679

COMPARISON OF TOXICITY WITH CP AND CAP*

achieved, but with less toxicity, by

the use of carboplatin. An trial (icon2) comparing CAP (cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, cisplatin 50 mg/m2) with optimum daily dose (in mg) carboplatin8 (5[glomerular filtration rate+25]) in advanced ovarian cancer is open to patient entry and at Aug 31,1992, had already recruited 189

international

randomised

patients.

MRC Cancer Trials Office, Cambridge CB2 2BB, UK

DAVINA GHERSI MAHESH K. B. PARMAR DAVID GUTHRIE CHRIS WILLIAMS

Group. Chemotherapy in advanced ovarian of randomised clinical trials. BMJ 1991; 303: 884-93. 2. Omura GA, Buyse M, Marsoni S, et al. CP versus CAP chemotherapy of ovarian carcinoma: a meta-analysis. J Clin Oncol 1991; 9: 1668-74. 3. Omura Ga, Bundy BN, Berek JS, et al. Gynecologic Oncology Group Study. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovanan carcinoma. J Clin Oncol 1989; 7: 457-65. 4. GICOG. Randomised comparison of cisplatin with cyclophosphamide/cisplatin with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer. Lancet 1987; ii. 353-59. 5. Conte PF, Bruzzone M, Chiara S, et al. GONO. A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin and cyclophosphamide in advanced ovarian cancer. J Clin Oncol 1986; 4: 965-71 6. Bertelsen K, Jakobsen A, Andersen JE, et al. A randomized study of cyclophosphamide and cisplatinum with or without doxorubicin in advanced ovarian carcinoma. Gynaecol Oncol 1987; 28: 161-69. 7. Ozols RF, Ostcheja Y, Curt G, Young RC. High-dose carboplatin in refractory ovarian cancer patients. J Clin Oncol 1987; 5: 197-201. 8. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989, 7: 1. Advanced Ovanan Cancer Trialists cancer: an overview

1748-56.

*CAP= cyclophosphamide + doxorubicin + cisplatin, CP cyclophosphamide + cisplatin ECOG Eastern Cooperative Oncology Group =

=

Gynecologic Oncology Group3 protocol allowed for dose received by doubling the dose of cyclophosphamide received by patients in the CAP arm. The Gruppo Oncologico Nord-Ovests trialists used a similar regimen to that of the Gruppo Interegionale Cooperative Oncologico Gineldogicia; however, they judged the treatments haematologically equitoxic. All studies obtained information on nausea and vomiting and reported similar toxicity levels on both types of treatment. Cardiac and renal toxicity was recorded for only a very few patients. No other non-haematological side-effects were reported, with the one exception of alopecia.5 Kaye et al report significantly higher levels of toxicity in patients receiving high-dose treatment, especially leucopenia (5% on low doses vs 16% on high doses), anaemia (0 vs 15%), ototoxicity (19% vs 26%), and nausea and vomiting (17% vs 39%). Routine use of this treatment was not recommended by the researchers until an effective method of managing toxicity becomes available. From this rather crude comparison we can say that the toxicity with the CAP regimen (where cisplatin is used at 50-60 mg/m2) does not seem greatly different from that in the high-dose cisplatin regimen. High-dose carboplatin might offer a solution to the difficulty of high-dose cisplatin toxicity and of multidrug CAP toxicity. The ability to administer high doses of carboplatin may, however, be limited by myelosuppression (especially thrombocytopenia),’ nonmyelosuppressive toxicity such as neurotoxicity, and cost. Myelotoxicity could be overcome by the inclusion of colonystimulating factors in carboplatin-based regimens, though this needs further investigation. The lack of long-term survival data relating to the use of carboplatin in advanced ovarian cancer is also prohibitive, though the results of the cisplatin vs carboplatin comparison in the advanced ovarian cancer overview1 did suggest that at the dosages used (cisplatin 50-60 mg/m2, carboplatin 300-400 mg(m2) the two drugs were equally effective. The follow-up data for this comparison were reliable to 4 years. More information on the long-term benefits of carboplatin will become available when the overview is updated in 1993. We conclude that a comparison of considerable clinical importance is CAP against an optimum dose of platinum. We do not think it appropriate, however, to compare two fairly toxic regimens (ie, CAP with high-dose cisplatin), which may demonstrate only modest differences in survival. Although these differences might be clinically worthwhile, they might similarly be

SIR,-Professor Kaye and colleagues contribute to the elucidation of the dose-response relation for cisplatin chemotherapy in epithelial ovarian cancer. However, their conclusions relating to the comparative importance of total dose and dose intensity in relation to therapeutic effect do not stand up to close scrutiny. They state that their results demonstrate the importance of both total dose and dose intensity as determinants of outcome, but because these indices of dose delivery differed (by design) between the two treatment groups they cannot reach this conclusion. In fact the cited study of McGuire et all showed no significant difference in response rate or overall survival in a large group of patients with advanced ovarian cancer when the dose intensity of both cisplatin and cyclophosphamide differed by a factor of two, but total doses were identical between the two treatment groups. These two studies, when taken together, surely suggest that total cisplatin dose is the important factor that determines therapeutic outcome? Cookridge Hospital, Leeds LS16 6QB, UK

D.

J. DODWELL

1. McGuire WP, Hoskins WJ, Brady MF, Homesley HD, Clarke-Pearson DL. A phase III trial of dose intense versus standard dose cisplatin and cytoxan in advanced ovanan cancer. Proc Am Soc Clin Oncol 1992; 11: 226.

Adjuvant propofol for refractory cisplatin-associated nausea and vomiting SIR,-High-dose metoclopramide alone or in combination has good efficacy against nausea and vomiting, although it has a high frequency of extrapyramidal movement disorders.’ Serotonin (5-HT3) antagonists have considerable antiemetic potency during cisplatin therapies, and with fewer side-effects.2 Despite these improvements, 20-30% of patients receiving cisplatin chemotherapy are unresponsive to the most efficient antiemetic regimens and have substantial psychological and physical morbidity.2 Propofol, an intravenous anaesthesia-inducing agent, is associated with less postoperative nausea and vomiting than other anaesthetics.3We have demonstrated propofol’s direct antiemetic efficacy.4 We did an open study of whether propofol in subhypnotic doses is antiemetic during cisplatin-based chemotherapy (80100 mg(m2) by adding a continuous infusion of propofol to the antiemetic regimen of patients who were previously not relieved of nausea and vomiting by 5-HT3 antagonists and dexamethasone.

680

10 patients with gynaecological cancers were studied. They had had more than 5 episodes of vomiting during the first 24 h of their first chemotherapy cycle despite antiemetic prophylaxis. In the next cycle, propofol was infused at 1 mg/kg per hour, starting 4 h before chemotherapy and continuing for 24 h after. Rescue (metoclopramide 1 mg/kg intravenously) was instituted in the case of more than 5 emetic episodes per 24 h (treatment failure). Total control was defined as no vomiting, retching, or nausea in the first 24 h. Major control constituted 1-2 vomiting or retching episodes and minor control, 3-5 vomiting or retching episodes per 24 h. The addition of propofol increased the number of patients free of vomiting in the first 24 h post-chemotherapy from 0 in the control cycle to 9 in the propofol cycle. The tenth patient had major control. A small increase in sedation was observed in 1 patient. Slight and transient burning at the forearm infusion site occurrred at the beginning of propofol infusion in 1 patient. All patients preferred propofol-supplemented antiemesis for future chemotherapy. Our patients were a subgroup who were not responsive to the most reliable currently available antiemetics. The addition of a low-dose propofol infusion to the 5-HT3 antagonist and dexamethasone resulted in improved antiemetic control during

cisplatin chemotherapy. A. BORGEAT O. H. G. WILDER-SMITH C. H. WILDER-SMITH M. FORNI P. M. SUTER

Departments of Anaesthesiology and Gynaecology and Obstetrics, Geneva University Hospital, 1211 Geneva, Switzerland, and

University Department of Gastroenterology, Inselspital Bern 1 Gralla RJ, Itri

LM, Pisko SE, et al Antiemetic efficacy of high-dose metoclopramide. N Engl Med 1981, 305: 905-09. J 2. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5HT3 antagonist ondansetron with high-dose metoclopramide in the control of cisplatin-induced emesis N Engl J Med 1990; 322: 816-22. 3. McCollum JS, Milligan KR, Dundee JW The antiemetic action of propofol Anaesthesia 1988; 43: 239-40.

Borgeat A, Wilder-Smith OHG, Saiah S, Rifat K Subhypnotic doses of propofol possess direct antiemetic properties Anesth Analg 1992; 74: 539-41. 5. Smith DB, Newlands ES, Rusint GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatincontaining chemotherapy Lancet 1991; 338: 487-90

4.

Cystic fibrosis

mouse

with intestinal

obstruction SIR,-Cystic fibrosis is characterised by excess mucus in the lungs, intestinal obstruction (meconium ileus), reduced ability to digest and absorb duodenal contents because of pancreatic insufficiency, male sterility, and elevated salt in sweat. The mutated gene, the cystic fibrosis transmembrane conductance regulator (cftr), encodes a chloride channel.1,2 Many mutations have been described in the human cftr gene, including missense, nonsense, splice site alterations, and frameshift deletions and insertions. We have inserted a disrupting genetic element into the mouse cftr locus in embryonal stem cells3 and derived mice carrying a disrupted cftr allele.

Heterozygote carriers were fertile and showed the expected 1/1 segregation of the normal:disrupted cftr allele. The genotypes of the F2 pups were not statistically different from the expected 1/2/1ratio of

wild-type/carrier/homozygote,

which indicates that there is

no

prenatal lethality associated with homozygosity of this mutant allele. Postnatally, however, many homozygote pups failed to thrive and died 2-5 days after birth: Genotype +/+ +; -

exp =

/-

Lme

(exp)

14 1

21 5

}

35 (29) (11)

Dead

3 } 9

13

(exp)

Totals 17

12 (18)

(7)

30 18

Intestine of normal and homozygous null cftr mice.

day 5, stomach (S) contains milk 2 = homozygous cftr day 5, showing meconium (M) blockage of ileum observed through peritoneum 3=2 dissected through peritoneum to show distended proximal intestine (DG); 4=normal, day 17, normal caecum (C) is filled with food, and 5= homozygous cftr mutant, day 17, caecum contains little food, jejunum (B) is blocked 1 =normal,

mutant,

failed to thrive. At day 17 one of these showed an intestinal obstruction in the jejunum and a reduced caecum (figure, 4 and 5). This second-stage blockage is similar in onset to the meconium ileus equivalent observed in older patients with cystic fibrosis. Kristidis et al4 demonstrated that nonsense, frameshift, or splice junction cftr mutations are associated with severe phenotypes m cystic fibrosis patients, including a severe pancreatic insufficiency phenotype. We would therefore expect this mutation in mice to give rise to a severe phenotype with pancreatic insufficiency. In some such severely affected human cases, one of the earliest pathological manifestations is meconium ileus. We interpret the early death of most of the homozygous mice to be due to such a condition. As in the human syndrome, some homozygous animals did not show this condition immediately; presumably any incipient blockage is cleared. Some developed intestinal blockages later. The variation in phenotypic penetrance between homozygotes possibly reflects the genetically diverse background of the animals and in this respect more closely resembles the situation in the outbred human population. Crosses have been set up to maintain the null cftr allele on a known inbred genetic background, which should allow controlled investigations to examine the influence of genetic background on expression and penetrance. This mutation in the murine cftr locus provides an animal model for the most common autosomal recessive disease in north Europeans. Other mutations experimentally introduced into the mouse cftr locus may lead to phenotypes that more closely parallel the milder forms of cystic fibrosis (eg, infertility only). The availability of these mutant mice should greatly facilitate tests of new drugs and gene therapies. We thank the Cystic Fibrosis Trust and the Wellcome Trust for support and the animal-house staff for husbandry. We also thank Alan Cuthbert for helpful advice, and all members of M. J. Evans’ laboratory.

Wellcome/CRC Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, UK, and Department of Biochemistry and Molecular Genetics, St Mary’s Hospital Medical School, London W2

WILLIAM H. COLLEDGE ROSEMARY RATCLIFF DIANE FOSTER ROBERT WILLIAMSON MARTIN J. EVANS

expected

Postnatal death of homozygotes was significantly correlated with the absence of a normal cftr allele (p < 0-005, X2). These pups had suckled and had a full stomach and distended gut. Their failure to thrive suggests poor food assimilation. The figure (2 and 3) shows the distended gut, apparently blocked in the ileum by meconium, of a homozygous pup that failed to thrive. In general, the few homozygotes that survived the immediate neonatal period also

JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene cloning and characterisation of complementary DNA Science 1989, 245: 1066-73. Kerem B, Rommens JM, Buchanan JA, et al Identification of the cystic fibrosis gene genetic analysis. Science 1989; 245: 1073-80. Ratcliff R, Evans MJ, Doran J, Wainwright BJ, Williamson R, Colledge WH. Disruption of the cystic fibrosis transmembrane conductance regulator gene in embryonic stem cells of gene targeting. Transplant Res 1992, 1: 177-81 Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992; 50: 1178-84

1. Riordan 2

3.

4