v~. ~ ~ 2 zCra_.J199o
Jou,,ud of eaia aN s y , ~ m M a , , ~ g ~
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Original Article
Randomized CrossoverComparison of High-Dose Intravenous Metodopramide Versus a Five-Drug Antiemetic Regimen Patricia M. Plezia, PlmrmD, David S. Alberts, MD, John F. Kessler, MD, Patrici~ L Berens, PharmD, Judy L Chase, PharmD, and Denise J. Roe, DrPh Colleges of Phan,~# and Medicine, University of A ~ , Tucson, Arizona; Depa,tment of Medicine (].F.K.), Travis Air Force Ba% California; Medical College of Virginia Hospital (P.LB.), Richmond, Virginia; and M.D. Anderson C¢ncer Center (].L.C), Houston, Texas
Abstract In a r a ~ i z e d open crossover study, the antie~etic eDicacyof a five-drug antiewetic regunen consisting of raetodopramide, dexar~tho~one, diaupara, diphenh~lramine, and • dlylper~in* was compared to that ofh~rh-dose metodopramide. Thirteen patients trw~ed with cisplatin combination dweaotherapy regiraeus were emlnated. The study terminated pier to orcrual of the planned number of pa6ents because of the stotistically dgn~mnt d~eronce in e~eacy between trmOnents Jbund at interim analysis. The •:uratlon of nausea and number of vomiting episodes on the day of chemotherapy were s i ~ c a n l l y let~ (p < 0.01) after receiving the five-drug combination. After receiving thefive.drug regiwen, 77% of the Faion~ did not exp~r~nce any episodes of romping on d~ 1, and 8% of ~ a had on~ one ep~o~, in eont, ast, onl.~31% of pationts treo~d with high-dose rastochq~amide di.' not have any eptsodes of v a m ~ g on day 1, and 61% of the patients had flve or more episodes. None of the patients treated with the flw-dn~g regimen required additional antiemetic administration. Although both regimau were, in general, well tolerated, when given Ow choice of continuing antiemetic therapies, 92% of the patients preferred the five-drug antiemetic combination. J Pain Symptom Manage 1990;~:101-108.
Kej wo,~ /tntie~6r combinatious, clsplatin
Iraroduct~n Despite recent advances, nausea and vomiting induced by cancer chemotherapy remain a
Addronrt,p ' ~ r~/usst~to: PatrtciaPlezla, phannD, Departmem of PharmacyPractice,Collegeof Pharmacy, Universityof Arizona,Tuscon, AZ 85721.
A~/orpublim#i~:
September 5, 1989.
O U.S*Caw~erPain ReliefCommiuee, 1900 PuMishedby EBevler, New York, New york
serious problem in cancer patients. Not only can this particular toxicity be physically deleterious, it may also directly contribute to patient noncompliance. In an effort m avoid this unpleasant effect of antineoplastic agents, many patients with potentially curable cancers may refuse treatment. Although difficult m evaluate, it has been suggested that up to 50% of pa0885-$924/00/$$.50
dents may be noncomplkmt in some treatment WoSrame.I In recent literature, new antlemetic agents have been evaluated with the hope of decreasing the incidence of nausea and vomiting for lowing chemotherapy, High-dose metcglopramkie and dexamethasone are two of the most active agents currently availage,s-s Neurutrammittor receptor binding studies, specifically the work of Peroutka and Snyder, have shown that "classical" antlemetic agents block at least one of three receptor sites: histamine (Hi), mmcarinic cholinergic, or doparnine (1~. None of the antiemetics currently used to prevent chemotherapy-induced nausea and vomiting block all three of these receptors. It has been hypothesized that by use of a combinetiogaof antiemetk a~,~ents,all three receptor sites can he Mocked. and beuer antiemetic efficacy may be men? Clinical experience with a variety of combination regimens seems to support this hypotheda.'-,0 Recent I/terature suggests that combinations containing metoclopramicle and dexamethasene may be superior to metocinpramide alone, li-I~ ~ 4 o u s repogts from our group have documented the eicacy of a five-drug antlemedc combiuation when administered in open-lehel trials,s,10 The emcacy and tolerabi. llty of this regimen has not been evahtated using a controlled study design with a standard treatment control Because of the lac~ integsubject variability in nausea and vomiting, patients should ideally serve as their own controls for evaluation of antlemetic response. The purpo~ of this study was to compare the antlemetk effu~lcy of a five-drug combination ~ m e n developed at our institution to h~ghdote metoclopramide utilizirtg a randomized ~ver de~Kn.
Maur~s and MetAods Patients with bistok~cally proven malignancy were eligibie to participate in the study if their chemotherapy regimen included cisplatin, and they were to receive identical chemothera. py during two consecutive chemotherapy courses, Padentsleu than Illyrofage wereexcludad Ih)m the gudy, as were Insunn.depen. dent dhtbetks, patknts with active I~ychosis, patlenW who lived Idolw, nlgl themewhole ~ p ~ ratory Uatus could not tolerate eedativetreat-
ment. The research protocol was approved by the Human Subjects Committee, and informed consent was obtained from all patients. A bi~tory of prior chemotherapy (including cisplatio) was not an exch~on criteria for the trial. Patients ~ere randomized via a random number table to receive one of two predefined antiemetic regimens with their next course of chemotherapy. Patients then recei.ed the alteruate antiemetic regimen with the sul~-quent course of chemotherapy. Treatment A was a five-drug combination regimen containing metoclopramide (2 mg/kg IV), dexamethasone (40 mg IV), diphenhydramine (25 rag IV), diazepam (5 mg PO), and thiethylperazine (10 mg IX)) administered 30 mln before and 90 rain after chemotherapy. Beginning 4 hr later, thiethylperazine 10 rag, diazepam 5 rag, and dexamethasone 12 mg were administered orally every 4 hi" for four doses. Treatment B consisted of a ingh-dose intravenous metoclopramide 2 mg/k~, 30 rain fore chemotherapy, every 2 hr for two doses, and then every S hr for three doses. A single dose of 25 mg intravenous diphenhydramine was given with the first metoclopramide dose to minimize extrapyramidal reactions, Patients who experienced five or more episodes of vomiting after chemotherapy were considered to he treatment failures and were rescued with metoclopramide ~' mg/kg IV, dexamethasone 40 mg IV, diphenhydramine 50 mg IV, thiethylperazine 10 mg IM, and diacepam 5 mg PO or IV. This parenteral antiemetic regimen has been previously evaluated and was found to effectively control intractable yoreking in 94¢~ of the patientq studied. I° An observer study for~., was completed for each patient and included current chemotheraW regimen, chemotherapy history, antlemetic history, and concurrent medications. In addition, the nurse recorded any nausea, vomiting, or side effects experienced by the patient on the day of treatment while in the clinic. Patients remeshed in the outpatient clinic for a mininturn of 4 hr. Sul~-quem do~.s were administerad by home heuldl care n u t . s for subjects who were OUtpatients. To evaluate the regimens used, each patient completed a standardized qumttnnnalre for 2 days after receiving chemotherapy, Telephone contact was ~ e d to ira. prove the validity of the questionnaire. E~cacy was evaluated by recording the duration of
VoL 5 No. 2 A[nl11990
IV Metaclopramide ~s Five-Drug Antk'me~ Plan
nausea (in hr) and the number of vomiting episodes experienced the day o f chemotherapy (day !) and the day after treatment (day 2). A 7-point visual analog scale was used to evaluate the subjective severity of nausea and vomiting on days 1 and 2. This same scale was used to rate potential dru~-related side effects, including dizziness, appetite, ability to concentrate, diarrhea, agitation, drowsiness, anxiety, dry mouth, twitching, and trembling. With our rating system, a score of one uniformly means that the reaction did not occur. The difference between two treatment regimens was evaluated with the use o f a paired t test. Differences were considered statistically significant ifp < 0.05 was found. The sign test was used to evaluate any differences in patient preference and necessity of rescue antiemetits. 16
Results A total of 20 patients received at least one treatmeut course. Thirteen patients completed both treatment regimens and were included in the data analysis. Seven patients were n~..~evaluable for both courses of treatment. Infi~rmation concerning these patients is outlined in Table I. The original goal of this tdal, based upon power analyses, was to treat approximately 30 patients. However, the study was fermi-
103
nated early because of the statistically significant difference in elficacy between the treatments found during interim analysis performed following entry o f the 20th patient. The mean age of the 13 patients who completed the study was 50.5 yr (range 33-72 yr). Eight patients were female. Tumor types represented included cervical and ovarian (two each), rectal (two), head and neck (two), esophagus (one), and colon (four). All patients received a cisplatin-containing combination chemotherapy regimen. T h e mean dose of cisplatin was 76.9 mg/m ~ (range 50-100 mg/m 2) with six patients receiving 100 mg/m 2 of cispiat~.n. Cisplatin was administered with standardized saline hydration and mannitol and infused over I hr. Two patients had received cisplatin.~ontaining chemotherapy prior to participating in the study. Three patients had received other chemotherapeutic regimens. Of these five, one had received the five-drog regimen, one received dexamethasone alone, two received autiemetics of unknown type, and one did not receive any antiemetic therapy. Twelve of the I$ patients who completed the crossover study received chemotherapeutic agents other than cisplatln. Nine patients received lluorouracil, one mitomycin, one doxorubicin and cyclophosphamlde, and one mitomycin, vincristine and bieomycin. On day 1, the patient's subjective assessment
Table l Inevaluable Patients
Patient Number $ 6 7 9 I1 16
18
Reason for Termination Missing doses in metoclopramide arm Patient experienced probable anaphylactic reaction to clsplatln Patient did not retu~~i iur second treatment; staff m~able to locate Patient required a leg amputation shortly after first treatment course and refused further participation Completed one course of therapy and care transferred to local hospital Severenausea and vomiting experienced after metoclopramide arm: patient ~ p re~dmitted with dehydration and MI; refused furthe~ treatment Pariem was not able to t e~,ai~ in clialc m receive all metodopramide dose~
Aotiemeti¢ Treatment Evaluable
Day t
Day 2
Vomiting Nausea Vomiting Ndu*ea Episodes Rating Episodes Rating
~-Dntg None*
0
0
0
0
5-Drug
2
4
0
2
0
4
0
6
0
0
0
0
None* Metoclopramide None*
5-Drug
*Complicating medical conditions prevented patient from completing evaluation questionnaire.
el' n a ~ and vomiting, duratio, of nausea. and numher of v~ntting eldsode~ were dgnificandy better with the five-drug regimen (p < 0.01). On day 2, the sorority and duration of nausea were both significandy leu following treatment with the five-drug regimen (p < 0.05). T h e ~ was no difference in vomiting ,core between the two regimens on day 2. Tablet 2 and 8 summarize the results of the efficacy of the two regimens on the day of chemotherapy and the following day, respectively. Itight patients (61%) failed the metoriopramida arm of the study and had to be retcued because they had fire or more episodes of vomiting after receiving chemotherapy. The pacenteral five.drug rescue wet uniformly succmsful in terminating vomiting in these patients. None of the patients required a rescue regimen when the five.drug combination was mud ~ < 0.008). Ten patients (77%) did not have any wmniting episodes on day I after recelvlnil the fire.drug regimen, on,mpal~.-d with 4 patients ($1%) on the metodopramlde arm (Table 4), T'ne nausea and vomidn8 data in the patients who completed only one evalnable u~-atment arm wene comintern with the overall ~udy resuhs (Tnlde I). Of the three patients who received the five-drug regimen, two had no n a ~ or vomiting, and one had two vomiting{ episodes as4tneiated with only mild nausea. One patient who received metodopramlde had m re. ceJve the re~tse mt~icattont and be treated lot" dahydrattoQ, which was felt to be serundary to nautea and vomiting. A secoud pattern did not expaHt.nee nny vomiting epimdes and expel. enced moderate nausea. There were no sigaillcant differences in
number of vomiting (p = 1.0) or retching (p = i.0) episodes, duration of nausea ~ = 1.0) or the patient's severity rating (p ~ 0,885) for vomiting between day I and day 2 for the firedrug regimen. Duration of nausea ~ = 0.589) and number of retching episodes (p = 0.174) were not different in the met~:lopramide arm when day ! was compared to day 2. However, the number of vomiting episodes (p = 0.015) and severity of vomiting ~ ~ 0.004) were ~ignificanlly worse on day ! in the metoclopramida arm. Six patients received the metoclopr~mide arm as their first treatment course and experienced eight, three, five, four, zero and six vomiting episodes. These patients had zero, zero, one, three, zero and zero vomiting episodes, respectively, during the subsequent five-drug regimen. All but one of the seven patients who received the fire-drug t~,imen first had no vomiting epi~wles. Three of these patients reported 0, two reported 5, and one reported 12 vomiting episodes when receiving metoclo. pramide. The one patient who vomited $ times on the five drug regimen experienced 20 emetic episodes when switched to metoclopramide. There were no significant differences between the treatment regimens with respect to dizziness, dry month, agitation, appetite, artxtety, or twitcbing. However, ability to concen. trate ~ ,, 0,055) and trembling ~ = 0.017) were substantially worse when the bigh-dme memclopramide regimen was given. Drowsiness was moderate to severe with both treattaunts but was present to a greater degree with the fire-drug regimen (p ~ 0.047). Patients experienced more diarrhea (p = 0.0fl) when re-
Ta6# 2 Resultsof Fire-Dim8 and MezodopramldeRes,Jmemon Day I
tvertty of tamest DUl~fi~ of nausea (hour) Subjetlive nxaeBrnentof severity~L votn~ing? Nnml~erof ~ l t i n g e~4M~les
Five-DrugRegimen Mean ± SD (Range)
High-Dine Memclopramide Mean 2: SD (Range)
(i.O-&O) 0.462 ~ 0.877 (O,O-3/t) I,tH~ ~ I,~61 (I,(i-5,0) [),5~8 ~ I, i ~? (t),O- 3.0)
(I,0-7,0) 3.~3 • 3,303* (0,0-8,0) S,7(%9± 2.204* (1,0-7,0i ~.30H ~ ,~,677' (0,0- 2(l,0)
,mt ?.poln| vts.ml~nai~ ~lel I ~ m~ p~eem~? - ~,eer,
Table3
Results of Fire-Drag and Metacloprsmide Regimens on Day 2 Five-Drug Regimen Mean - SD (Range)
High-Dose Metoclopramide Mean ± SD (Range)
1.538 ± 1.198 ( 1.0- 5.0) 0.402 ± 0.967 (0.0-3.0) 1.538 ± 1.I08 (1.0-5.0) 0.538 ~ 1.050 (0.0-3.0)
2.769 ± 1.787" ( 1.0-6.0) 3.231 -- :L395" (0.0-8.0) 1.769 ± 1.166 (1.0-4.0) 0.9~3 ± 1.188 (0.0-3.0)
Subjective assessment o1 severity of nauseat Duration of nausea (hour) Subjective assessment of severity of vomitingt Number of vomiting episodes
*p < 0.05, paired t test. t'Based on a 7-w, int visual analog scale: I = not present: 7 = severe. ceiving the high-dose metoclopramide therapy Gable 5). Twelve patients (92%) preferred the fivedrug combination regimen. One patient preferred high-dose metoclopramide as an antiemetic. The difference was statistically significant at p value ~ 0.003.
Despite recent advances in anliemetic therapy, chemotherapy-induced nausea and vomiting continues to occur, to some degree, in the majority of patients. Although singie antiemelic agents have been found to decrease the incidence, no one drug has completely prevented chemotherapy-induced vomiting. The theory o f Peroutl~ and Snyder 7 offered a possible explanation tbr the failure of singleagent therapy. They found that effective
Ta~'4 Ahsulme Number of Vomiting Epised~ Number of Episodes Duyl
0 I-2 ~;-4 ~,5
Da~z
0 I-2 ~- ~, ~5
Five-Drug Regimen (~)
High.Dose Metoclopramlde (%)
10 t"~'7~ t (8) 2 ( I s) 0
4 (31) 0 ! (8) 9 (81)
IO (77) It (1~) I (8) 0
7 (~4l 401) 2 (15) 0
agents block at least one of three known neurotransmitters, that is, histamine (Hi), acetylcholine, and dopamioe (I)2). No single agent substantially inhibited the activity of all three neurotransmitters. In an attempt to achieve complete responses in the majority of patients, a number of investigators have admini~te~'~l various combinations of antiemetic agents in both controlled and uncontrolled settings,s-'°,tt It has recendy been demonstrated, however, that andneoplastic agents do not act directly at the level of the three identified neurotransmitter receptors. 17 This would suggest that the emetic effect of these agents is mediated through secondary factors, such as metabolites or through still undetermined neurotransmitter receptors. The most effective regimens currently available contain metoclopramide 5~sand dexamethasone? with or without other agents, s''o-'s Little overlapping toxicity exists with these agents, and they appear to act by distinct mechanisms. ~ In general, they appear to be more efficacious and better tolerated than high-dose metodopramide alone. Metoclopraraide is a dopamine antagonist of moderate potency that has been found to decrease nausea and vomiting effectively when used in high doses, s Recendy, this drug has demonstrated significant activity at the newly described 5-HT~ ieceptor. 's Thiethylperazine is thought to act primarily at the dopamine receptor sites in the chemoreceptor trigger zon~. t~ |t has dtmonstrated eificacy compared wiih placebo as an antiemetic in patients receiving n~cisp~atin cancer chemotherapy, m Diphenhydramine is an antihistamine agent active
Side E/feet Profile*
Ds~n~ln~ [Nmdnela API~ (~nmm,atlen Wmrrh~ Am~ Dr~ mmath
~11 Tmnb~ *Basedon a 7-9olnt ~
rlve-DraKRt,gimco Mean * SD (RanKs)
Met~clopramld~ Mean ± SD (Ran~cl
5,5 £ 1.4(~-7) 2,8 ± 1,5(I-01 4.0 + 1,0(i-71 2,2 ± 1,5(I-4) 0,8~t .~, IA (0-S)
4.$ ± 1.4(i-7) ~,8 ± 1,9(I-7) 5.~ ± IL9(I-7) 8.2 ± 2,$ (I-7) 1.5 ± ~,~ (0-6)
1,7 "*" 1,5(I-6) ~.$ ± 1,4 ( I - 4 ) 2,6 ± I , g ( I - 7 ) 1.8 ± 1.3(I-8)
2.6 2.8 2,4 2.8
1.8 ± I,I (I-41
± ± ± ±
2.1 (I -7) 1.7 (I-61 1.7(I-5) 2.1 (1-7)
3.3 ± 2.4 (1-7)
p Value
0,047 0.918 0,147 0,058 0.060 0.118 0.475 0.819
0.182 0.017
anaioKscale: I - pot present; 7 = seve~.
~t the H; ~prepfm'; it al~o pm~t~,~ antirholineqpc xtivttyJ The primary benefit of thb qp, m it a d~reaw in the m, eflty of metoc~ pemtde.indtged eurapyremidal t ~ i o m , Dr. uepam is both an anxiolytk and amnesic, Pre]itn~ry ~ sn~tt that the bentedlatepinm may decrees the incidenceof anttctpatcw,/imutea and vomiting symptmm,s* HiBb.dmalge denarnethasom~ ~tnd methylpsedt~u/one h e ~ shown favor~tbie multi in a nUl~J~ of t l n ~ Lrlab wlt~ont i i l ~ i ~ t toxicity from ~ r t - t ~ m u,e,s~ The mechaOf action of ll,~e a~nts remains unclear, 0khou~ an amtpmMaglandln effect he~ been mglpated. An optimal do~ of degamethamne for control of enw~it in mou patients has been mglpmed to he in the range of 40 ml~ given over a IS-hr period. Howt'~r, about L~0%of patients may I~l~fit from higher dines? ~ieveralInvesttptm havereported imp~x~.d enlkmetic efficacyol~Ns at~or patient preferenceIs for toetoclopramide plu-. dexametham e . reslmem compared to memciopramlde alone, The percenta~ of patients experiencing on vontidng eplmck with the two-drug comb~nation in there tl~ah range from ~ % to fi4%. "lherefore. a high percent~e ( > f ~ t ) of patients who h~ve received these antlemebe, ~till experier.ct one m ,~.ore ~mlflng epis~,,h,'~,, it| addltk~, up to ot~ third of p,tdents still axperl. e,x, I l r e ~ ~.m two vor~ttnll e l d ~ m 1be day of ~'mothe~py, h it appe~nt thm a mo~ i g t t ~ m ~ reilimen it needed in 8 suix~miil mlNm of pathmtt, In thb small u ~ , complete rmpomm (no vomktnlD e ~ u r ~ d in 7"/~t and complete plus major
(";two vnnddn8 et~mdel) re~pome~ were o1>. ~rved in g5% of patlents treated. These muhs are superior to the reported t~tponre rates for the two-d~g combination, None of me patients sgt-ated with the five-drug combination t~,imen requited an antiemebe rescue; over hair of the pabents needed to be ~ after receiving metcgk)psamide. Twelve of the iS patients f ~ ) preferred and chine to continue on the five.druil reL0man, Delayed nausea and vomiting (24-48 hr) occurl~d in three patients while on the combination and six patient, on metocl~psamide. Our data, indicating that less than one third of patients receiving metoclo. psamide alone experienced a complete respgmse, are ~xmlietent with the majority of prevlondy r~orted trials, tl-I" The small number of patients completing this trial limits our ability 1o extrapoJate the results to the pop.la~ion of patients receiving cisplatin. An important ques'Jon that remains to be answered is whether it is I.~ossibieto identify those patients who require Rore a~gressive antiemetic prophylaxis prior to treatment with chemo. therapy. Roils and coileaKuest~ have suggested that young women are at signifwantly greater risk of nausea and vomiting than other groups of patleno, In a previous report? we have demonltrated that increaJting age rewlts in decreasing emetic response to chemotherapy, In addition, ~t hat been suggested that patients with a ItittoTT of alcoholism experience significantly leM nausea and vomiting. Aggressive treatnsents, such as the current regimen, may be best uUlised in popuhtions lamwn to he at high risk of nausea and vomiting,
SroL~ No. 2 April 1990
IV laetock,prmide vs Fit*-Drug A n t l m ~ Plan
Carryover effect was not evident in this ~rial, as no patients who received the five-drug regimen, after having thiled metoclopramide, required additional antiemetic reseue. While both regimens were well tolerated overall, the differences in several aide effects approached or ~ached statistical significance. The five-drug regimen had less effect on concentration than did toetoclopramide. Diarrhea and trembling were worse when high-dose metoclopramido was used. The five-drng regimen was somewhat more sedating. The decision to terminate a clinical trial early based on the accumulating data can lead to biascq in the study results, ss'24 In our study, a danger of the early terminath,a is that the differences reported reflect only random vari~-don, rather than superiority of the five-drug regimen. One approach to allay this concern is to consider the stopping rule that would have resulted if thi': study had been conducted as a sequential trial with assessment after each patient completed both regimens. Such a sequential design would have appropriately adjusted for multiple assessments throughout the trial. As shown in the appendix, a sequential design would have m'esuhed in the trial being terminated after the 13th patient who received both reghoens, This, in fact, is when patient accrual to our trial was halted, because of the perceived superiority of the five-drug regimen. This nbservatien suggests that the study results were not an artifact of the early study termination. The high dropout rate obscrved in this trial (35%) was of concern and was partially (15%) due to difficulty experienced in adm;nlstering the metoclopramide treatment. One patient experienced severe nausea and vomiting, and two were excluded because of difficulty in adhering to the schedule of administration. Overall, the patients entered into the trial were fairly debilitated. In addition, several foreign nationals who were being treated at our center did not return for follow-up appointments and could not be contacted. While, in general, the patients who completed only one evaluable course experienced nausea and vomiting consistent with the entire study group, the high d~opout rate confounds the interpretation of this trial, The metodopramide regimen used requires six doses of parenteral metoclopramide over a pariedof approximately I ~ hr, This regimen is not only titoe-consumlng, hot scheduled doses
107
can easily be missed or given at the wrong times. In addition, the patient is obligated to stay in the treatment office in order to receive all six doses, ~mlessa home health care agency is available. The five-drng regimen requires the administration of parenteral medications only twice, and the patient is discharged from clinic within 2 hr after receiving chemotherapy. The oral medications can then be taken at home. Which of the agents are critical to the response of the five-drug regimen remains to be estab lished. It was our goal to ~'ompare these two regimens when administered on an outpatient basis, which made the blinding of these complex regimens dimcuh. An effort was made to decrease investigator bias by having patients complete all questionnaires themselves while at home. Telephone folhiw-up was utilized to address ambiguities in the questionnaires. Observer evaluations were not employed in this study. The five-drug regimen we have described seems to offer several advantages over highdose metoclopramide therapy: better antiemetic efficacy overall, fewer side effects, and less complicated administration. All of these factors combined may decrease the risk of noncompliance in patients receiving cancer chemotherapy. Further study is ongoing in an attempt to simplify the regimen without compromising antiemetic efficacy.
.4p/e~/x sa, dy Tm./,,m/on . ~ . , , / , ¢ a S, e u , a ~ O,~%,,, If the comparison of the efficacy of the two antiemetic regimens had been designed as a sequential study with assessmeng after each patient who completed both regimens, the following stopping rule would have been obtained. The outcome selected for this computation was *he number of vomiting episodes during the first 24 hr, since thh has become the primary assessment of outcome in chemotherapy induced antiemetic trials. It was assumed that high-dose metoclopramide would result in a lower number of vomiting episodes in 50% of the patients with vomiting after at least one regimen; the five-drug regimen would be considered superior if it resulted in a lower number of vomiting episodes in 70% of the patients with vomiting. It was anticipated that a third of the
p~tienta ($$%) would not experienoe vomiting after either regimen. With me of a sequential probability ratio testss to determine stopping boundaries (at a significance level o f 0.08), the study would have been terminated after the thirteenth patient who received both regimens.
We would like to thank Vickie Wihon and the nursing staff o f the Arizona Cancer Center for their clinical assistance. This work was supported by Grants CA 17094 and CA 25024 Cancer Center Core from the National Institutes o f Health, Betheeda, Maryland, and a donation from the Phi Beta Psi National Sorority.
e,4,~'w I. ~ J. Emefis az limitingtoxicity in cancer chemotherapy. In: LmzloJ, ed. Andemetk~t and cancer e.hemotherap,/. Batthnare: Williams and WUkins, 1988:~-ll. 2. Aapao MS, lqezin PM, Alhem DS, et at. Doubleblind cnmsover study of the antiemetlc e~cacy of hlgh-dme d~tamethamnc venus hilih-do~ r~,~!o-
praeslde.J cltn ~ l
!9~t~2~);466.
$. Aapao MS, Albem DS. High.dine de~umwthemne for prevention of cisplalln-indoced vomidnll. Cancer Chemother Pharnmcol 1961;7:11. 4. Drapkin R, SOkolG, Patndinc W, etal. The antiemetic effect and dine respome of dexamethamne in dems receiving dsplatinum [abstr]. Proc Am Soc Or,col 1982;25:61. 5. Gralla RJ, Itri LM, Pltko SE, et at. Antiemetic e[6cecy of high do*age memclopramide: randomized tP.ah agatmt placebo and prochlncperazine in patients with chemotherapy induced nausea and vomiting. N EnglJ Med 1981;805:905. 6. Strum SB. McDormed JE, Opfen RW. et at. Intravenous met~lopeamide, an effective antlemetic in cancer chemotherapy. JAMA 1981;247~2683. 7. Pemutka SJ, Snyder SH. Antlemetio: neumtrammioer receptor binding predicts therapeutic actions. Lancet 1982;1:658. 8. KesalerJF. Alherts DS, Pled~ PM~ e~ at. An effective five-drug antiemetk comhina*~-~,,fo~ prevention of chemotherapy related nauK~ and ~,~m;dng. Cancer Clu'~h~.~ Pha~macol 1986~16:28~. 9, Lane L Mr,Gor R, giakln S. Antiemetk comblna, don (BCDVR) for mnzmt vf platinum iz~lncedemesit [almtr|, Plxx:A m Sac Clln Oncol 198ll;'~8:6S, Ill. PlUlU PM, Alhem I~, Keuler J, etal, Immediate termination of intractable vor~itinll induced by ti~ nn~combinatinn chemotherap~ ruing an intensive II anttemetic regimen. Cancer Tceat Pep 1984;68:1498,
II. Alim SG, Cncnbiaet MA, Warrtngton i~, et at. Dexam :thasone and high dose metoriopramide: efli. cacy ir. controlling clsplatin induced nausea and vomiting. Br MedJ 1984;289:878. 12. Bruera ED, Rora E. Cedaro L, et at. Improved control o f chemotherapy.indnced emesis by the addition of dexamethasone to meteclopramide in patients resistant to meteclopeamide. Cancer Treet Pep 1988;67:$8 I, 18. Grunherg SM, Akerley WL. Krailo MD, et at. C~i-,ari~on of metocloprandde and naetodopramide plus dexametha:~ue for complete protection from chplatinum induced emesis. Cancer Invest 1986;4: 379. 14. Kfis MG, Gralia RJ, Tyson LB, et al. Improved control of cisldatin-indnced emesis with high..dme metoclopramide and with combinations of raetoclo~ pramide, dexamethasone, and diphenhydramine: remira of consecutive trials in 255 patients. Cancer 1985;58:827. 18. Strum SB, McDermed JE, lJpoin DF. High.dose intsavenous metnclopramlde versus combination high-doze metodopaamide and intravenous dexamethamnc in preventing cisplatin-induced nm~sra and emesis: a single-blind crmmver comparison olE antiemetic efficacy. J Clio Oncol 1985;$~245. 16. Sncdecm GW, Cochran WG. Statistical Ioethnds, ¢d 6. Ames: Iowa State University Pcess~ |976. 17. Peroutka SJ. Chemotherapeutic t~ents do not interact with neucotransmitter receptors. Cancer Che. mother Pharmaco11987~ 19:151. 18. IZ.i~hardannBP, Engel G. The pharmacology and function of 8HTs recepton. Trends ~eucosci 1986;7:424. 19. Wampler G. The pharmacolo~/and clinical effectiveness of phenothiazines and related drugs for managing chemotherapy-lnduced emesis, Drugs 1982;25(suppl I):SS. 20. Moetsel CG, Reitemeier R]. Controlled clinical studies of orally administered antiametic drags~ Gastcoentero]ogy 1969;57:262. 21. Robins HI, Erschler WB, DeJongh L, et al. Anti. emetic effect of intravenous diazepam in patients receiving cls-thchlorodlammineplatinom (!1): a pilot study. Med Pediatr Onool 1979;7:247. 22. Roiia F. Tonato M, Basurto C, • al. Antiemetic activity of high doses of metoclopramide combined with meLhylprenholone versus metodopramide alone in chplatin-treated cancer petients: a randomized double-blind trial of the ltaliao oncology groop for dinlcat reseatl:h. J Clln Onc~ 1987;5:141. 28, Geller NL, Pocock 8J. Interim analyses in ran. domlzed cgnkat triath: ramiftcations and guidelines for practitioners. Btoraetries 1987;4S:21& 24. Poceck SJ. Clinical trinb: a practical approach. Chichester, UK: John Wiley and Sore, 1988. 25. Whitehead J. The design and anatysh c,r sequential dinlcat trials. Chlchester, UK: Ellis I~nrwood, 1988.
Jou,,ud of eaia aN s y , ~ m M a , , ~ g ~
lo~
Original Article
Randomized CrossoverComparison of High-Dose Intravenous Metodopramide Versus a Five-Drug Antiemetic Regimen Patricia M. Plezia, PlmrmD, David S. Alberts, MD, John F. Kessler, MD, Patrici~ L Berens, PharmD, Judy L Chase, PharmD, and Denise J. Roe, DrPh Colleges of Phan,~# and Medicine, University of A ~ , Tucson, Arizona; Depa,tment of Medicine (].F.K.), Travis Air Force Ba% California; Medical College of Virginia Hospital (P.LB.), Richmond, Virginia; and M.D. Anderson C¢ncer Center (].L.C), Houston, Texas
Abstract In a r a ~ i z e d open crossover study, the antie~etic eDicacyof a five-drug antiewetic regunen consisting of raetodopramide, dexar~tho~one, diaupara, diphenh~lramine, and • dlylper~in* was compared to that ofh~rh-dose metodopramide. Thirteen patients trw~ed with cisplatin combination dweaotherapy regiraeus were emlnated. The study terminated pier to orcrual of the planned number of pa6ents because of the stotistically dgn~mnt d~eronce in e~eacy between trmOnents Jbund at interim analysis. The •:uratlon of nausea and number of vomiting episodes on the day of chemotherapy were s i ~ c a n l l y let~ (p < 0.01) after receiving the five-drug combination. After receiving thefive.drug regiwen, 77% of the Faion~ did not exp~r~nce any episodes of romping on d~ 1, and 8% of ~ a had on~ one ep~o~, in eont, ast, onl.~31% of pationts treo~d with high-dose rastochq~amide di.' not have any eptsodes of v a m ~ g on day 1, and 61% of the patients had flve or more episodes. None of the patients treated with the flw-dn~g regimen required additional antiemetic administration. Although both regimau were, in general, well tolerated, when given Ow choice of continuing antiemetic therapies, 92% of the patients preferred the five-drug antiemetic combination. J Pain Symptom Manage 1990;~:101-108.
Kej wo,~ /tntie~6r combinatious, clsplatin
Iraroduct~n Despite recent advances, nausea and vomiting induced by cancer chemotherapy remain a
Addronrt,p ' ~ r~/usst~to: PatrtciaPlezla, phannD, Departmem of PharmacyPractice,Collegeof Pharmacy, Universityof Arizona,Tuscon, AZ 85721.
A~/orpublim#i~:
September 5, 1989.
O U.S*Caw~erPain ReliefCommiuee, 1900 PuMishedby EBevler, New York, New york
serious problem in cancer patients. Not only can this particular toxicity be physically deleterious, it may also directly contribute to patient noncompliance. In an effort m avoid this unpleasant effect of antineoplastic agents, many patients with potentially curable cancers may refuse treatment. Although difficult m evaluate, it has been suggested that up to 50% of pa0885-$924/00/$$.50
dents may be noncomplkmt in some treatment WoSrame.I In recent literature, new antlemetic agents have been evaluated with the hope of decreasing the incidence of nausea and vomiting for lowing chemotherapy, High-dose metcglopramkie and dexamethasone are two of the most active agents currently availage,s-s Neurutrammittor receptor binding studies, specifically the work of Peroutka and Snyder, have shown that "classical" antlemetic agents block at least one of three receptor sites: histamine (Hi), mmcarinic cholinergic, or doparnine (1~. None of the antiemetics currently used to prevent chemotherapy-induced nausea and vomiting block all three of these receptors. It has been hypothesized that by use of a combinetiogaof antiemetk a~,~ents,all three receptor sites can he Mocked. and beuer antiemetic efficacy may be men? Clinical experience with a variety of combination regimens seems to support this hypotheda.'-,0 Recent I/terature suggests that combinations containing metoclopramicle and dexamethasene may be superior to metocinpramide alone, li-I~ ~ 4 o u s repogts from our group have documented the eicacy of a five-drug antlemedc combiuation when administered in open-lehel trials,s,10 The emcacy and tolerabi. llty of this regimen has not been evahtated using a controlled study design with a standard treatment control Because of the lac~ integsubject variability in nausea and vomiting, patients should ideally serve as their own controls for evaluation of antlemetic response. The purpo~ of this study was to compare the antlemetk effu~lcy of a five-drug combination ~ m e n developed at our institution to h~ghdote metoclopramide utilizirtg a randomized ~ver de~Kn.
Maur~s and MetAods Patients with bistok~cally proven malignancy were eligibie to participate in the study if their chemotherapy regimen included cisplatin, and they were to receive identical chemothera. py during two consecutive chemotherapy courses, Padentsleu than Illyrofage wereexcludad Ih)m the gudy, as were Insunn.depen. dent dhtbetks, patknts with active I~ychosis, patlenW who lived Idolw, nlgl themewhole ~ p ~ ratory Uatus could not tolerate eedativetreat-
ment. The research protocol was approved by the Human Subjects Committee, and informed consent was obtained from all patients. A bi~tory of prior chemotherapy (including cisplatio) was not an exch~on criteria for the trial. Patients ~ere randomized via a random number table to receive one of two predefined antiemetic regimens with their next course of chemotherapy. Patients then recei.ed the alteruate antiemetic regimen with the sul~-quent course of chemotherapy. Treatment A was a five-drug combination regimen containing metoclopramide (2 mg/kg IV), dexamethasone (40 mg IV), diphenhydramine (25 rag IV), diazepam (5 mg PO), and thiethylperazine (10 mg IX)) administered 30 mln before and 90 rain after chemotherapy. Beginning 4 hr later, thiethylperazine 10 rag, diazepam 5 rag, and dexamethasone 12 mg were administered orally every 4 hi" for four doses. Treatment B consisted of a ingh-dose intravenous metoclopramide 2 mg/k~, 30 rain fore chemotherapy, every 2 hr for two doses, and then every S hr for three doses. A single dose of 25 mg intravenous diphenhydramine was given with the first metoclopramide dose to minimize extrapyramidal reactions, Patients who experienced five or more episodes of vomiting after chemotherapy were considered to he treatment failures and were rescued with metoclopramide ~' mg/kg IV, dexamethasone 40 mg IV, diphenhydramine 50 mg IV, thiethylperazine 10 mg IM, and diacepam 5 mg PO or IV. This parenteral antiemetic regimen has been previously evaluated and was found to effectively control intractable yoreking in 94¢~ of the patientq studied. I° An observer study for~., was completed for each patient and included current chemotheraW regimen, chemotherapy history, antlemetic history, and concurrent medications. In addition, the nurse recorded any nausea, vomiting, or side effects experienced by the patient on the day of treatment while in the clinic. Patients remeshed in the outpatient clinic for a mininturn of 4 hr. Sul~-quem do~.s were administerad by home heuldl care n u t . s for subjects who were OUtpatients. To evaluate the regimens used, each patient completed a standardized qumttnnnalre for 2 days after receiving chemotherapy, Telephone contact was ~ e d to ira. prove the validity of the questionnaire. E~cacy was evaluated by recording the duration of
VoL 5 No. 2 A[nl11990
IV Metaclopramide ~s Five-Drug Antk'me~ Plan
nausea (in hr) and the number of vomiting episodes experienced the day o f chemotherapy (day !) and the day after treatment (day 2). A 7-point visual analog scale was used to evaluate the subjective severity of nausea and vomiting on days 1 and 2. This same scale was used to rate potential dru~-related side effects, including dizziness, appetite, ability to concentrate, diarrhea, agitation, drowsiness, anxiety, dry mouth, twitching, and trembling. With our rating system, a score of one uniformly means that the reaction did not occur. The difference between two treatment regimens was evaluated with the use o f a paired t test. Differences were considered statistically significant ifp < 0.05 was found. The sign test was used to evaluate any differences in patient preference and necessity of rescue antiemetits. 16
Results A total of 20 patients received at least one treatmeut course. Thirteen patients completed both treatment regimens and were included in the data analysis. Seven patients were n~..~evaluable for both courses of treatment. Infi~rmation concerning these patients is outlined in Table I. The original goal of this tdal, based upon power analyses, was to treat approximately 30 patients. However, the study was fermi-
103
nated early because of the statistically significant difference in elficacy between the treatments found during interim analysis performed following entry o f the 20th patient. The mean age of the 13 patients who completed the study was 50.5 yr (range 33-72 yr). Eight patients were female. Tumor types represented included cervical and ovarian (two each), rectal (two), head and neck (two), esophagus (one), and colon (four). All patients received a cisplatin-containing combination chemotherapy regimen. T h e mean dose of cisplatin was 76.9 mg/m ~ (range 50-100 mg/m 2) with six patients receiving 100 mg/m 2 of cispiat~.n. Cisplatin was administered with standardized saline hydration and mannitol and infused over I hr. Two patients had received cisplatin.~ontaining chemotherapy prior to participating in the study. Three patients had received other chemotherapeutic regimens. Of these five, one had received the five-drog regimen, one received dexamethasone alone, two received autiemetics of unknown type, and one did not receive any antiemetic therapy. Twelve of the I$ patients who completed the crossover study received chemotherapeutic agents other than cisplatln. Nine patients received lluorouracil, one mitomycin, one doxorubicin and cyclophosphamlde, and one mitomycin, vincristine and bieomycin. On day 1, the patient's subjective assessment
Table l Inevaluable Patients
Patient Number $ 6 7 9 I1 16
18
Reason for Termination Missing doses in metoclopramide arm Patient experienced probable anaphylactic reaction to clsplatln Patient did not retu~~i iur second treatment; staff m~able to locate Patient required a leg amputation shortly after first treatment course and refused further participation Completed one course of therapy and care transferred to local hospital Severenausea and vomiting experienced after metoclopramide arm: patient ~ p re~dmitted with dehydration and MI; refused furthe~ treatment Pariem was not able to t e~,ai~ in clialc m receive all metodopramide dose~
Aotiemeti¢ Treatment Evaluable
Day t
Day 2
Vomiting Nausea Vomiting Ndu*ea Episodes Rating Episodes Rating
~-Dntg None*
0
0
0
0
5-Drug
2
4
0
2
0
4
0
6
0
0
0
0
None* Metoclopramide None*
5-Drug
*Complicating medical conditions prevented patient from completing evaluation questionnaire.
el' n a ~ and vomiting, duratio, of nausea. and numher of v~ntting eldsode~ were dgnificandy better with the five-drug regimen (p < 0.01). On day 2, the sorority and duration of nausea were both significandy leu following treatment with the five-drug regimen (p < 0.05). T h e ~ was no difference in vomiting ,core between the two regimens on day 2. Tablet 2 and 8 summarize the results of the efficacy of the two regimens on the day of chemotherapy and the following day, respectively. Itight patients (61%) failed the metoriopramida arm of the study and had to be retcued because they had fire or more episodes of vomiting after receiving chemotherapy. The pacenteral five.drug rescue wet uniformly succmsful in terminating vomiting in these patients. None of the patients required a rescue regimen when the five.drug combination was mud ~ < 0.008). Ten patients (77%) did not have any wmniting episodes on day I after recelvlnil the fire.drug regimen, on,mpal~.-d with 4 patients ($1%) on the metodopramlde arm (Table 4), T'ne nausea and vomidn8 data in the patients who completed only one evalnable u~-atment arm wene comintern with the overall ~udy resuhs (Tnlde I). Of the three patients who received the five-drug regimen, two had no n a ~ or vomiting, and one had two vomiting{ episodes as4tneiated with only mild nausea. One patient who received metodopramlde had m re. ceJve the re~tse mt~icattont and be treated lot" dahydrattoQ, which was felt to be serundary to nautea and vomiting. A secoud pattern did not expaHt.nee nny vomiting epimdes and expel. enced moderate nausea. There were no sigaillcant differences in
number of vomiting (p = 1.0) or retching (p = i.0) episodes, duration of nausea ~ = 1.0) or the patient's severity rating (p ~ 0,885) for vomiting between day I and day 2 for the firedrug regimen. Duration of nausea ~ = 0.589) and number of retching episodes (p = 0.174) were not different in the met~:lopramide arm when day ! was compared to day 2. However, the number of vomiting episodes (p = 0.015) and severity of vomiting ~ ~ 0.004) were ~ignificanlly worse on day ! in the metoclopramida arm. Six patients received the metoclopr~mide arm as their first treatment course and experienced eight, three, five, four, zero and six vomiting episodes. These patients had zero, zero, one, three, zero and zero vomiting episodes, respectively, during the subsequent five-drug regimen. All but one of the seven patients who received the fire-drug t~,imen first had no vomiting epi~wles. Three of these patients reported 0, two reported 5, and one reported 12 vomiting episodes when receiving metoclo. pramide. The one patient who vomited $ times on the five drug regimen experienced 20 emetic episodes when switched to metoclopramide. There were no significant differences between the treatment regimens with respect to dizziness, dry month, agitation, appetite, artxtety, or twitcbing. However, ability to concen. trate ~ ,, 0,055) and trembling ~ = 0.017) were substantially worse when the bigh-dme memclopramide regimen was given. Drowsiness was moderate to severe with both treattaunts but was present to a greater degree with the fire-drug regimen (p ~ 0.047). Patients experienced more diarrhea (p = 0.0fl) when re-
Ta6# 2 Resultsof Fire-Dim8 and MezodopramldeRes,Jmemon Day I
tvertty of tamest DUl~fi~ of nausea (hour) Subjetlive nxaeBrnentof severity~L votn~ing? Nnml~erof ~ l t i n g e~4M~les
Five-DrugRegimen Mean ± SD (Range)
High-Dine Memclopramide Mean 2: SD (Range)
(i.O-&O) 0.462 ~ 0.877 (O,O-3/t) I,tH~ ~ I,~61 (I,(i-5,0) [),5~8 ~ I, i ~? (t),O- 3.0)
(I,0-7,0) 3.~3 • 3,303* (0,0-8,0) S,7(%9± 2.204* (1,0-7,0i ~.30H ~ ,~,677' (0,0- 2(l,0)
,mt ?.poln| vts.ml~nai~ ~lel I ~ m~ p~eem~? - ~,eer,
Table3
Results of Fire-Drag and Metacloprsmide Regimens on Day 2 Five-Drug Regimen Mean - SD (Range)
High-Dose Metoclopramide Mean ± SD (Range)
1.538 ± 1.198 ( 1.0- 5.0) 0.402 ± 0.967 (0.0-3.0) 1.538 ± 1.I08 (1.0-5.0) 0.538 ~ 1.050 (0.0-3.0)
2.769 ± 1.787" ( 1.0-6.0) 3.231 -- :L395" (0.0-8.0) 1.769 ± 1.166 (1.0-4.0) 0.9~3 ± 1.188 (0.0-3.0)
Subjective assessment o1 severity of nauseat Duration of nausea (hour) Subjective assessment of severity of vomitingt Number of vomiting episodes
*p < 0.05, paired t test. t'Based on a 7-w, int visual analog scale: I = not present: 7 = severe. ceiving the high-dose metoclopramide therapy Gable 5). Twelve patients (92%) preferred the fivedrug combination regimen. One patient preferred high-dose metoclopramide as an antiemetic. The difference was statistically significant at p value ~ 0.003.
Despite recent advances in anliemetic therapy, chemotherapy-induced nausea and vomiting continues to occur, to some degree, in the majority of patients. Although singie antiemelic agents have been found to decrease the incidence, no one drug has completely prevented chemotherapy-induced vomiting. The theory o f Peroutl~ and Snyder 7 offered a possible explanation tbr the failure of singleagent therapy. They found that effective
Ta~'4 Ahsulme Number of Vomiting Epised~ Number of Episodes Duyl
0 I-2 ~;-4 ~,5
Da~z
0 I-2 ~- ~, ~5
Five-Drug Regimen (~)
High.Dose Metoclopramlde (%)
10 t"~'7~ t (8) 2 ( I s) 0
4 (31) 0 ! (8) 9 (81)
IO (77) It (1~) I (8) 0
7 (~4l 401) 2 (15) 0
agents block at least one of three known neurotransmitters, that is, histamine (Hi), acetylcholine, and dopamioe (I)2). No single agent substantially inhibited the activity of all three neurotransmitters. In an attempt to achieve complete responses in the majority of patients, a number of investigators have admini~te~'~l various combinations of antiemetic agents in both controlled and uncontrolled settings,s-'°,tt It has recendy been demonstrated, however, that andneoplastic agents do not act directly at the level of the three identified neurotransmitter receptors. 17 This would suggest that the emetic effect of these agents is mediated through secondary factors, such as metabolites or through still undetermined neurotransmitter receptors. The most effective regimens currently available contain metoclopramide 5~sand dexamethasone? with or without other agents, s''o-'s Little overlapping toxicity exists with these agents, and they appear to act by distinct mechanisms. ~ In general, they appear to be more efficacious and better tolerated than high-dose metodopramide alone. Metoclopraraide is a dopamine antagonist of moderate potency that has been found to decrease nausea and vomiting effectively when used in high doses, s Recendy, this drug has demonstrated significant activity at the newly described 5-HT~ ieceptor. 's Thiethylperazine is thought to act primarily at the dopamine receptor sites in the chemoreceptor trigger zon~. t~ |t has dtmonstrated eificacy compared wiih placebo as an antiemetic in patients receiving n~cisp~atin cancer chemotherapy, m Diphenhydramine is an antihistamine agent active
Side E/feet Profile*
Ds~n~ln~ [Nmdnela API~ (~nmm,atlen Wmrrh~ Am~ Dr~ mmath
~11 Tmnb~ *Basedon a 7-9olnt ~
rlve-DraKRt,gimco Mean * SD (RanKs)
Met~clopramld~ Mean ± SD (Ran~cl
5,5 £ 1.4(~-7) 2,8 ± 1,5(I-01 4.0 + 1,0(i-71 2,2 ± 1,5(I-4) 0,8~t .~, IA (0-S)
4.$ ± 1.4(i-7) ~,8 ± 1,9(I-7) 5.~ ± IL9(I-7) 8.2 ± 2,$ (I-7) 1.5 ± ~,~ (0-6)
1,7 "*" 1,5(I-6) ~.$ ± 1,4 ( I - 4 ) 2,6 ± I , g ( I - 7 ) 1.8 ± 1.3(I-8)
2.6 2.8 2,4 2.8
1.8 ± I,I (I-41
± ± ± ±
2.1 (I -7) 1.7 (I-61 1.7(I-5) 2.1 (1-7)
3.3 ± 2.4 (1-7)
p Value
0,047 0.918 0,147 0,058 0.060 0.118 0.475 0.819
0.182 0.017
anaioKscale: I - pot present; 7 = seve~.
~t the H; ~prepfm'; it al~o pm~t~,~ antirholineqpc xtivttyJ The primary benefit of thb qp, m it a d~reaw in the m, eflty of metoc~ pemtde.indtged eurapyremidal t ~ i o m , Dr. uepam is both an anxiolytk and amnesic, Pre]itn~ry ~ sn~tt that the bentedlatepinm may decrees the incidenceof anttctpatcw,/imutea and vomiting symptmm,s* HiBb.dmalge denarnethasom~ ~tnd methylpsedt~u/one h e ~ shown favor~tbie multi in a nUl~J~ of t l n ~ Lrlab wlt~ont i i l ~ i ~ t toxicity from ~ r t - t ~ m u,e,s~ The mechaOf action of ll,~e a~nts remains unclear, 0khou~ an amtpmMaglandln effect he~ been mglpated. An optimal do~ of degamethamne for control of enw~it in mou patients has been mglpmed to he in the range of 40 ml~ given over a IS-hr period. Howt'~r, about L~0%of patients may I~l~fit from higher dines? ~ieveralInvesttptm havereported imp~x~.d enlkmetic efficacyol~Ns at~or patient preferenceIs for toetoclopramide plu-. dexametham e . reslmem compared to memciopramlde alone, The percenta~ of patients experiencing on vontidng eplmck with the two-drug comb~nation in there tl~ah range from ~ % to fi4%. "lherefore. a high percent~e ( > f ~ t ) of patients who h~ve received these antlemebe, ~till experier.ct one m ,~.ore ~mlflng epis~,,h,'~,, it| addltk~, up to ot~ third of p,tdents still axperl. e,x, I l r e ~ ~.m two vor~ttnll e l d ~ m 1be day of ~'mothe~py, h it appe~nt thm a mo~ i g t t ~ m ~ reilimen it needed in 8 suix~miil mlNm of pathmtt, In thb small u ~ , complete rmpomm (no vomktnlD e ~ u r ~ d in 7"/~t and complete plus major
(";two vnnddn8 et~mdel) re~pome~ were o1>. ~rved in g5% of patlents treated. These muhs are superior to the reported t~tponre rates for the two-d~g combination, None of me patients sgt-ated with the five-drug combination t~,imen requited an antiemebe rescue; over hair of the pabents needed to be ~ after receiving metcgk)psamide. Twelve of the iS patients f ~ ) preferred and chine to continue on the five.druil reL0man, Delayed nausea and vomiting (24-48 hr) occurl~d in three patients while on the combination and six patient, on metocl~psamide. Our data, indicating that less than one third of patients receiving metoclo. psamide alone experienced a complete respgmse, are ~xmlietent with the majority of prevlondy r~orted trials, tl-I" The small number of patients completing this trial limits our ability 1o extrapoJate the results to the pop.la~ion of patients receiving cisplatin. An important ques'Jon that remains to be answered is whether it is I.~ossibieto identify those patients who require Rore a~gressive antiemetic prophylaxis prior to treatment with chemo. therapy. Roils and coileaKuest~ have suggested that young women are at signifwantly greater risk of nausea and vomiting than other groups of patleno, In a previous report? we have demonltrated that increaJting age rewlts in decreasing emetic response to chemotherapy, In addition, ~t hat been suggested that patients with a ItittoTT of alcoholism experience significantly leM nausea and vomiting. Aggressive treatnsents, such as the current regimen, may be best uUlised in popuhtions lamwn to he at high risk of nausea and vomiting,
SroL~ No. 2 April 1990
IV laetock,prmide vs Fit*-Drug A n t l m ~ Plan
Carryover effect was not evident in this ~rial, as no patients who received the five-drug regimen, after having thiled metoclopramide, required additional antiemetic reseue. While both regimens were well tolerated overall, the differences in several aide effects approached or ~ached statistical significance. The five-drug regimen had less effect on concentration than did toetoclopramide. Diarrhea and trembling were worse when high-dose metoclopramido was used. The five-drng regimen was somewhat more sedating. The decision to terminate a clinical trial early based on the accumulating data can lead to biascq in the study results, ss'24 In our study, a danger of the early terminath,a is that the differences reported reflect only random vari~-don, rather than superiority of the five-drug regimen. One approach to allay this concern is to consider the stopping rule that would have resulted if thi': study had been conducted as a sequential trial with assessment after each patient completed both regimens. Such a sequential design would have appropriately adjusted for multiple assessments throughout the trial. As shown in the appendix, a sequential design would have m'esuhed in the trial being terminated after the 13th patient who received both reghoens, This, in fact, is when patient accrual to our trial was halted, because of the perceived superiority of the five-drug regimen. This nbservatien suggests that the study results were not an artifact of the early study termination. The high dropout rate obscrved in this trial (35%) was of concern and was partially (15%) due to difficulty experienced in adm;nlstering the metoclopramide treatment. One patient experienced severe nausea and vomiting, and two were excluded because of difficulty in adhering to the schedule of administration. Overall, the patients entered into the trial were fairly debilitated. In addition, several foreign nationals who were being treated at our center did not return for follow-up appointments and could not be contacted. While, in general, the patients who completed only one evaluable course experienced nausea and vomiting consistent with the entire study group, the high d~opout rate confounds the interpretation of this trial, The metodopramide regimen used requires six doses of parenteral metoclopramide over a pariedof approximately I ~ hr, This regimen is not only titoe-consumlng, hot scheduled doses
107
can easily be missed or given at the wrong times. In addition, the patient is obligated to stay in the treatment office in order to receive all six doses, ~mlessa home health care agency is available. The five-drng regimen requires the administration of parenteral medications only twice, and the patient is discharged from clinic within 2 hr after receiving chemotherapy. The oral medications can then be taken at home. Which of the agents are critical to the response of the five-drug regimen remains to be estab lished. It was our goal to ~'ompare these two regimens when administered on an outpatient basis, which made the blinding of these complex regimens dimcuh. An effort was made to decrease investigator bias by having patients complete all questionnaires themselves while at home. Telephone folhiw-up was utilized to address ambiguities in the questionnaires. Observer evaluations were not employed in this study. The five-drug regimen we have described seems to offer several advantages over highdose metoclopramide therapy: better antiemetic efficacy overall, fewer side effects, and less complicated administration. All of these factors combined may decrease the risk of noncompliance in patients receiving cancer chemotherapy. Further study is ongoing in an attempt to simplify the regimen without compromising antiemetic efficacy.
.4p/e~/x sa, dy Tm./,,m/on . ~ . , , / , ¢ a S, e u , a ~ O,~%,,, If the comparison of the efficacy of the two antiemetic regimens had been designed as a sequential study with assessmeng after each patient who completed both regimens, the following stopping rule would have been obtained. The outcome selected for this computation was *he number of vomiting episodes during the first 24 hr, since thh has become the primary assessment of outcome in chemotherapy induced antiemetic trials. It was assumed that high-dose metoclopramide would result in a lower number of vomiting episodes in 50% of the patients with vomiting after at least one regimen; the five-drug regimen would be considered superior if it resulted in a lower number of vomiting episodes in 70% of the patients with vomiting. It was anticipated that a third of the
p~tienta ($$%) would not experienoe vomiting after either regimen. With me of a sequential probability ratio testss to determine stopping boundaries (at a significance level o f 0.08), the study would have been terminated after the thirteenth patient who received both regimens.
We would like to thank Vickie Wihon and the nursing staff o f the Arizona Cancer Center for their clinical assistance. This work was supported by Grants CA 17094 and CA 25024 Cancer Center Core from the National Institutes o f Health, Betheeda, Maryland, and a donation from the Phi Beta Psi National Sorority.
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