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Pediatric cancer chemotherapy: an updated review
Caner Trea~ntntRrai,wt (1979) 8, 155-164
Pediatric cancer chemotherapy: an updated review I. Cis.Diaxnmlnedichloroplatinum II ( c i s p l a ~ n ) , VM-26 (teniposide), VP-I6 (etoposide), mltomycin
C
Manuel L. Gutierrez* a n d S t a n l e y T. Crooke The Department of Clinical Cancer Research, Bristol Laboratories, Syracuse, .New 2"ork 13201, U.S.A.
Introduction "tVith the rapidly increasing n u m b e r of new agents developed for clinical trials, a n d the relatively limited n u m b e r of pediatric patients with neoplastic disease, it is essential to periodically review the information on agents undergoing evaluation to a.mure that they a r e adequately evaluated in a broad spectrum o f pediatric tumors. It is also important to r e - e v a l u a t e older agents w h e n new developments Which increase their efficacy in adults suggest that they may b e more useful in children. This paper will serve as the first !in a series of reviews o f old and n e w chemotherapeutic agents used i n childhood cancer, Cis,diamminedichloroplatinum (cisplatin), teniposide (V1~[-26), etoposide (VP-16), a n d mitomycin C will be t h e subjects of ttlis initial report. C/s-diamminedichloroplatinum II: (cisptatin) a n d the epipodophyllotoxin analogs, teniposide (VM-26) a n d etoposide (VP-16) are antineoplastic agents recently introduced for clinical trials. In a limited n u m b e r of studies involving childrer~ with~various types of malignancies these agents have s h o w n significant antitumor activity.. H o w e v e r the utility of these agents in most pediatric ttmmrs Ls not clearly defined. Y,~tomycin C is an a n t i t u m o r agent w h i c h was studied initially several years ago, and failed ~to be of significant value. However, recently d e v e l o p e d ' i n t e r m i t t e n t dosage regimens have resulted i n improved clinical utility-in adults. T h u s a review of its activity against pediatric: t u m o r s n~ay suggest new avenues of clinical researcl~ emplo)qng the lfigh :dose i n t ~ i t t e n t schedules. C i s - d l a t n m l n e d i c h l o r o p l a t l n u m II ( c i s p l a t l n ) Extensive clinical trials of cisplatin as a single agent in a wide varlcty o f a d u i t neoplasms !iaj)e d e m 0 n s ~ t e d a c t i v i t y against testicuIar tumors; lymphomas; head and neck cancer, ovarian ~ i n b m a a n d m a i n I u r r g ~ C ~ (18; 2I; 43, 44):: In combination with o t h e r * Address reprint:rextueststo:2~LanuelL. Guticrrc~ ~¢LD.,Brlstol Laboratories, P.O. Box 657, Syracuse, New Y0rk I3201~'U.S:A. 0305-7372/79/030153+ 12 802.00/0 (~) I979 Ac~demlcPress Inc. (London) Ltd. 153
154
M.L. G U T I E R R E Z
ANrD S. T. C R O O K E
antincoplastic agents, cisplatin has d e m o n s t r a t e d a favorable response r a t e in tumors of the testes, prostate, bladder, ovary, h e a d a n d n e c k a n d lungs (8, 5, 10, 47). M o r e o v e r in certain tumors, e.g. testicular, cisplatin c o n t a i n i n g regimens h a v e p r o d u c e d m a r k e d l y i m p r o v e d survival charactcTisties. Clinical trials in c h i l d h o o d c a n c e r h a v e been initiated but only a very limited n u m b e r of patients h a v e been studied. Dose schedules T a b l e 1 presents information on :the dose schedules e m p l o y e d in studies o n pediatric neoplasms. Prior to the utilization of h y d r a t i o n to avoid elsplatin i n d u c e d n e p h r o toxicity, two r e g i m e n w e r e e v a l u a t c d in children, a n d a third was a d m i n i s t e r e d to one p a t i e n t only. T h e most extensively e v a l u a t e d r e g i m e n e m p l o y e d a dose of 15-20 rag/re'a d m i n i s t e r e d as an intravenous bolus daily for 5 days every 3 weeks (29, 25). This r e g i m c n was e v a l u a t e d in two i n d e p e n d e n t studies a n d c o m p a r a b l e results w e r e reported. I n addition, a r e g i m e n e m p l o y i n g a dose of 50 mg/nl2/week a d m i n i s t e r e d as a n intravenous bolus :for 4-5 weeks was e v a h m t e d (25). M o r e t ecenfly, aggressive h y d r a t i o n with or w i t h o u t diuresis has resulted in a r e d u c t i o n in the ncphrotoxicity of cisplatin, m i d two additional regimens h a v e been evaluated, 120 m g ] m 2 / d a y given eve D, 3-4 weeks a n d 3-4.5 m g ] k g also a d m i n i s t e r e d as single intravenous bolus dose every 3 weeks (3, 30). T a b l e I, Cisplat~n d o s a g e s c h e d u l e s in c ~ I d r e n
References Nitschkc a a/. (29) Kamalakar a aL (25)
Och's a d. (30) Baurn et~'..(3)
Dose rt~iraen 15-20 rag/rat/day × 5 day, every 3 wee~ (A) 20 rag/mS/day × 5 days every 3-4 weeks (B) 50 regime/dose once a wcck (C) 60 rag/mS/day x 2 days every ~ weeks 120 rag/m~/day evta-y 3 week5 3-4.5 mgdkg/do~e xA~-wee~
No. of patients treated 78 11 4" I
8 I6
Antitumor activity as a £ingle agent Leukemia3. T a b l e 2 s u m m a r i z e s the response rates o f various t u m o r t y p ~ to cisplatin as a single agent by differen t investigators. T h e response to cisptatin o f both adults a n d children w i t h l e u k e m i a was disappointing. A p p r o x i m a t e l y a 9 % response r a t e was observed in 43 e v a l u a b l e a d u l t patients w i t h a c u t e l e u k e m i a (6, 19, 20). T w e l v e p e d i a t r i c patients ,~4th acute iyrnphocydc leukemia W e r e treated with 2 or m o r e :courses of cisplatin (29). Cisplatin was ,giveaaby rapid int~-avcnous infusiondaily for 5 days without increased fluid intake or diuresis.T h r e e children h a d a tcmporax T decrease in the liver a n d spleen: sizes b u t n o n e of t h e 12 .patients - a ~ e v e d remission. Solid. tt~mors.. T h o u g h .the n u m b e r o f patients i n v o l v e d in almost all p e d i a t r i c studies is limited, ,consistent. a n d s i g ~ f i c a n t ~ p o n s e f a t e s "iia p a t i e n ~ " ~ t h c e r t a ~ n t u m o r types h a v e b e e n 0bser~ed. Osteogenic S a r c o m a a n d n e u r o b l a s t o m a :have s h o w n t h e greatest
PF_.DIATRIC Ca~t.NCIER. CHE, M O T H E R A P Y
155
therapeutic responses to clsplatin. Since most of the patients included in these studies had far advanced disease, and were resistant to almost all of the conventional daemotherapeutic agents and regimens, the response rates are relatively impressive. T h e overall response x~ate of osteogenie sarcoma and neuroblastoma to D D P from these limited number of cases studied wm'e approximately 34% and 30% respectively. T a b l e 2, R e s p o n s e
r a t e s t o c l s p l a t l n i n c h i l d r e n mnlth l e u k e m i a a n d s o l i d t u m o r s
Baum et o2. (3)
T u m o r types
~teosafco~
3/16
Neuroblastoma E~wing's sarcoma ghabdomyosarcoma Tcsticular,embryonal cell carcinoma Semlnoma Brain tumor Medullary CA, d~)a'oid Retinoblastoma ~rAacellaneous Leukemia
(No. o f rcsponders/No, of evaluable patients) Nitsehke Kamalakar Och's a at. (29) et at. (25) tt at, (30)
~i1 Gz~2 ~2 0/s
1/4 1/3 o/2 012
~!8
Tailey et al. (41)
1/1
i/i 0/I I/1
0/2 0/4 0/it
0!t
It: combination with other agents
Steinherz et al. (39) treated a group of patients with various types of solid tumors using a combination ofcispladn, v;zablastine, daetinomycin, cyclophosphamide, a n d bleomycia (VAB I I l ProtocoI--sho~a: in Table 3). O f the 12 evaluabte previously treated patients , three complete and four partial remissions were observed (5]6 NHL, I/1 ALL, 1/1 angi0sarcoma); A n additional three previously untreated patients with endodermal sin us tumors were treated x~fith t h e same regimen after incomplete surgical removal of the primary tlmmrs. All three were free of disease from 2 to 8 months after initiation of treatment at the time of the report. T a b l e 3. V A B IXI C o m b i n a t i o n c h e m o t h e r a p y
Drug
Dose and schedule
Induction Vinblastine Daetinomycia Oydophosphamide Bleomycixi Cisplatin Maintenance Chlorambucil 7v'inbtasrine
,Xdri.~mY~ or Da~oniycin
C~!ath
or
4 mg/rnZ/dose× l o n Day 1 1 mg/m:/dosc × 1 on Day 1
600 mg/m~/dose x 1 on Day l 20 rag/mS/day for 7 days as continuous irdiasion .90-120 rag/mS/dose x 1 on Day 8 4 m g / m Z / d a y (Total ot'six 14-day tourney) 4 mg/rn 2 On D~y I 0fchlorambucil llmg/rn~ ~ on Day I o f d d o r a m b u c i l and I mg/m'~ each drug is given in 5 0 mglrra ~) sequence
156
NI. L. GUTIERRE, Z ~N3D S. T. C R O O K E
As adjuvant chemotherapy Ettinger and associates (11} at the Roswell Park Mern:oHal Institute reported the preliminary results of a combined regimen o f a d r i a m y c i n and clsplatin given as adjuvant therapy in patients with osteogenic sarcoma. Cisplatin at 100 mg]m'- Lv. × I was given altcamatety with adriamycin at 30 mg/m~]day :< 3 days every three weeks. Adriamyein was given to a total dose of 540 mg]m". Cisplatin administration ,,¢&~limited to 8 courses. All 8 patients were free ofdisease from 3 to 21 months from tim initiation of t h e r a p y with a mean duration Of 12 months at the tLme of the report.
Toxicitie, T h e major toxic effects of cisplatin in children were similar to those observed iu adults except that they were more transient a n d moderate. T h e y included gastrointestinal, renal, audiologic and hematopoietic toxiciti~. The toxicities reported are summarized in Table 4. T a b l e 4. Cisplatln toxicity in c h i l d r e n llll I
2 ~
Toxicitiea Nausea and vomiting Nephrotoxlcity , BUN I" C.reotinine Eacctrol~'te imbalance ,~ Ckaicium ff Calcium
.
.
.
.
.
.
.
.
.
.
.
.
.
.
26]78
16]I6
7[8
[1116
!4178 14/78
3/16 2116
6/8
2116
118
2t15
2/78
3116
! 1/11 10131
6129 Ix,
,
I
,
,,
, HL,
~18
2/16
"l-~nn~tus attd hearing 1 ~ ,
_:
5/71 2/71
J, Magntalum L~ve.Jr toxic.it)" t SGOT Hematologic toxicity ~, ]?lcmoglobln ¢. Platclcts ,
_fill
(No, manifcsting toxicity[No, of evaluablc patients) Nitschke I'Gamlakar Och*s Baum et ai. (29) et al. {25) et al. (30) c t a l . (3)
,
,,
m,,___
,.
,,.
,,,
,
3116 ,,,
*,,,,',,
.
Gastrointestinal toxicity. Nausea a n d vomiting w e r e a l m o s t u n i v e r s a l , occun~ing with varying severity but generally were controlled by antiemetics (3,25, 29, 30).
Nephrotoxidty. Evidence of renal
t O ' C i t y Was manif~tcd initially by elevation i n B U N and creatinine a n d a dec.Tease in creatinine clearance. It x~ts u.stu'dly cumubative:and was reversible if detected early (25, 29). None of ~he p a d e n t s t r e a t e d w i t h aggressive hydration and diuresis devdoped severe r~.nal toxicity (3). :Autopsiesdone in 6 patients treated w i t h I--4 course o£cisplatin showed exttmsive tumor involvement b u t no evidence of renal p:attmtogy (25).
Hematologic/o~'tr~ ~£oder'ate myelosuppression occurred i n approximately 5 0 % of patients treated v,4th cispladn (25~ 29, 30).f I n mos t cast.~., t h e n a d i r was approximately 14 days after; dierapy a n d rct~'m to :pre~@txnen t values was us~'~H.V observed by the third week[ I n n o in~.tance was c l a e m o t h ~ p y :discontinued~ because o f hematologic toxicity.
PEDIATRIC CANCER
CHEMOTHERAPY
157
OtotoMd9,. Tinnitus and high frequency hearing loss detected by serial audiograms were the most prominent changes referable to the audiologic systean observed. These toxicities also appeared to be cumulativc, Two patients in Kamalakar's series (25) developed these symptoms aftcr cumulative doses of 200 and 250 mg/mL Vigorous hydration and diuresls did not seem to prevent dcvelopmcnt of this side effect (3). Z,1iscellaneous toxic effect, Moderate elevation of S G O T (100-300 mg %) was reported in one patient (30). O n e child developed anaphyla.xis following treatment with DDP. Prcmcdication with Bcnadryl prevented further rcactior, s in subsequent courses of fllerapy (3).
Epipodophyllotoxln analogs Tcniposide (V2vl-26), 4t--demethyl- l-0-[4,6-0-(2-thcnylidenc)-fl-D-glucopyranosyl] cpipodophyIIotoxin or N S C - 122819 and ctoposide (VP-I 6), 41-
The dose schedtfles used in O~e Phase I ' I I studies of Vh,~-26 and VP-16 in children arc outlined in Table 5. Bofll drugs were given intravenously. The oral administration of VP-16 in clfildreax has not been studied. It has bccn suggemted tJlat a m i n i m u m cumulative dose of 400 rag/m"- given over at least a 2-week pc-tiod should be considered for evaluating the antitumor activity of V ~ - 2 6 (33). Hypotension following r a p i d intravenous administa'ation (i.v. push) has been reported a.s a pos.sible side effect (28, 34,~ 36). To prevent: tiffs, the drugs were" diluted (usually witl: 5 % dextrose, water in 0.33 nornhxI saline) and given as a slow infusion over 30-60 rain. "Fable 5. Dosage administr~t&~t s,¢h~dzdeg o f VM-~6 a n d VP-16 in pediatric clinic1 trials VM-26
VP-16
~tleycr ..-tat. (4)
I30---180rng/m~/dose .;..v. wocldy
Rivcra ,t at. (32)
100 mg/m~/dosci.v. x'wlce weekly for 4 wc,ek~ I-J5 mgtkg/dc,sc i.'e. r~c.c w ~ y 100,I30 mglmSldo~c i.v.: ever)"2 wee~ks
10~.150 mg/m3[dose i;v, Ibr 5 da~-sglven:e~,cry 2"~ w~ks 75 mglmS'dc~ i.v~twlce
P.~t:e, rc~:c
Ros~r,.stocket d, (34} Sklamky et aL (36}
•;;.,celdy
for4 Weeks
158
NL L. G U T I E R R E Z A~N'D S. T . C R O O K E
Antlturnor aa,krit~
Only those studies conducted exclusively in children ,,vill be discussed. A certain percentage of patients included in the early clinical trials especially ithose b y the European investigators are pediatric cases. However, in almost all of those studies patient stratification as to age is lacking i n the reports.
~ia. Encouraging results were obtained with b o t h agents in acute leukemia. As sk~own in Table 6, V P - 1 6 has been shown to b e a n active a g e n t i n acute n o n lympboblastic leukemia whercas V ' M - 2 6 seemed to be more active against the acute lymphocytic type (ALL). The disappointing lack of response obtained by Rosenstock et al. (34) in treating 12 ALL patients with V~[-26 may have been duc to the dose schedule employed. T a b l e d. VM-*-6 a n d VP*t6 i n c h i l d h o o d c a n c e r (NO. o f reapondcrs/2{o, o f evaluablc ~ s c s ) V~I-26 Tumor t~
Blcycr st at. (4)
Riv~ra el M. (33)
Sldamky e! a / . (36)
VP-16
Rosemtock t t aL (3"})
el al. (4)
Bleyer
Olt2
1/I1
Acute lymphoc~-tic
1..mkcmia Acute non-lymphocy tic leukemia Malignant lymphomas Neuroblastorna
Brain tumor WiLm's tumor R h a bdom~a:m~rct~ma
E,,,.,ing'=sarcoma Carcinoma Miscellaneoussarcomaa I-X~t~oc-~oS;s
4/15
9159 2/6
1114 2/6
10/31 0/10 1/16 0/1
016 217 0111
3/7
2t4
216 =t5 1/4
0/2 i/2_
R~vcra a al; (32) at St Jude Children's R e s e a r ~ Hospital conducted a crossover study
using both agenis in 29 chilth'en with leukemia. Patients were given one or:both drugs, Nine patients responded to treatment. Five'responded :to VP- 16 whereas f o u r padents experienced a remission iwhile receiving V:~.I-26. O f the four patients who responded to Vl~$J26 no response was 0 b t a i n e d t o previous treatment oF VP-I 6, Solid tumors. T h e most Significant response obtained, with these• :two a g e n ~ against the
various types of childhood solid tumorswas the effect of V IVL.26 on ncurobtastoma. The results Obtained by the C ~ l d r e n ' s CanCer :Study Group ~ d : t h e group at: s t Jude's compare favorably wiLh:the:0thcr single age//ts u s e d i n the treatment 0fneuroblastoma
(I6, 23, 45). with VM-26. TWO 0f the four patients ~ : 18 y ~ 0 f a c e ~ 0bjcctive ~ i 0 n 0f thc~tumor~:Although-the number o f Patl r~atsiwas:vcr3"s ~ l ; both ComP0unds:'ha~.'e also tun~o~ and.: ~ n :rare-carcinoma.: F,~::inyestig~atJon :-oFt h ~ hgcaits/agaimt'/these tumors ShouId be:considered in:the future.
P E D I A T R I C Ct~NCER ( ~ L E M O T I ~ . R A P Y
159
Toxidties T h e major toxic effects of V M - 2 6 and: VP-16 were gastrointestinal and hematologic (4, S3, 34).
Gastrointestinal. Gastrointestinal toxicity consisted of nausea, v o m i t i n g a n d diarrhea. T h e y were usually mild b u t were troublesome in some cases. T h e relative incidence of these side effects was Similar for both V~'I-26 a n d VP-16.
Hematologic. ~Myelosuppression a p p e a r s : t o lie a dose limiting toxicity for both agents. Assemmcnt ofhematologie toxicity could be done only on solid tumor patients. Moreover, evaluation of the hematologic toxicity was q u i t e difficult in view of the poor clinical status of the patients treated. The nadirs of leukopenla a n d dlrombocytopenia following MM-26 therapy 'were reported to bc on the 16th a n d 18th day of treatment respectively (32, 33). Neutropenia has b e e r reported to occur in approximately 45% of patients treated with either drug (4). ~Iiscellanzoux ,'idle effect. Nfild hypotension following rapid infusion of V2~{-26 was reported in: o n e patient (34). Subsequent doses were administered at a lower rate and no drop in the blood pressure was noted. Alopecla and drug induced fever secondary to V1~I-26 a n d VP-16 have been reported
(32, 33). Other very unusual side effects observed with V M - 2 6 therapy included a case of anaphylactic reaction (4) and swelling and tenderness of forearm axound the injection site (33).
Mitomycin C Niitomycin CI was d i s c o v e r e d a n d initially studied in J a p a n a n d was found to have significant antitumor activity against a variety of adult neoplasms especially carcinomas (!7). I n 1958, the d r u g w a s i n t r o d u c e d to the U.S.A. a n d initial studies have s h o w n demonstrable c.hcmotherapeutic activity b u t a discouragingly: high level o f toxicity (14, 24). Subsequent refinements a n d modifications in the dose sc~edu'Ling have resulted in the reduction of myelosuppresslon associated w i t h m i t o m y c i n C. In adults, i t h a s sii0wn a e t i v i t y i n breast, Stomach, colorectal, pancreatic a n d h e a d a n d neck carcinomas (7i 26i: 27,- 46). It"is also possibly active in. adenocarcinomas o f the; lung,-:ovary, biLiary t r e e a n d squamous cell :carcinoma o f t h e cervix (:7, 26,:27). M i t 0 m y c i n C has b c ~ s t u d i e d i n a n u m b e r of combinations. I n several diseases such as adenoc~~rcJnon~ of the stomach (31), and:squamous cellc~cinomaof the cervix (2), miiomycin C,c6ntainingregimens have demonstratedsigrfificant activity. Although : i t : h a s a w i d e : range ofl antineoplastic activityi i n adults, mitomycin C demonstrated a irelatively limited activity in t h e t r e a t m e n t of childhood: malignancies. T h e : d i s a p p o i n t i n g r ~ l t s o b t a i n e d b y early:workers probably accounted:for the sub~ U e n t i i m i t e d ~ s t u d i ~ Utilizing diis :drug in childho0ddancer.
Dosage'.~dutes The:first-chmcal~.trmlof,~-lJtomycm.C re:children~wasreported by:Evans (!.)m ~01" ~.Var)~ng l:iigh~t.[dosC~[ 2.5mg/~"gi~)eiii:o~ci::~lsi~cc~.~ SiJbSequcnc doses varied t~0m~o.4~:to
160
~f. L. GUTIER.REZ AND S. T. CROOKE
1.0 m g / k g g i v e n o v e r 2 - I 0 days. Doses h i g h e r t h a n 0.6 m g l k g w e r e associated w i t h severetoxicity. D o s e s b e t w e e n 0.4 a n d 0.6 m g / k g given as 0.1 or 0.2 m g / k g / d a y injection w e r e s u g g e s t e d as most satisfactory in a v o i d i n g significant toxicity. S u t o w et al. (40) o f the SOuthwest O n c o l o g y G r o u p in 1970 i n i t l a t e d a P h a s e I trial utilizing several dose schedules. H o w e v e r , t h e n u m b e r o f patients i n c l u d e d i n e a c h regimen w-'Lstoo small for proper evaluation of its efficacy.The various dose rcgimem are o u t l i n e d in T a b l e 7. Table 7. Mitonayein C
Ph~
I
study (Dose regimen--SWOG, 1970)
Schedule
Dose rt~men
A
0.1 mg/kg/daV×,~
A B B C
D
0.I mg/kg/day x 5 0.15 mg/kg]day X 4 0.15 mg/kg/da7 × 5 0.4 mg/kg x I 0.6 mg]kg x I
E
1.0mg/kg x I
No. of courses "2
8 2 l0 7 2
I
I n c o m b i n a t i o n w i t h p h c n y l a l a n i n e m u s t a r d a n d vincristine,-Jaffe et al:: (22) used m i t o m y c i n C at a dosc of 0.1 mg/kg. T h e t h r e e drugs w c r c a d m i n i s t e r e d i n t r a v e n o u s l y at w e e k l y intervals. Antitwnor actidty as a single agent A total of 42 c h i l d r e n w i t h l e u k e m i a a n d various types o f solid tumors w e r e i n c l u d e d in the initial s t u d y by Evans (14). Significant t u m o r regression o c c u r r e d in 4 [ I 7 p a d e n t s w i t h m e t a s t a t i c osteogenic sarcoma. T w o o f the 7 patients with r h a b d o m y o s a r c o m a , I[3 w i t h H o d g k i n ' s disease a n d I/1 With c h r o n i c grartulocytic l e u k e m i a also s h o w e d objective responses. Odaer t u m o r types t r e a t e d ,/chert: no r e s p o n s c w a s o b t a i n e d i n c l u d e d a c u t e l e u k e m i a , Ewings s a r c o m a , n e u r o b l a s t o m a , a n d miscellaneous sarcomas. I n this p a r t i c u l a r s t u d y the overall r ~ p o n s c r a t e to m i t o m y c i n C was a p p r o x i m a t e l y 16~/0.. T h i s r e g i m e n was associated w i t h severe myclosupprcssion observed in 0 v c r 5 0 ~ o f the patients. A follow-up s t u d y was u n d e r t a k c r t - b y the s a m e g r o u p - u s i n g au~ i n t e r m e d i a t e dose s c h e d u l e to" lessen toxi'eity :(15).:-Thirtcmn patients w i t h metas ~tatic 0 s t e o g e n i c s a r c o m a r e c e i v e d m i t o m y c i n C. a t . a d0sc io[ 0.2 m g / k g or 6 m g / m z, e v e r y 114 days for_ 5 doses i n 10 wceks:J A l t h o u g h t h e toxicity v a r i e d from. n o n e t o severe, myclosupprcsslon, no .response was obtained., A t t e m p t s :.to.d u p l i c a t e the initial.favorable: response o b t a i n e d by Evans (14) in: subsequent studies b y o t h e r workers were.unsuccessful i (15, 22,:40). U s i n g m u l t i p l e- dose :schedules as o u t l i n e d in :Table. 7,. Sutow,rt: aL !(40). o f t h e S o u t h , west O n t o l o g y G r o u p .treated- 21: patients with. different.types o f solid :.tumors.i..Threc respon.y~: w e r e =reported; o n e each:: in... unclassified s a r c o m a , - : . n e u r o f i b r o s a r c o m : a n d rhabdomyosarcoma. T a b l e 8 summarizes, the.t~sults o~ tlic, e t h r e e e a r l y ~tudles o f m i t o m y c i n C : i n . Childh o o d ':neoplasms.
In :combination: udth:otheriantineo~laatiragerax iiri-ti ionian:: i:Ciii~ :.~Ombi.rmfi6n :::,.~th!::: 0the: iandtumor. ~:.agents:.i With ~:thei:~ *
-it&xicides ~ u n t ~ : : .
ih! t h e c a r l y : Studies, i:
PEaDtATRIC GANCF~ C H E ~ I O ~ Y T a b l e $. M i t o m y c i n C i n .,
.
Tumor tyims Ostcosarcoma Rhabdomyosarcoma Hodgkin's disease Ncuroblnstoma Ewlng's sarcoma
Neurofibrosar~ma Unclassifiedsarcoma .~li.sce31aneous Acute Icukemla Chronic leukemia
161
childhood c t m c e r . . . . .
,
,|
..................
_
.........
=
,
.
...,.
_ _
(No. of r~pondcrs/No, of ~raluablc patients) Evans Sutow Evans (14) a al. (15) et al. (40) 3/14 2/7 113
0]2
0/I
0./13
015
I/'4
0/1 0/2
1/ I 1/5
0/9 0t3 I/1
0/3
T h e effect of a combination of mitomycin C, phenylalanine mustard and vineristine against metastatic osteogenic sarcomas was reported by Jaffe (22) and co-workers. Ten patients: were t r e a t e d with the combined regimen. Dose limiting toxicity was not encountered. I-Iowever, only I transient)partial response was obtained. SirmLah:et al. (35) in a review of 20 patients with p r i m a r y hepatic cancer in Kuala Lumpur, ~vLalaysia reported an increase in the duration of survival of patients if adjuvant chemotherapy was employed betbre or after surgery. Mitomycin C and vincristine a p p e a r e d to be t h e most effective combination. Six patients ranging in age from I to 2½ months were gi~:en Vincristirm (2 mg/m 2 X 1dose) and mitomYcin C (0.05--2 mg/m-* × I t o 4 doses)prior to surgery. Postoperatively 5/6 patients received a single dose of the same combination, One patient was given/3 weekly doses after surgery, Three of the 6 patients were alive a n d well from 36--54 months aRer surgery at the time of d!e report. Toxirity
In adults myelosuppression affecting particularly the leukocytes and" pIatelets was the m o s t p r o m i n e n t toxicity encountered. T h e hematologic toxicity is delayed a n d dose related. After a single dose of 20 mg/m~, the m e a n time to nadir was 3.5 a n d dr.I weeks for leukopcnia~ and: thrombocytopenia respectively. Other less commort side effects include gastrointestinal disturbances ~ alopecia, stomatitis, severe ccllulitis at the injcction~sitc ifcxtravasati0n occurred and, rare!y, skin rash. •/m C2hildrcn,.the toxic effects of the agent were similar to:those in adults. Over 50% o f thosep~,tients, who received a, total dose of 0;5 m g / k g o r more. in the study by. Evans (!4) developed se~,,~e toxicity, Each subsequent course of therapy was Usually associated w i t h m o ~ . pro!o~ged: depression of-the: bon e rnarrow~: Inh'acrania!, i n t ~ t i n a l a n d p u I m o n a x y h e m o r r h a g e h a v e b e e n reportedih: two patients: In: the study of SUtOW et a L (40)~ a U t h e dosc:regimcns:used (~ab!e 7): wc~e freqt~ently associated w i t k m o d e r a t e to ~ e ~ -!e~pexfiai~andl t h r o m b 0 ~ 0 p e n i a i The:isifigle • large" i/v;.: d o s e s w e r e better t o l e r a t ~ ~T h e nadlr'of, t h e thromboeytop~aia:occurred usually in: the latter p a r t o f b e ~ a :t0 sixtl~iW ~ k Of~treatment;: ~ C nadi r. of tile: Icukocytes.~ual]y coincided w i t h tlie ioweSt~,"i~lat6et~/coUnt.i:ReC0very-!ofthc.bonci:marrow to its,i:pretreatmentivalue was' achievedapp~tcly:R:wecks~tfter tlie:last d ~ i ofmitotnyciix.:Ci n most pati6xits.
162
M.L. GUTIERREZ
A N D S. T. C R O O K E
Summary Promising results obtained with D D P a n d the epipodophyllotoxin analogs, V1~-26 and VP-16 as single agents in certain types of childhood tumors warrant a prompt further investigation of these compounds in P h ~ e I I clinical trials and also i n combination regimens. VM-26 and VP-I6 have d e m o n s t r a t e d a consistent and significant response rate in certain types of childhood cancer. VP-16 has been shown to be effective in acute nonIymphoblastic leukemia. Its activity against l y m p h o m a , rhabdomyosarcoma, Wilms' tumor and Ewing's sarcoma observed in a small n u m b e r of patients deserves furdter investigation. VM-26 is active against n e u r o b l ~ t o m a and acute l y m p h o b l ~ t i c leukemia. I t is also possibly useful in certain types of intracranial neoplasms. Available data have suggested that cisplatin as a single agent is active in the treatment of osteogenic sarcoma a n d neuroblastoma. When given as a n adjuvant in combination with adriamycin in osteogenie sarcoma, preliminary results were encouraging. It should be rioted, however, daat i n m o s t of these studies, the patients treated h a d far advanced disease (some end-stage) and were resistant to almost a l l o f the conventional chemotherapeutic agents. Perhaps, the inclusion 0 f p a t i e n t s with a better performance status would better define the optimal antineoplastic potentials of these agents. Finally, we feel that a r e n e w e d interest should be generated with mitomycin (21 in childhood cancer. Tllere are still Certain aspects of the d r u g that h a v e n o t been exterLsively examined in childrem. Tile use of the large infrequent 0r intermittent dosage schedule which is considered to b e ioptimal based u P o n adult data has never: been thoroughly studied in p e d i a t r i c tumors. A study utilizing such a schedule should at least be initiated before completely abandoning its use in childhood neoplasms.
Acknowledgements T h e authors wish to thank Drs S. D. Reich and B. F' Issell for review of the manuscript and Miss Carol Boyd for t y p i n g dm manuscript.
References I. Averv, T. L.. Roberts, D. & Price, R. A. (1973) Delayed to.city of 4X-.demcthylcpipodophyllotoxin 9-(4,6-0-2-thcnylidene-~-v.-glucopyranoslde)(NSC.-122819---~G~[-26)inmlce; Cw~-~'rCJav~tlwr. R~. 57: 165-173. 2. Baker, L~1{, Caoli, F. I~l. a aL (1974) A comparative study of mhomycln C and portiomycln. Prec. ~tm.. Soc, Clin. Omola~ 15: 182. 3. Baum, E~, G~nberg, L.~:Ga~non, P. a aL 41978) Use of ffs-platlnum diamm~ncd~chlorid¢(CPDD) in 0st~genlc~sa~m .(os)ix! c h i l ~ , (Abstract). P~. Am. So¢,Clin. O~L~19: 315. 4. Bleycr, W.: A.i ~nard,:R~ a a/;(1978) Eplpodophy!Iotoxintl/erapy of c h i l d l ~ k~eoplasia:,a comparatlvc phaac II anal)aiS of;V~i-26 and VP-16-2i 3.'Pr0e.Ara. Sac. Clin.iOr~alog~ 19i 267. 5. Bruckncr,.H. r~;,Cohen, Cr Gttsbc!g'S;B. a a L (!976).Chcm0thcrapy of ovarlan:canccr with adriamycin (AD~'I)~~ d c/S-platinum (DDP~i'(Alxm2act)~=/h~¢..4m. :A.t~ac. Cam~ Ra,/Proc. tim.. Sac. Clln. OmoL 17i 287, 6. Corder.:i~L:P~, Elliott, T, E,,~B¢I!~ nephrotoxlcity Whh:a w6e-klYout-patlenf~edul¢ of¢//-platlnum:~(II}: : d l a ~ c h l o r i d e . : j% Cf/a. ttcraatd: and O ~ t . V.i:(2)-164".5.~I.
P F ~ I A T R I G C A N C E R . CHEMOTHER.APY
163
7. Crooke; S. T. & Bradner, W. T. (I976) IvXitomycin C: a review. Cancer Treatment Reviews 8: 121-139. 8. Cvitkovlc, I:.., Wittes, R., Golbey, R. et al. (1976) Primary comhinatlon chemotherapy (VAIl III) for metastatic or unresectable germ cell tumors (Abstract). Proe. Am. Assoc. Cancer Res./Pro¢. Am. So¢. Clin. aheM. 17: 29{3. 9. Dombernowsky, P. & Nissen, N. I. (1973) Schedule dependency of the antileukemic activity of the podophy llotoxin-derivat ire VP-16-21:3 (NSC,- 141540) in L 1210 leukemia. Arch. Path. Alicrobiot. Stand. 81: 715-724. 10. ~agan, R. T., Frytak, S. & Rubin, J. (1976) Dianhydrogalaetitol (DAG) vs. polychemotherapy in non-small cell hmg cancer (Abstract). Prec..tim. Ass~, Cancer Res,/Pmm. Am...,eae. Clbl. Oncoi. 17: 21. 1I. Ettinger, L . J . , Douglass, t I . O. et al. (1978) Adjuvant adrlamycin (ADP,) and ds-diamminedichloro. platinum (DDP) in primary osteogenle sarcoma. Proc. Am. So¢. Clin. Oncol. 19: 67. 12. European Organization for Research on the Treatment of Cancer Clinical Screening Group (1972) Epip0dophyllotoxin VM-26 in malignant l y m p h o m ~ and solid tumors. Br. A fed. ,7. ii: 744-748. I3. Europe.art Organization for Research on the Treatment of Cancer Clinical Screening Group (1973) EpipodophyUotoxin VP-16-213 in treatment of acute leukemias, haematosarcomas and solid tumora. Br. 3fed. 07. iii: 199-202. 14. Evans, A. E. (1961) Mitomycln C. Cancer Chemotherapy Rtp. 14: I-9. 15. Evans, A. E. ¢tal. (1969) Evaluation of mitomycin C (NSC-26980) in the treatment of metastatic ¢xsteogenic sarcoma. Cancer ClwmoduralCt Rep. fiJ: 297-298. 16. Finklestein, J. Z., Albo, V., Ertel, I. a al. (1975) 5-(3,3-dlmethyl-ltrlazcno) imldazole-4-carboxamide (NSO-4538B) in the tretament of solid tumors in children. Cancer Cheraother. Rep. ~;9: 351-357. 17. Frank, W, & Osterberg, A. E. (1960) Mitomyein C : an evaluation o1"the Japanese reports. Cancer Cd6cntoO~erapy Rep. 9:: 1142-119. 18. Higby, D . J . , Wallace, H . J . , J r . , Alberts, D . J . & Holland,J. F. (1974) Diamminedichloroplatinum~ a phase I study showing responses in testieular and other tumors. Cancer 3a: 1219-1225. 19. Hill, j . Nf., Loeb, E., ~iacLellan, A., ]gill, N. O., Khan, A. &King, J. j . 09?5) Clinical studies of platinum coordination compounds in the treatment Of various malignant disease. Cancer Chemother. Rep. 59: 647....659. 20. Hill,J. bf., Pardue, A. S,, Khan, A., Hill, N. O,, King, J . j ' & Hill, R. W. (1977)Platinum coordination compounds in thc treatment of acute leukemia and other malignant disease with particular ref~'ence to rnalonato 1,2-diamminocyclohexane platinum (II)..7. Clin. tl¢Tnotol; and OncoL 7 (2): 681-701, 21. H i l l , j . I~,L, Loeb, E., ~facLellan, A. S., Hill, N . O . , Khan, A. & Kogler, J. (1974)Further clinic.M experience with dar-plati:ium 1I dlamminedichl0ride.: In PlatinumCoordlnatlon Comptexes in Cancer Chcmatherap~r. (Connors, T~ A ; & Roberts, J. J.i eds.), Sprlnger-3/crlag, ]-Ieldelberg, pp.:! 45-152, 22, Jaffe, N., Traggls, D. & Enriquez., C. (1971) Evaluation of a combination oF mitomycin (3 (NSC26980), phenglalanine: mustard (NSC-14210), and Vincristine (NSC-67574)in tim treatment o f osteogenic sarcoma. C~ncer C/~emot.~r.:Rtp., 5~: 189-191. 23. James, D. & George, P. (1964) Vincristine in children with malignant solid tumors, ft. Pediatr. 64: 534-541, 24. J0nes, R . , J r . (1959) Mitomyein C: a preliminary repoz~ of studies ofhuman pharmacology and initial therapeutic trial. Ca~xr ChratOtlwrapj Rep. 2: 3-7, 25. Kamalakar, P., Freeman, A. etaL (1977) Clinical Response and toxicity with c/s-DDP (II)in chi:dren. Cancer T , ~ I R e ~ U 61: 835=-839. 26.;l~{anhelmer; L~ & Vital, J : (I966) Mitomycin C in the therapy of far advanced malignant:tumors. Canur119: 207-2 ! 2 . 27. i*toore,~G. E.~ Bro~, L D. etal. :(1968):Effects ofmltomyeln C (NSC.26980) in 346 patients with 28' ~iUgg~, F. ~M2. Sela~yry, O, S. &7Hanseni H. H . (!971) Clinical studies with a new podophyllotoxin derlvative, ~ epip0dophylloi0xim:!41/ Demethyl-9-(4,6-0-2~tiienylidene-/g-I)2glucopyra/io~ide ( N S C 29. N!LsC&e, ~ Starll/~g, K . : a aL,(1978)i C/~-d~amminedicld0roplatinum I~(NSC-!! ~ 7 5 ) i n cttildhood rtmiigtmncles.~ASotithwestoncology:GtToUpStUdy/.Afediealw~Pdiatri¢ 0m0/oO 4 , 127-!32. . 302 C/s~i~ic~orodL.tmmineplatinum (II) in advanced ~osteogerdc
31. Ota, iK~g Sojii K.~al aI. ~972) Combination ttm~ap~ w i t h mitomycln
a n d cytcmne a r a b ~ t d e (NS~-~3878)" for advanced cancer in: man. c a m ~ C/wmatlueap~
164
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A N D S. T. CROOKE
32. Rivcra, G., Avery, T. & Pratt, C. (1975) 41-Dcmcthyleplpodophy~oxin 9-(4,6.0-2.thenylidene-,B-t~ glucopyranosidc) (NSC-122819) (VM-26) r nd 41-dcmethylepipodophyUotoxin 9-(4fi-0-cthylidcnc,-~v-glucopyranoside) (NSC-IoH540--VP-16-213) in childhood cancer: preliminaryobscrvatlom. Camel C/~ot/~r. Rep. ~9: 743-749. 33. Rivcra, G., Green, A. el d. (1977) Epipodophyllotoxin VM-26 in the tr~tmcnt of childhood ncuroblaztoma. Caner Trial. P,tp. 61: 1243-1248. 34. Ro~nstock, J. G. & Domddson, M. H. (I976) Phase I-II trial of VM-26 (NSC,-122819) in the treatment of children with late stage lenkcmia. Cara:tr Treat. Rtp. 60: 265--267. 35. Sirmlah, D., Campbell, P. E. and Golcbatch, H. J. (1974) Primary hepatic cancer in infancy and childhood a survey of twenty ca~es. Progresz in Pcdlatrir Sur&e{yVol. 7, 141-170. 36. Sklansky, B. D., Mann-Kaplan, R. S., Re)mold, A. F., Jr., Rosenblum, M. L. & Walker, M. D. (1974) 4t-Demcthylepipodophyllotoxln-~-o-thenylidcnc-glucoside ( P T G ) i n the treatment of mallgnant intracr.miM neoplasms. Camtr 3~: 460-467. 37. Stahclin, I I . (1970) 42 Demcthyl-eplpodophyllotoxin thenylidenc glucoaldc (VM-26) a podophyllum compound witha new mechanism of action. Eur. 07. Cancer 6: 303-311. 38. Stahclin, H. (1973) Activity ofnmv glycosidic lignan derivative (VP-16-213) related to podophyllotoxin in cxpcrimeutal tumors. Eur. 07. Canctr 9:215-221. 39. Stelnherz, P., "Tan, C.j Ghavimi, R. tS a/. (1977) VAB III combination chemotherapy in childhood malignancim. Pro¢. Am. So¢. Clin. OncoL 18: 231. 40. Sutow, W. W., V¢ilbur, j. I7,.tt al. (1971) Evaluation of dosage schedule~ ofmitomycin C (NSC-26980) in children. Career CAenvaherapj Rtp. 55: 189-19I. 41. Tallcy, R. W., O'Bryan, R . M . , Guaerman , J. U., Bvo~Ice, R . W. &i McCredic, K . B. (1973) Clinical evaluation of toxic cffectt ofdz-diamminedichloroplatinum (NSC~119875)~Phasc I clinical study. Cancr.r Chtmoa~. Rtp. 57: 46.5-471. 42. Vemdlttl, J. M. (197 l)-Treatrnent scho:lUIedependency ofexperinmntally active antiieukemic {Ll2 I0) drug~. CancerC&.mor~tr~P.tp. 2: 35--59~ 43. Wallace, FL J. & Higby, D.J. (1974) Phmm I evaluation of d.J-platinum (H) diamminedichloride (PDD) and a combination of PDD plus adriamycizt. In Plallmvn Coordination Compltxea in Camtr Chemo. thrrapy. (Gonnors, T. A. & Roberts, j. J., eds.), Springer-Vcrlag, Heidclberg, p. 167. 44. Wihshaw, E. & Cart, B. (1974)C/~-platinuro (II) diamminedichloride-cilnical ex'perlenccoftheRoyal Marsdem Hospital and Imtitutc of Cancer Research, London. In Platinum Coordination Complt.~s in CamrrChtrnothtrap.y. (C,onnors, T.A. &Roberts, J.J., eds.). Springcr-Verlag, Heideltxrg, pp. I78-182. 45. Windmiller , j., Berry, D. H., Victti, T. a aL (1966) Vincristine sulfate in the treatment of neur~ bl~toma in children. Am. ft. Dis. C/did 111 : 75-78. 46. Wi~e, G; R., Kuhn, I. N. et al. (1976)Mitomycin C in large infrequent dosm in brea, t cancer. 3ftdfcal and Pediatric OncoloD,2: 55-60. 47. Wittes, R, E., Brescia, F., Young, C. W. a aL (1975) Comblnadon chemotherapy with ds-diam. min0:llchloroplatinum (II) and bleomycin in tumors of the head and neck. OncMogy32: 202-207.
Pediatric cancer chemotherapy: an updated review I. Cis.Diaxnmlnedichloroplatinum II ( c i s p l a ~ n ) , VM-26 (teniposide), VP-I6 (etoposide), mltomycin
C
Manuel L. Gutierrez* a n d S t a n l e y T. Crooke The Department of Clinical Cancer Research, Bristol Laboratories, Syracuse, .New 2"ork 13201, U.S.A.
Introduction "tVith the rapidly increasing n u m b e r of new agents developed for clinical trials, a n d the relatively limited n u m b e r of pediatric patients with neoplastic disease, it is essential to periodically review the information on agents undergoing evaluation to a.mure that they a r e adequately evaluated in a broad spectrum o f pediatric tumors. It is also important to r e - e v a l u a t e older agents w h e n new developments Which increase their efficacy in adults suggest that they may b e more useful in children. This paper will serve as the first !in a series of reviews o f old and n e w chemotherapeutic agents used i n childhood cancer, Cis,diamminedichloroplatinum (cisplatin), teniposide (V1~[-26), etoposide (VP-16), a n d mitomycin C will be t h e subjects of ttlis initial report. C/s-diamminedichloroplatinum II: (cisptatin) a n d the epipodophyllotoxin analogs, teniposide (VM-26) a n d etoposide (VP-16) are antineoplastic agents recently introduced for clinical trials. In a limited n u m b e r of studies involving childrer~ with~various types of malignancies these agents have s h o w n significant antitumor activity.. H o w e v e r the utility of these agents in most pediatric ttmmrs Ls not clearly defined. Y,~tomycin C is an a n t i t u m o r agent w h i c h was studied initially several years ago, and failed ~to be of significant value. However, recently d e v e l o p e d ' i n t e r m i t t e n t dosage regimens have resulted i n improved clinical utility-in adults. T h u s a review of its activity against pediatric: t u m o r s n~ay suggest new avenues of clinical researcl~ emplo)qng the lfigh :dose i n t ~ i t t e n t schedules. C i s - d l a t n m l n e d i c h l o r o p l a t l n u m II ( c i s p l a t l n ) Extensive clinical trials of cisplatin as a single agent in a wide varlcty o f a d u i t neoplasms !iaj)e d e m 0 n s ~ t e d a c t i v i t y against testicuIar tumors; lymphomas; head and neck cancer, ovarian ~ i n b m a a n d m a i n I u r r g ~ C ~ (18; 2I; 43, 44):: In combination with o t h e r * Address reprint:rextueststo:2~LanuelL. Guticrrc~ ~¢LD.,Brlstol Laboratories, P.O. Box 657, Syracuse, New Y0rk I3201~'U.S:A. 0305-7372/79/030153+ 12 802.00/0 (~) I979 Ac~demlcPress Inc. (London) Ltd. 153
154
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ANrD S. T. C R O O K E
antincoplastic agents, cisplatin has d e m o n s t r a t e d a favorable response r a t e in tumors of the testes, prostate, bladder, ovary, h e a d a n d n e c k a n d lungs (8, 5, 10, 47). M o r e o v e r in certain tumors, e.g. testicular, cisplatin c o n t a i n i n g regimens h a v e p r o d u c e d m a r k e d l y i m p r o v e d survival charactcTisties. Clinical trials in c h i l d h o o d c a n c e r h a v e been initiated but only a very limited n u m b e r of patients h a v e been studied. Dose schedules T a b l e 1 presents information on :the dose schedules e m p l o y e d in studies o n pediatric neoplasms. Prior to the utilization of h y d r a t i o n to avoid elsplatin i n d u c e d n e p h r o toxicity, two r e g i m e n w e r e e v a l u a t c d in children, a n d a third was a d m i n i s t e r e d to one p a t i e n t only. T h e most extensively e v a l u a t e d r e g i m e n e m p l o y e d a dose of 15-20 rag/re'a d m i n i s t e r e d as an intravenous bolus daily for 5 days every 3 weeks (29, 25). This r e g i m c n was e v a l u a t e d in two i n d e p e n d e n t studies a n d c o m p a r a b l e results w e r e reported. I n addition, a r e g i m e n e m p l o y i n g a dose of 50 mg/nl2/week a d m i n i s t e r e d as a n intravenous bolus :for 4-5 weeks was e v a h m t e d (25). M o r e t ecenfly, aggressive h y d r a t i o n with or w i t h o u t diuresis has resulted in a r e d u c t i o n in the ncphrotoxicity of cisplatin, m i d two additional regimens h a v e been evaluated, 120 m g ] m 2 / d a y given eve D, 3-4 weeks a n d 3-4.5 m g ] k g also a d m i n i s t e r e d as single intravenous bolus dose every 3 weeks (3, 30). T a b l e I, Cisplat~n d o s a g e s c h e d u l e s in c ~ I d r e n
References Nitschkc a a/. (29) Kamalakar a aL (25)
Och's a d. (30) Baurn et~'..(3)
Dose rt~iraen 15-20 rag/rat/day × 5 day, every 3 wee~ (A) 20 rag/mS/day × 5 days every 3-4 weeks (B) 50 regime/dose once a wcck (C) 60 rag/mS/day x 2 days every ~ weeks 120 rag/m~/day evta-y 3 week5 3-4.5 mgdkg/do~e xA~-wee~
No. of patients treated 78 11 4" I
8 I6
Antitumor activity as a £ingle agent Leukemia3. T a b l e 2 s u m m a r i z e s the response rates o f various t u m o r t y p ~ to cisplatin as a single agent by differen t investigators. T h e response to cisptatin o f both adults a n d children w i t h l e u k e m i a was disappointing. A p p r o x i m a t e l y a 9 % response r a t e was observed in 43 e v a l u a b l e a d u l t patients w i t h a c u t e l e u k e m i a (6, 19, 20). T w e l v e p e d i a t r i c patients ,~4th acute iyrnphocydc leukemia W e r e treated with 2 or m o r e :courses of cisplatin (29). Cisplatin was ,giveaaby rapid int~-avcnous infusiondaily for 5 days without increased fluid intake or diuresis.T h r e e children h a d a tcmporax T decrease in the liver a n d spleen: sizes b u t n o n e of t h e 12 .patients - a ~ e v e d remission. Solid. tt~mors.. T h o u g h .the n u m b e r o f patients i n v o l v e d in almost all p e d i a t r i c studies is limited, ,consistent. a n d s i g ~ f i c a n t ~ p o n s e f a t e s "iia p a t i e n ~ " ~ t h c e r t a ~ n t u m o r types h a v e b e e n 0bser~ed. Osteogenic S a r c o m a a n d n e u r o b l a s t o m a :have s h o w n t h e greatest
PF_.DIATRIC Ca~t.NCIER. CHE, M O T H E R A P Y
155
therapeutic responses to clsplatin. Since most of the patients included in these studies had far advanced disease, and were resistant to almost all of the conventional daemotherapeutic agents and regimens, the response rates are relatively impressive. T h e overall response x~ate of osteogenie sarcoma and neuroblastoma to D D P from these limited number of cases studied wm'e approximately 34% and 30% respectively. T a b l e 2, R e s p o n s e
r a t e s t o c l s p l a t l n i n c h i l d r e n mnlth l e u k e m i a a n d s o l i d t u m o r s
Baum et o2. (3)
T u m o r types
~teosafco~
3/16
Neuroblastoma E~wing's sarcoma ghabdomyosarcoma Tcsticular,embryonal cell carcinoma Semlnoma Brain tumor Medullary CA, d~)a'oid Retinoblastoma ~rAacellaneous Leukemia
(No. o f rcsponders/No, of evaluable patients) Nitsehke Kamalakar Och's a at. (29) et at. (25) tt at, (30)
~i1 Gz~2 ~2 0/s
1/4 1/3 o/2 012
~!8
Tailey et al. (41)
1/1
i/i 0/I I/1
0/2 0/4 0/it
0!t
It: combination with other agents
Steinherz et al. (39) treated a group of patients with various types of solid tumors using a combination ofcispladn, v;zablastine, daetinomycin, cyclophosphamide, a n d bleomycia (VAB I I l ProtocoI--sho~a: in Table 3). O f the 12 evaluabte previously treated patients , three complete and four partial remissions were observed (5]6 NHL, I/1 ALL, 1/1 angi0sarcoma); A n additional three previously untreated patients with endodermal sin us tumors were treated x~fith t h e same regimen after incomplete surgical removal of the primary tlmmrs. All three were free of disease from 2 to 8 months after initiation of treatment at the time of the report. T a b l e 3. V A B IXI C o m b i n a t i o n c h e m o t h e r a p y
Drug
Dose and schedule
Induction Vinblastine Daetinomycia Oydophosphamide Bleomycixi Cisplatin Maintenance Chlorambucil 7v'inbtasrine
,Xdri.~mY~ or Da~oniycin
C~!ath
or
4 mg/rnZ/dose× l o n Day 1 1 mg/m:/dosc × 1 on Day 1
600 mg/m~/dose x 1 on Day l 20 rag/mS/day for 7 days as continuous irdiasion .90-120 rag/mS/dose x 1 on Day 8 4 m g / m Z / d a y (Total ot'six 14-day tourney) 4 mg/rn 2 On D~y I 0fchlorambucil llmg/rn~ ~ on Day I o f d d o r a m b u c i l and I mg/m'~ each drug is given in 5 0 mglrra ~) sequence
156
NI. L. GUTIERRE, Z ~N3D S. T. C R O O K E
As adjuvant chemotherapy Ettinger and associates (11} at the Roswell Park Mern:oHal Institute reported the preliminary results of a combined regimen o f a d r i a m y c i n and clsplatin given as adjuvant therapy in patients with osteogenic sarcoma. Cisplatin at 100 mg]m'- Lv. × I was given altcamatety with adriamycin at 30 mg/m~]day :< 3 days every three weeks. Adriamyein was given to a total dose of 540 mg]m". Cisplatin administration ,,¢&~limited to 8 courses. All 8 patients were free ofdisease from 3 to 21 months from tim initiation of t h e r a p y with a mean duration Of 12 months at the tLme of the report.
Toxicitie, T h e major toxic effects of cisplatin in children were similar to those observed iu adults except that they were more transient a n d moderate. T h e y included gastrointestinal, renal, audiologic and hematopoietic toxiciti~. The toxicities reported are summarized in Table 4. T a b l e 4. Cisplatln toxicity in c h i l d r e n llll I
2 ~
Toxicitiea Nausea and vomiting Nephrotoxlcity , BUN I" C.reotinine Eacctrol~'te imbalance ,~ Ckaicium ff Calcium
.
.
.
.
.
.
.
.
.
.
.
.
.
.
26]78
16]I6
7[8
[1116
!4178 14/78
3/16 2116
6/8
2116
118
2t15
2/78
3116
! 1/11 10131
6129 Ix,
,
I
,
,,
, HL,
~18
2/16
"l-~nn~tus attd hearing 1 ~ ,
_:
5/71 2/71
J, Magntalum L~ve.Jr toxic.it)" t SGOT Hematologic toxicity ~, ]?lcmoglobln ¢. Platclcts ,
_fill
(No, manifcsting toxicity[No, of evaluablc patients) Nitschke I'Gamlakar Och*s Baum et ai. (29) et al. {25) et al. (30) c t a l . (3)
,
,,
m,,___
,.
,,.
,,,
,
3116 ,,,
*,,,,',,
.
Gastrointestinal toxicity. Nausea a n d vomiting w e r e a l m o s t u n i v e r s a l , occun~ing with varying severity but generally were controlled by antiemetics (3,25, 29, 30).
Nephrotoxidty. Evidence of renal
t O ' C i t y Was manif~tcd initially by elevation i n B U N and creatinine a n d a dec.Tease in creatinine clearance. It x~ts u.stu'dly cumubative:and was reversible if detected early (25, 29). None of ~he p a d e n t s t r e a t e d w i t h aggressive hydration and diuresis devdoped severe r~.nal toxicity (3). :Autopsiesdone in 6 patients treated w i t h I--4 course o£cisplatin showed exttmsive tumor involvement b u t no evidence of renal p:attmtogy (25).
Hematologic/o~'tr~ ~£oder'ate myelosuppression occurred i n approximately 5 0 % of patients treated v,4th cispladn (25~ 29, 30).f I n mos t cast.~., t h e n a d i r was approximately 14 days after; dierapy a n d rct~'m to :pre~@txnen t values was us~'~H.V observed by the third week[ I n n o in~.tance was c l a e m o t h ~ p y :discontinued~ because o f hematologic toxicity.
PEDIATRIC CANCER
CHEMOTHERAPY
157
OtotoMd9,. Tinnitus and high frequency hearing loss detected by serial audiograms were the most prominent changes referable to the audiologic systean observed. These toxicities also appeared to be cumulativc, Two patients in Kamalakar's series (25) developed these symptoms aftcr cumulative doses of 200 and 250 mg/mL Vigorous hydration and diuresls did not seem to prevent dcvelopmcnt of this side effect (3). Z,1iscellaneous toxic effect, Moderate elevation of S G O T (100-300 mg %) was reported in one patient (30). O n e child developed anaphyla.xis following treatment with DDP. Prcmcdication with Bcnadryl prevented further rcactior, s in subsequent courses of fllerapy (3).
Epipodophyllotoxln analogs Tcniposide (V2vl-26), 4t--demethyl- l-0-[4,6-0-(2-thcnylidenc)-fl-D-glucopyranosyl] cpipodophyIIotoxin or N S C - 122819 and ctoposide (VP-I 6), 41-
The dose schedtfles used in O~e Phase I ' I I studies of Vh,~-26 and VP-16 in children arc outlined in Table 5. Bofll drugs were given intravenously. The oral administration of VP-16 in clfildreax has not been studied. It has bccn suggemted tJlat a m i n i m u m cumulative dose of 400 rag/m"- given over at least a 2-week pc-tiod should be considered for evaluating the antitumor activity of V ~ - 2 6 (33). Hypotension following r a p i d intravenous administa'ation (i.v. push) has been reported a.s a pos.sible side effect (28, 34,~ 36). To prevent: tiffs, the drugs were" diluted (usually witl: 5 % dextrose, water in 0.33 nornhxI saline) and given as a slow infusion over 30-60 rain. "Fable 5. Dosage administr~t&~t s,¢h~dzdeg o f VM-~6 a n d VP-16 in pediatric clinic1 trials VM-26
VP-16
~tleycr ..-tat. (4)
I30---180rng/m~/dose .;..v. wocldy
Rivcra ,t at. (32)
100 mg/m~/dosci.v. x'wlce weekly for 4 wc,ek~ I-J5 mgtkg/dc,sc i.'e. r~c.c w ~ y 100,I30 mglmSldo~c i.v.: ever)"2 wee~ks
10~.150 mg/m3[dose i;v, Ibr 5 da~-sglven:e~,cry 2"~ w~ks 75 mglmS'dc~ i.v~twlce
P.~t:e, rc~:c
Ros~r,.stocket d, (34} Sklamky et aL (36}
•;;.,celdy
for4 Weeks
158
NL L. G U T I E R R E Z A~N'D S. T . C R O O K E
Antlturnor aa,krit~
Only those studies conducted exclusively in children ,,vill be discussed. A certain percentage of patients included in the early clinical trials especially ithose b y the European investigators are pediatric cases. However, in almost all of those studies patient stratification as to age is lacking i n the reports.
~ia. Encouraging results were obtained with b o t h agents in acute leukemia. As sk~own in Table 6, V P - 1 6 has been shown to b e a n active a g e n t i n acute n o n lympboblastic leukemia whercas V ' M - 2 6 seemed to be more active against the acute lymphocytic type (ALL). The disappointing lack of response obtained by Rosenstock et al. (34) in treating 12 ALL patients with V~[-26 may have been duc to the dose schedule employed. T a b l e d. VM-*-6 a n d VP*t6 i n c h i l d h o o d c a n c e r (NO. o f reapondcrs/2{o, o f evaluablc ~ s c s ) V~I-26 Tumor t~
Blcycr st at. (4)
Riv~ra el M. (33)
Sldamky e! a / . (36)
VP-16
Rosemtock t t aL (3"})
el al. (4)
Bleyer
Olt2
1/I1
Acute lymphoc~-tic
1..mkcmia Acute non-lymphocy tic leukemia Malignant lymphomas Neuroblastorna
Brain tumor WiLm's tumor R h a bdom~a:m~rct~ma
E,,,.,ing'=sarcoma Carcinoma Miscellaneoussarcomaa I-X~t~oc-~oS;s
4/15
9159 2/6
1114 2/6
10/31 0/10 1/16 0/1
016 217 0111
3/7
2t4
216 =t5 1/4
0/2 i/2_
R~vcra a al; (32) at St Jude Children's R e s e a r ~ Hospital conducted a crossover study
using both agenis in 29 chilth'en with leukemia. Patients were given one or:both drugs, Nine patients responded to treatment. Five'responded :to VP- 16 whereas f o u r padents experienced a remission iwhile receiving V:~.I-26. O f the four patients who responded to Vl~$J26 no response was 0 b t a i n e d t o previous treatment oF VP-I 6, Solid tumors. T h e most Significant response obtained, with these• :two a g e n ~ against the
various types of childhood solid tumorswas the effect of V IVL.26 on ncurobtastoma. The results Obtained by the C ~ l d r e n ' s CanCer :Study Group ~ d : t h e group at: s t Jude's compare favorably wiLh:the:0thcr single age//ts u s e d i n the treatment 0fneuroblastoma
(I6, 23, 45). with VM-26. TWO 0f the four patients ~ : 18 y ~ 0 f a c e ~ 0bjcctive ~ i 0 n 0f thc~tumor~:Although-the number o f Patl r~atsiwas:vcr3"s ~ l ; both ComP0unds:'ha~.'e also tun~o~ and.: ~ n :rare-carcinoma.: F,~::inyestig~atJon :-oFt h ~ hgcaits/agaimt'/these tumors ShouId be:considered in:the future.
P E D I A T R I C Ct~NCER ( ~ L E M O T I ~ . R A P Y
159
Toxidties T h e major toxic effects of V M - 2 6 and: VP-16 were gastrointestinal and hematologic (4, S3, 34).
Gastrointestinal. Gastrointestinal toxicity consisted of nausea, v o m i t i n g a n d diarrhea. T h e y were usually mild b u t were troublesome in some cases. T h e relative incidence of these side effects was Similar for both V~'I-26 a n d VP-16.
Hematologic. ~Myelosuppression a p p e a r s : t o lie a dose limiting toxicity for both agents. Assemmcnt ofhematologie toxicity could be done only on solid tumor patients. Moreover, evaluation of the hematologic toxicity was q u i t e difficult in view of the poor clinical status of the patients treated. The nadirs of leukopenla a n d dlrombocytopenia following MM-26 therapy 'were reported to bc on the 16th a n d 18th day of treatment respectively (32, 33). Neutropenia has b e e r reported to occur in approximately 45% of patients treated with either drug (4). ~Iiscellanzoux ,'idle effect. Nfild hypotension following rapid infusion of V2~{-26 was reported in: o n e patient (34). Subsequent doses were administered at a lower rate and no drop in the blood pressure was noted. Alopecla and drug induced fever secondary to V1~I-26 a n d VP-16 have been reported
(32, 33). Other very unusual side effects observed with V M - 2 6 therapy included a case of anaphylactic reaction (4) and swelling and tenderness of forearm axound the injection site (33).
Mitomycin C Niitomycin CI was d i s c o v e r e d a n d initially studied in J a p a n a n d was found to have significant antitumor activity against a variety of adult neoplasms especially carcinomas (!7). I n 1958, the d r u g w a s i n t r o d u c e d to the U.S.A. a n d initial studies have s h o w n demonstrable c.hcmotherapeutic activity b u t a discouragingly: high level o f toxicity (14, 24). Subsequent refinements a n d modifications in the dose sc~edu'Ling have resulted in the reduction of myelosuppresslon associated w i t h m i t o m y c i n C. In adults, i t h a s sii0wn a e t i v i t y i n breast, Stomach, colorectal, pancreatic a n d h e a d a n d neck carcinomas (7i 26i: 27,- 46). It"is also possibly active in. adenocarcinomas o f the; lung,-:ovary, biLiary t r e e a n d squamous cell :carcinoma o f t h e cervix (:7, 26,:27). M i t 0 m y c i n C has b c ~ s t u d i e d i n a n u m b e r of combinations. I n several diseases such as adenoc~~rcJnon~ of the stomach (31), and:squamous cellc~cinomaof the cervix (2), miiomycin C,c6ntainingregimens have demonstratedsigrfificant activity. Although : i t : h a s a w i d e : range ofl antineoplastic activityi i n adults, mitomycin C demonstrated a irelatively limited activity in t h e t r e a t m e n t of childhood: malignancies. T h e : d i s a p p o i n t i n g r ~ l t s o b t a i n e d b y early:workers probably accounted:for the sub~ U e n t i i m i t e d ~ s t u d i ~ Utilizing diis :drug in childho0ddancer.
Dosage'.~dutes The:first-chmcal~.trmlof,~-lJtomycm.C re:children~wasreported by:Evans (!.)m ~01" ~.Var)~ng l:iigh~t.[dosC~[ 2.5mg/~"gi~)eiii:o~ci::~lsi~cc~.~ SiJbSequcnc doses varied t~0m~o.4~:to
160
~f. L. GUTIER.REZ AND S. T. CROOKE
1.0 m g / k g g i v e n o v e r 2 - I 0 days. Doses h i g h e r t h a n 0.6 m g l k g w e r e associated w i t h severetoxicity. D o s e s b e t w e e n 0.4 a n d 0.6 m g / k g given as 0.1 or 0.2 m g / k g / d a y injection w e r e s u g g e s t e d as most satisfactory in a v o i d i n g significant toxicity. S u t o w et al. (40) o f the SOuthwest O n c o l o g y G r o u p in 1970 i n i t l a t e d a P h a s e I trial utilizing several dose schedules. H o w e v e r , t h e n u m b e r o f patients i n c l u d e d i n e a c h regimen w-'Lstoo small for proper evaluation of its efficacy.The various dose rcgimem are o u t l i n e d in T a b l e 7. Table 7. Mitonayein C
Ph~
I
study (Dose regimen--SWOG, 1970)
Schedule
Dose rt~men
A
0.1 mg/kg/daV×,~
A B B C
D
0.I mg/kg/day x 5 0.15 mg/kg]day X 4 0.15 mg/kg/da7 × 5 0.4 mg/kg x I 0.6 mg]kg x I
E
1.0mg/kg x I
No. of courses "2
8 2 l0 7 2
I
I n c o m b i n a t i o n w i t h p h c n y l a l a n i n e m u s t a r d a n d vincristine,-Jaffe et al:: (22) used m i t o m y c i n C at a dosc of 0.1 mg/kg. T h e t h r e e drugs w c r c a d m i n i s t e r e d i n t r a v e n o u s l y at w e e k l y intervals. Antitwnor actidty as a single agent A total of 42 c h i l d r e n w i t h l e u k e m i a a n d various types o f solid tumors w e r e i n c l u d e d in the initial s t u d y by Evans (14). Significant t u m o r regression o c c u r r e d in 4 [ I 7 p a d e n t s w i t h m e t a s t a t i c osteogenic sarcoma. T w o o f the 7 patients with r h a b d o m y o s a r c o m a , I[3 w i t h H o d g k i n ' s disease a n d I/1 With c h r o n i c grartulocytic l e u k e m i a also s h o w e d objective responses. Odaer t u m o r types t r e a t e d ,/chert: no r e s p o n s c w a s o b t a i n e d i n c l u d e d a c u t e l e u k e m i a , Ewings s a r c o m a , n e u r o b l a s t o m a , a n d miscellaneous sarcomas. I n this p a r t i c u l a r s t u d y the overall r ~ p o n s c r a t e to m i t o m y c i n C was a p p r o x i m a t e l y 16~/0.. T h i s r e g i m e n was associated w i t h severe myclosupprcssion observed in 0 v c r 5 0 ~ o f the patients. A follow-up s t u d y was u n d e r t a k c r t - b y the s a m e g r o u p - u s i n g au~ i n t e r m e d i a t e dose s c h e d u l e to" lessen toxi'eity :(15).:-Thirtcmn patients w i t h metas ~tatic 0 s t e o g e n i c s a r c o m a r e c e i v e d m i t o m y c i n C. a t . a d0sc io[ 0.2 m g / k g or 6 m g / m z, e v e r y 114 days for_ 5 doses i n 10 wceks:J A l t h o u g h t h e toxicity v a r i e d from. n o n e t o severe, myclosupprcsslon, no .response was obtained., A t t e m p t s :.to.d u p l i c a t e the initial.favorable: response o b t a i n e d by Evans (14) in: subsequent studies b y o t h e r workers were.unsuccessful i (15, 22,:40). U s i n g m u l t i p l e- dose :schedules as o u t l i n e d in :Table. 7,. Sutow,rt: aL !(40). o f t h e S o u t h , west O n t o l o g y G r o u p .treated- 21: patients with. different.types o f solid :.tumors.i..Threc respon.y~: w e r e =reported; o n e each:: in... unclassified s a r c o m a , - : . n e u r o f i b r o s a r c o m : a n d rhabdomyosarcoma. T a b l e 8 summarizes, the.t~sults o~ tlic, e t h r e e e a r l y ~tudles o f m i t o m y c i n C : i n . Childh o o d ':neoplasms.
In :combination: udth:otheriantineo~laatiragerax iiri-ti ionian:: i:Ciii~ :.~Ombi.rmfi6n :::,.~th!::: 0the: iandtumor. ~:.agents:.i With ~:thei:~ *
-it&xicides ~ u n t ~ : : .
ih! t h e c a r l y : Studies, i:
PEaDtATRIC GANCF~ C H E ~ I O ~ Y T a b l e $. M i t o m y c i n C i n .,
.
Tumor tyims Ostcosarcoma Rhabdomyosarcoma Hodgkin's disease Ncuroblnstoma Ewlng's sarcoma
Neurofibrosar~ma Unclassifiedsarcoma .~li.sce31aneous Acute Icukemla Chronic leukemia
161
childhood c t m c e r . . . . .
,
,|
..................
_
.........
=
,
.
...,.
_ _
(No. of r~pondcrs/No, of ~raluablc patients) Evans Sutow Evans (14) a al. (15) et al. (40) 3/14 2/7 113
0]2
0/I
0./13
015
I/'4
0/1 0/2
1/ I 1/5
0/9 0t3 I/1
0/3
T h e effect of a combination of mitomycin C, phenylalanine mustard and vineristine against metastatic osteogenic sarcomas was reported by Jaffe (22) and co-workers. Ten patients: were t r e a t e d with the combined regimen. Dose limiting toxicity was not encountered. I-Iowever, only I transient)partial response was obtained. SirmLah:et al. (35) in a review of 20 patients with p r i m a r y hepatic cancer in Kuala Lumpur, ~vLalaysia reported an increase in the duration of survival of patients if adjuvant chemotherapy was employed betbre or after surgery. Mitomycin C and vincristine a p p e a r e d to be t h e most effective combination. Six patients ranging in age from I to 2½ months were gi~:en Vincristirm (2 mg/m 2 X 1dose) and mitomYcin C (0.05--2 mg/m-* × I t o 4 doses)prior to surgery. Postoperatively 5/6 patients received a single dose of the same combination, One patient was given/3 weekly doses after surgery, Three of the 6 patients were alive a n d well from 36--54 months aRer surgery at the time of d!e report. Toxirity
In adults myelosuppression affecting particularly the leukocytes and" pIatelets was the m o s t p r o m i n e n t toxicity encountered. T h e hematologic toxicity is delayed a n d dose related. After a single dose of 20 mg/m~, the m e a n time to nadir was 3.5 a n d dr.I weeks for leukopcnia~ and: thrombocytopenia respectively. Other less commort side effects include gastrointestinal disturbances ~ alopecia, stomatitis, severe ccllulitis at the injcction~sitc ifcxtravasati0n occurred and, rare!y, skin rash. •/m C2hildrcn,.the toxic effects of the agent were similar to:those in adults. Over 50% o f thosep~,tients, who received a, total dose of 0;5 m g / k g o r more. in the study by. Evans (!4) developed se~,,~e toxicity, Each subsequent course of therapy was Usually associated w i t h m o ~ . pro!o~ged: depression of-the: bon e rnarrow~: Inh'acrania!, i n t ~ t i n a l a n d p u I m o n a x y h e m o r r h a g e h a v e b e e n reportedih: two patients: In: the study of SUtOW et a L (40)~ a U t h e dosc:regimcns:used (~ab!e 7): wc~e freqt~ently associated w i t k m o d e r a t e to ~ e ~ -!e~pexfiai~andl t h r o m b 0 ~ 0 p e n i a i The:isifigle • large" i/v;.: d o s e s w e r e better t o l e r a t ~ ~T h e nadlr'of, t h e thromboeytop~aia:occurred usually in: the latter p a r t o f b e ~ a :t0 sixtl~iW ~ k Of~treatment;: ~ C nadi r. of tile: Icukocytes.~ual]y coincided w i t h tlie ioweSt~,"i~lat6et~/coUnt.i:ReC0very-!ofthc.bonci:marrow to its,i:pretreatmentivalue was' achievedapp~tcly:R:wecks~tfter tlie:last d ~ i ofmitotnyciix.:Ci n most pati6xits.
162
M.L. GUTIERREZ
A N D S. T. C R O O K E
Summary Promising results obtained with D D P a n d the epipodophyllotoxin analogs, V1~-26 and VP-16 as single agents in certain types of childhood tumors warrant a prompt further investigation of these compounds in P h ~ e I I clinical trials and also i n combination regimens. VM-26 and VP-I6 have d e m o n s t r a t e d a consistent and significant response rate in certain types of childhood cancer. VP-16 has been shown to be effective in acute nonIymphoblastic leukemia. Its activity against l y m p h o m a , rhabdomyosarcoma, Wilms' tumor and Ewing's sarcoma observed in a small n u m b e r of patients deserves furdter investigation. VM-26 is active against n e u r o b l ~ t o m a and acute l y m p h o b l ~ t i c leukemia. I t is also possibly useful in certain types of intracranial neoplasms. Available data have suggested that cisplatin as a single agent is active in the treatment of osteogenic sarcoma a n d neuroblastoma. When given as a n adjuvant in combination with adriamycin in osteogenie sarcoma, preliminary results were encouraging. It should be rioted, however, daat i n m o s t of these studies, the patients treated h a d far advanced disease (some end-stage) and were resistant to almost a l l o f the conventional chemotherapeutic agents. Perhaps, the inclusion 0 f p a t i e n t s with a better performance status would better define the optimal antineoplastic potentials of these agents. Finally, we feel that a r e n e w e d interest should be generated with mitomycin (21 in childhood cancer. Tllere are still Certain aspects of the d r u g that h a v e n o t been exterLsively examined in childrem. Tile use of the large infrequent 0r intermittent dosage schedule which is considered to b e ioptimal based u P o n adult data has never: been thoroughly studied in p e d i a t r i c tumors. A study utilizing such a schedule should at least be initiated before completely abandoning its use in childhood neoplasms.
Acknowledgements T h e authors wish to thank Drs S. D. Reich and B. F' Issell for review of the manuscript and Miss Carol Boyd for t y p i n g dm manuscript.
References I. Averv, T. L.. Roberts, D. & Price, R. A. (1973) Delayed to.city of 4X-.demcthylcpipodophyllotoxin 9-(4,6-0-2-thcnylidene-~-v.-glucopyranoslde)(NSC.-122819---~G~[-26)inmlce; Cw~-~'rCJav~tlwr. R~. 57: 165-173. 2. Baker, L~1{, Caoli, F. I~l. a aL (1974) A comparative study of mhomycln C and portiomycln. Prec. ~tm.. Soc, Clin. Omola~ 15: 182. 3. Baum, E~, G~nberg, L.~:Ga~non, P. a aL 41978) Use of ffs-platlnum diamm~ncd~chlorid¢(CPDD) in 0st~genlc~sa~m .(os)ix! c h i l ~ , (Abstract). P~. Am. So¢,Clin. O~L~19: 315. 4. Bleycr, W.: A.i ~nard,:R~ a a/;(1978) Eplpodophy!Iotoxintl/erapy of c h i l d l ~ k~eoplasia:,a comparatlvc phaac II anal)aiS of;V~i-26 and VP-16-2i 3.'Pr0e.Ara. Sac. Clin.iOr~alog~ 19i 267. 5. Bruckncr,.H. r~;,Cohen, Cr Gttsbc!g'S;B. a a L (!976).Chcm0thcrapy of ovarlan:canccr with adriamycin (AD~'I)~~ d c/S-platinum (DDP~i'(Alxm2act)~=/h~¢..4m. :A.t~ac. Cam~ Ra,/Proc. tim.. Sac. Clln. OmoL 17i 287, 6. Corder.:i~L:P~, Elliott, T, E,,~B¢I!~ nephrotoxlcity Whh:a w6e-klYout-patlenf~edul¢ of¢//-platlnum:~(II}: : d l a ~ c h l o r i d e . : j% Cf/a. ttcraatd: and O ~ t . V.i:(2)-164".5.~I.
P F ~ I A T R I G C A N C E R . CHEMOTHER.APY
163
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