leone, ~ , Kyle, R., ~rnwc|l, G. G., Harley, J., Kochwa, S~, V~'eksler, B. & Glowienka~ L (198|) Nitro~ur~as in the treatment of rnl/tld#e myeMma, in (ercstayko, A. W., Crake, S~ T., Baker, L. H., ~r~er, S. K. & Schein~ P., eds) : Curr~t Statu~ and f~em New York: A~demie Press, pp. 3|3-324. 58. McKdvcy, E. M., Luce, J. K~, Tallc~¢, R. W~ Her~h, ~. M.~ Hcwlctt, J. S. & M ~ n , T. S. (1977) Combination chemotherapy with bis chloroethy! nitr0sourea (BCNU), ~,Sncr:~tine ar~l dimethyl tri~eno imidazo|e ear~xamide (DTIC) in disseminated ruminant melanoma. Ca~er 39" 1-~. 59. i c ~ n n a n ~ R. & Taylor, H. P.~ (1978) Optic neuroretlnitis in ~ i a t l o n with BC~'-~Uand procarb~ine therapy. Jl4[ed.~ a t r . OntaL ~ 43-48. ~ . Marker, P. C.~ VV~in~ky, I. & Geran, R. L (! 975) Review ofselc~etedex~rimcntM b ~ i n tumor m~Melsused in chemotherapy ~pcfimen~. C~7~tr Rip. 59." 729~73g. 61. M~rt¢l, C. G. (1975) C|inieal management ofadvanced gastrointestinal cancer. C~ter 36: 67~682. 62. Mocrtcl, C. G. (1979) Drug summary: nitr~ottre~. Int. ft. Radial OmoL BieL P~,. 5: 1593-1595~ 63. M~rtcl, C. G., Schutt, A. J., Reitemeler, R.J. & Hahn, R. G. (1976} Therapy for g~troint~tinal cancer ~ t h the nitrosour~ ~onc and in drug combination. Can¢~ Treat. Rcp~ 60: 729-737. 64. M ~ n t g ~ m ~ J ~ ~* ~l 976) ~vem~try and stru~tur~*act~vit~ studi~ of the nitr~ureas- Cane~r Treat~ ~p~ ~ t 651-664. 65. N i g h , N. I,, Pajak, T. F . Glidewell, et aL Far the Cancer and ~ u k c m i a Group B (1979) A comparative study of a B C N U containing ~ r o g p versus MOPP vc~t~s 3Mrng eomMnafions in advanc~ HodgMn ~ C ~ r 43:31 ~ 0 . 66, Nugent, J. L., Bnnn, P. A., M a t t h ~ M.J., Ihde, D. C., Cohen, i . H., Gazdar~ A, & Minna, J. D. (1979) CNS met~tases in small cell bronchogcnic carcinoma, Increasing frequency and changing pattern ~ t h lengtheMng survival. Caput 44: 1 ~ t 8 9 3 . 67. Ogawa, M. ( ! ~ 0 ) Pha~e I study of GANU and M C N U . C ~ Treat. R~. 7: 1 9 7 ~ 3 . ~ . OliveHo, V. T. (I976) Pha og~.¢of the nitrosoureas: an o v e ~ e w . Cancer T-eat. ~ . ~ : 703-71 I. 69. O m u ~ , G., DiSaia, P., BL~ing, J . , R., H yn, M. &Park, R. (1977) Chemotherapy For m rant ovarian adenoearcinomm a randomized trial o C C C N U and mcth#-CCNU. Cancer Treat. Rep. 61: I533-1535, 70. O m u ~ G, A;, Shlngleton, H. M . C r ~ m a n , W. T,, Bles~ngJ. A, & ~aronow, R, C. (I 978) Chemothe~py of~necologic ~ n c e r ~ t h rfitro~oureas: a randomlzed trim ~ C C N U and methyl CCNU in ~the cervix, ~ , vagina, and v-ul~. ~ , r TreaL/?xp. 62t 8 3 ~ 3 5 . 71. , M., Cohen, Hi, %J. R..&, everc and protracted b,mnemarrow d~f'ancfon following long-term therapy ~ t h me,h# i Se~, Clin. On~L 18: 303.

CA~MUSTINE AND LOMUSTINE

3~

7~. Palm~J.. Ga~ani, S., F r c ~ a n , A., Sinks, L. & HoUaud, J. F. (1972) Treatment of met~tatic E~ng's sarcoma with BCNU. C a r ~ 30: ~ 9 1 3 . 73~ P a n . i , L. Co~ G ~ n ~ D . Nagou~ey, R.~ Fox~ P. & Scheio, P. S. (1977) A s ~ c t u r e - a c d ~ t y an~ys~ of c h e m i ~ and b l o l ~ paramete~ ofch|orocthylnit~oure~ in mice. Ca~er Rtz. 37: 2615-2618. 74. Porzis, K~ G~ P o r t i a , C. S,~ Ro~t~on~ A. & R c ~ S. A~ (1978) Treatment of advanced Hodskln's d~e~c ~th ~ V e follo~ng M O P P fMlure.Cancer41: 167~1675. 75~ P . ~ a n , T~J. B~L H~ F., D. S~ Layton~ D. D., Rhoton, & L & Taylor, W. F. (|976) ~ n t r o l l ~ study of C C N U and radiationthe~py in m~ignant ~str~om~. ~. ~ 186-I~. 76. Saijo,N. & NiltanL H~ (i9~) ExperimemM and cUnic~ effectof A C N U inJapan, ~th emphasis on small ceil carcinoma of the lung. C~## 4: 16~171. 77, Salmon~ S~ (1976) N i t r ~ u r ~ in multiple mC/eaoma. Camel Tirol .~p. 60: 78~794. 78. Scha~L F. M.,Jr. (1976) Nitr~ou~a.s: a review ofcxperi audtumor actifity. ~ T r ~ . ReF. 79~ 80. 8I. 82. 83. 84.

t, R~ G.~ Felner, H~ D.~ GMlo, G. R . ~ e b e ~ a n , A. & Baldw.4n, D~ S. (198l) Nephrotoxlcity of n i t r ~ u r e ~ ~ t r 4 ~ 1328-133¢. ~U,~ Re n, R. W.~ Phelan~ R~ S.~ Ethier, ~ F. & Luthra, Y~ K~ (~974~ CCN U ~NSC~79037): pr~lluica| toxl evaluation of a single|at imruMon in d ~ and monkey. ~ w t r Rep. lXart 3 5: ~3-fi4~ ~hepxrtz, S, A. (1976) E~arly hlstow attd devdopment &the nitr~urea~s~ C ~ o ~ t a t . Rip. ~ 6 4 7 ~ 9 . ~horer~ A. ~., Okra, i . M, &Joh~on~ G~J~ (~978)G~ecornasfia ~Cn n i t - - u r e a therapy~ C ~ t r Treat. R~O. 62:5 ~lker, R. G.~Ja~m~, S~ A., Moore~ P. B~ lV~ld~ M~, F~her, E~ R~, ~hen~ M. & ~Uot, P. (|980} BCNU (l,3.bL~{~*ch|o~th#).l-nitrovour~) induced pulmonaD' f i b r ~ 7: 65. Selker, R~ G~, M ~ r c , P. & ce, D. (1978) ~ n c * m a r ~ w dep ~ t h fimctldlne pim c a p . f i n e .

~ . Silver, H~ Ko B. & Mortoli, D. L~ (|979) C ~ U nephrotoxieity ~g s~taiocd ~ in oat ~ ~inoma. T t t ~ Rep. ~ : ~26-227, ~ . S|avik, M. (1976~ Clinical studic~ ~ t h n i t ~ o u r e ~ in va~do~ solid tumors. ~ - t t ~ . 87~ ~lero~ C:L,, Monfa~ini, S~, B ~ m M ~ C., Vaghi~ A~, V M a g ~ , P~, Morello, G. ~ , G' (1979) ~ n t r o l i ~ study with BCNU ~ CCNU a~ adjuvant chemothc~py foliowlng ~ c r T # m mdiothc~py for gliob|~tomA mu|fifo~e. C ~ ¢ r Clin~ Tdm~ 2: 43~8~ 88. , R., W., E~Vita~ V. T. & Olivefio~ V. T . (1973) Physiologic d ~ s i d o n of l-(2-chloroethyl)-3~fclohex#*l~nit~sou~a (CC~*U} a~M ]*(2*ch~.~thyl}-3-(4-mcth# ~cloh~yl)-l-nit~our~a (i U) in m a n C~dtr 31: i 1 5 ~ i 159. 89. S t r u C k , P., MahMey, i ~ s.,Jr., Raymond, U.~ Zinn, D. C~t Lipper, S . Mah~ey, J~ L. & Bigner~ D~ D. (1979) Syne~ism ~ t w c e n BCNU and ir~diadonln the t~atment ofanaplastic # i o t a s . An ~ ~ study uslr~ the avian saro~ma virus~induccd #ionia mM~. ,751: $8|-586~ 90. StMin~ky, D~ C . Bull, F~ E~, Pajak, T. F. & BatemanJ. R. (1975) Trim of l-(2-chlorocthyl*3
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s u p ~ t e n t o r i a l ~trocytomas~ ~, .,~rjr~rg. '15:

99. ~Jelss, R. B, (1978) Small-eel! earcinoma o f the lung: t h e r a ~ u d c m a n a g e m e m . Ann. Intern. Aled. ~ : 522"531. 1~ .

101. 10210B. 1~. 105. IC~. 10L

V~:eiss~R. B. & Bz~ano, S~ ( 1981 ) Hypcr~enshi~fity reactions from cancer c h e m o t h e r a ~ u f i c a g e n t . Ann. 1,1era. 3ledo 94: 66~-72. ~,rei~, R. 15. & Posler~ D. S, (1982} T h e ~ n a I t o , city of cancer c h e m o t h e r a p e u 0 c a g e n t . Can¢~ 7Treat.Nee. 9: 37-56. "¢¢~s~, R. B., Pc~ter, D. S. & Penta,J. S. ( I ~ l ) T h e n i t r ~ a r e a ~ and puimona.~ toxicity. CaJteer Treat. R~,. 8: 111-I25. '~Vheclcr, G. P. (1976) A r~vlew o f s t u d i ~ o n the mcchanlsm o f a c d o n o f z ~ t r o s o u ~ . I n (Sartorclli, A. C., ~ . ) Cancer C ~ VV~hlnglon, D. C.: Araerlcan Chemical Society, pp. 87-119. ~Vheeler, K. T., K~ufmaa, K. & Feldstdn, M. (1979) R ~ l y z ~ o f a rat brain t u m o r to'fracdo~tat~J t h e ~ p y with low d o s ~ o f B C N U and irradiation. Int..7. Radiat. OrxoL Biol. Phys. 5~*1553-1557~ ~Vhltehead~ V. M. (i 975) C a n c e r treatment needs ~ t t e r antlemeti~. #5 EagL dT~,~ted. 293~ 199-200. Young, R° C., DeVita, x¢, T., Sevpick, A~ A. & C~:lne|lc~, G. P. (1971) T ~ a t m e n t of advanced H ~ t g k i n ' s d~ease ~,~.~th ~1~3 b ~ ( 2 - c h l o r o e t l l # } - l - n i t ~ o u r c a ] BCNU. 2~. EngL .7. AIed. 285: 4 7 5 ~ 7 9 , Ze|tzer, P. l'vl. & Feig, S. A. (1979) Thc~phyliin-induccd lomustlne toxlc~ty. Lancet ii: ~ o - ~ I ,