Chemotherapy for epithelial ovarian cancer: an update

Current Obstetrics & Gynaecology (1997) 7, 50-60 © 1997 Pearson Professional Ltd

Drugs

Chemotherapy for epithelial ovarian cancer: an update

D. Pea and C. Poole

Despite many recent advances, chemotherapy for ovarian cancer remains an imperfect and potentially harmful tool, and these shortcomings remain a stimulus to research. Against this background, the last 2 or 3 years have seen an almost disconcerting degree of change over a surprisingly broad front. This extends far beyond a few new cytotoxics fulfilling the criteria for activity in phase II trials. The drugs in question include several compounds with novel mechanisms of action, the 'Holy Grail' of drug development, prerequisite for the design of 'non-cross resistant' firstline regimens. Defining the place of newer drugs in routine practice is likely to be an increasingly complex and perpetual task, which can only succeed with a much wider preparedness and commitment to offering patients treatment within clinical trials and, in the U K at least, the targeted provision of NHS R&D funds. 'Trialists' are often regarded by their 'jobbing' colleagues as living in a 'different world'. In fact, we all live in the same world, one where a mere 10% of patients with ovarian cancer requiring chemotherapy currently achieve long-term survival, and we need to share this preoccupation. Clinical research is never easy, and the development and evaluation of rationally designed or mechanistically targeted drugs has brought particular problems. Early fears that as we ventured away from the comforting familiarity of the murine leukaemia screen as a source of new cytotoxics, we might well encounter drugs with bizarre side effects and unusually shaped dose-response curves have proved justified. We now appreciate that conventional phase I trial dose-escalation methodology may be of limited use in mapping their introduction to the clinic, and that studies with mechanistic endpoints (such as measurement of enzyme inhibition in serum) will assume a more important role in drug development.'

INTRODUCTION Chemotherapy is one of several modalities available for the treatment of ovarian cancer. Its use is coordinated with surgery in multidisciplinary protocols, its design is influenced by tumour stage and natural history, as well as coexisting medical problems and psychosocial factors. Besides choice of drugs, there are four other variables: dose intensity (dose per unit time, usually expressed in mg/m2/week); scheduling (for example 3 h versus 24 h infusion); route of administration (e.g. intravenous versus intraperitoneal); and timing in relation to other modalities (e.g. primary or 'neoadjuvant' chemotherapy ahead of surgery). The intensity of treatment used often reflects therapeutic intent: for most patients, chemotherapy will achieve symptomatic improvement and a modest prolongation of survival. However, for patients in poor general condition, for whom the risks of side effects may be higher and the prospects of benefits less, considerable discretion may be required. An oncologist's main task in such circumstances is the minimization of treatment related toxicity, by careful drug selection and pharmacokinetically and pharmacodynamically guided dosing. Sensitivity to the impact of treatment on patients' performance status is every bit as important as objective response evaluation. A partial response has little impact on survival; with attention to detail, it can represent the best form of palliation. Dan Rea, Senior Registrar Medical Oncology, Chris Poole,

Macmillan Senior Lecturer in Medical Oncology and Palliative Care, CRC Institute for Cancer Studies, University of Birmingham, Queen Elizabeth University Hospital and City Hospital, Dudley Rd, Birmingham B 15 2T J, UK Correspondence to: C.J.R

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Chemotherapy in epithelial cancer On a more mundane level, many doubts remain about the optimal use of established drugs, for example, the results of recent randomized trials addressing the use of intraperitoneal chemotherapy and 'intervention debulking surgery' threaten dramatic change in the way we employ cytotoxics and integrate them with other treatment modalities. However, to trade in all our old paradigms for new, ahead of confirmatory studies, would be premature. Furthermore, it seems likely that the lot of the ovarian cancer patient could be significantly improved by wider implementation of currently acknowledged standards of best multi-disciplinary clinical practice) Implicit to this approach is the ready availability of sub-specialist expertise in both gynae-oncological surgery and chemotherapy, as well as specialist nurses, pharmacists and clinical psychologists, a complex magic bullet that is only just being bitten.

THE INTERPLAY OF CHEMOTHERAPY AND SURGERY

The effort being placed on the development of a multidisciplinary approach to this disease is predicated on the notion that neither surgery nor chemotherapy can be properly considered in isolation. Their interrelationship is now examined.

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CHEMOTHERAPY IN EARLY STAGE OR

COMPLETELY RESECTED OVARIAN CANCER The disappointing long-term survival of patients treated for advanced stage disease has encouraged the evaluation of adjuvant chemotherapy in early stage disease. An Italian study, reported provisionaly in 1992, has shown a modest difference in disease-free survival at 5 years, 3 and more mature data are awaited with interest. The current Advanced Ovarian Cancer Trialist Group (AOCTG), MRC-sponsored ICON-1 trial addresses a similar question. Eligibility is defined by the clinician's uncertainty about the indication for immediate chemotherapy. By March 1996, about 300 patients had been randomized to immediate platinumbased chemotherapy versus observation, with treatment only on relapse. ICON-1 will be analysed alongside a very similar EORTC trial, the ACTION study that has itself accrued just over 300 patients. Interim analysis, by an independent data monitoring committee, was undertaken in May 1996, with the unanimous conclusion that neither closure nor modification of the study was required. The next review is due in the summer of 1997. The factors determining prognosis in either limb of this trial will be interesting. A Norwegian study of cisplatin chemotherapy versus intraperitoneal P32 in 265 patients with stage I disease, revealed that differentiation grade and FIGO substage were the only independent prognostic factors on multivariate analysis. 4

EARLY STAGE DISEASE: NATURAL HISTORY Early stage ovarian cancer is for the most part clinically silent. When symptoms do arise, they are often non-specific and the disease is usually advanced. However, despite their age at presentation, patients' symptoms are now being increasingly labelled as 'irritable bowel syndrome', a further exacerbating diagnostic delay. Thus, only 25% have disease limited to the ovaries at diagnosis. Most patients present with advanced disease, with spread by defoliation into the peritoneal cavity, which involves the pelvis alone in just 15% and the abdomen in about 45%. Spread beyond the peritoneum, whether to the parenchyma of liver or spleen, or outwith the abdominal cavity altogether, is also relatively uncommon, affecting just 15% of patients. Unfortunately, however, occult micrometastases are a frequent occurrence in patients with ostensibly early stage disease. In this population, typically 33% of peritoneal washings, 10% of para-aortic node biopsies, 11% of diaphragmatic peritoneal biopsies and 3% of omental biopsies reveal microscopic tumour involvement. Histological grade increases the likelihood of subclinical spread. The care with which a laparotomy is undertaken also matters: in a US study of 100 patients with apparent stage I or II disease referred for additional surgical staging, some 31% were upstaged, 77% of these to stage III.

ADVANCED DISEASE: PROGNOSTIC FACTORS In the advanced setting, the potential for surgery alone to afford long-term survival is obviously limited, and chemotherapy is, therefore, recommended for most patients with stage II, III and IV disease. Multivariate analyses have defined a number of independent determinants of treatment outcome. These include residual disease after primary surgery (___1.5 cm), grade of tumour differentiation, and performance status. Early initiation of chemotherapy may improve survivalY Some studies show that performance status abrogates the influence of both age and FIGO stage, both of which have been correlated with survival in univariate analysis. In the West Midlands, women aged 15-44 years have a 5-year survival rate of 60%, whereas for women over 65 the figure is just 20%. 7 The influence of morphological subtype is less well defined, as analyses are confounded by grading considerations. In several series, clear cell or mucinous histology has a worse prognosis.

PRIMARY DEBULKING SURGERY

The greatest interest in the influence of prognostic factors has naturally focused on therapeutic variables,

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in particular the extent of surgery. In the mid 1970s, Griffiths showed that for a group of 102 patients with stage II and III disease, the success of treatment with single agent melphalan varied with the bulk of residual tumour after initial cytoreductive surgery. However, he noted that extensive debulking surgery that failed to reduce residuum below a 1.45 cm diameter threshold appeared futile, with no affect on prognosis. This finding may be relevant to the conclusion of a more recent overview that analysed inter-study differences in the percentage of cases in which optimal debulking was achieved, for influence on median survival, adopting a residuum of _ 3 cm as a discriminant definition of optimal surgery. Multivariate analysis found only a weak relationship between the proportion of patients debulked in each series and its median survival: 8 far stronger was the impact of the type of chemotherapy used, platinum-containing regimens being considerably more effective. The question of whether the outcome of chemotherapy is improved by the act of debulking per se, or the indirect influence of permissive biological tumour-specific factors, is a matter of continued debate. It seems plausible that aggressive, hardto-resect tumours might be inherently more chemoresistant, and tumours that lend themselves to radical debulking relatively more chemo-sensitive. Were the latter the case, then much of the effort put into radical debulking might be misplaced. At least two randomized clinical trials have attempted to address this question prospectively. The Gynaecologic Oncology Group (GOG) trial GOG 80 and the West Midlands GOG (WMGOG) trial OV-3006. Both have failed on account of recruitment problems, exacerbated by unresolved design difficulties. For the WMGOG, these centred on the requirement for an initial laparotomy to establish the diagnosis and staging and, given the needs of informed consent, a second procedure to accomplish radical debulking. Patients whose disease was judged suitable at laparotomy were offered randomization to radical debulking surgery or biopsy. Both groups were given the same standard postoperative chemotherapy. Patients whose disease could be completely excised without bowel resection, splenectomy, or peritoneal stripping were excluded, as were those whose disease could not be resected even with such radical measures. These exclusions are important. The former group, with no macroscopic residual disease, has an excellent prognosis following surgery, typically showing a 50% survival rate at 4 years. Schwartz showed that if such patients were excluded from analysis of the effects of debulking on survival, then the prognosis of those with residual tumour nodules < 2 cm was no better than those with larger residuum. This suggests that the apparent benefits of cytoreduction may derive from those patients within the group who have undergone complete excision. Circumstantial evidence for the influence of biological factors on prognosis following chemotherapy

is provided by two studies that analysed outcome with respect to their initial disease volume prior to surgery. Hacker et aP showed that the prognosis of patients debulked from ___10cm diameter disease was worse than for patients with smaller tumours; Hoskins et al~° showed the outcome for all patients cytoreduced to 1 cm was worse than that of patients presenting with 1 cm or less diameter metastatic disease. Others suggest that the number of peritoneal nodules may be more important than the cross-sectional diameter of residual disease, H and that patients who require bowel resection to achieve maximal cytoreduction do badly.12The consensus at present is that both extent of primary surgery and intrinsic biological factors play a role.

INTERVENTION DEBULKING SURGERY

The EORTC Gynae Cancer Co-operative Group avoided some of the problems implicit in prospective trials of primary cytoreduction with a study evaluating the role of intervention debulking surgery (IDS) during chemotherapy?3 319 patients with residual disease of more than 1 cm in diameter after initial surgery were randomly assigned to either undergo intervention debulking or not after three cycles of chemotherapy. 278 patients were evaluated, 140 were randomized to surgery, of whom 130 underwent surgery, and details of 127 were presented. At IDS, 83 patients (65% of 127) were found to have lesions measuring more than 1 cm, and 37 of these (45% of 83) were surgically cytoreduced to less than 1 cm. Progression-free and overall survival were analysed on the basis of treatment received. The median survival of those who underwent surgery was 26 months and 20 months for those who did not. Survival at 2 years was 56% for those undergoing IDS and 46% for those who did not. Multivariate analysis showed intervention surgery as an independent prognostic factor, reducing the risk of death by 33% (95% CI, 10-15%). One smaller randomized trial in the UK also showed an improved survival with IDS, but owing to the small size of the study this failed to reach significance? 4 A large confirmatory trial is underway in North America.

ALKYLATING AGENTS Alkylating agents provided the first effective chemotherapy for ovarian cancer. They were popularized by their ease of use and reversible, manageable toxicities. Reported single agent phase II response rates vary from 31% for nitrogen mustard to 63% for Thiotepa. Median survival varies from 10-14 months, and the 5-year survival rate following melphalan is 9%2' A randomized trial, which compared chlorambucil with no active therapy, demonstrated a survival benefit for chemotherapy.~6

Chemotherapy in epithelial cancer CISPLATIN Cisplatin was discovered serendipitously in the mid 1960s. It was the first drug to show significant secondline activity after alkylating agent therapy, with overall response rates of 25M0%. A randomized trial of cisplatin and cyclophosphamide versus cyclophosphamide alone revealed a 52% 2-year survival rate for cyclophosphamide and cisplatin, against 19% for cyclophosphamide alone. Trials by the GOG showed that the addition of cisplatin to cyclophosphamide and doxorubicin improved the complete remission (CR) rate from 26% to 51%, and median survival from 9.7 to 15.7 months? Direct comparisons of cisplatin versus single alkylating agent therapy are few. The North Thames Co-operative Group found cisplatin had a longer duration of response (18 months versus 8 months) and significantly improved median survival (19 versus 12 months)? 7 Interestingly, this question is being obliquely revisited by the West of Scotland Group in a trial comparing single agent carboplatin with treosulfan, in patients unfit for cisplatin containing treatment. Throughout the 1980s 'standard' first-line chemotherapy comprised of five or six cycles of cisplatin 75 mg/m 2 and cyclophosphamide 750 mg/m 2, given at 3-weekly intervals. Ten cycles proved no better than five: ~8 reported survival for cisplatincontaining chemotherapy varied between 22% and 28% at 3-5 years, declining to just 7-10% at 10 years? Cisplatin proved an awkward drug to use in practice. Although initial problems with nephrotoxicity were quickly overcome using saline diuresis, emetic toxicity remained largely intractable until the development of high dose metoclopromide/dexamethasone prophylactic regimens, and difficult until the advent of the 5HT3-antagonists. Neurotoxicity and ototoxicity (cochlear damage) are both dose-related and may be cumulative. Deafness, when it occurs, is initially high tone, and usually irreversible. Peripheral neuropathic injury may resolve only slowly, over months or years. The considerations prompted an early search for analogues with more manageable side effects, and the first of these to enter widespread clinical use was carboplatin (CBDCA). Carboplatin is very rarely nephrotoxic or neurotoxic and only 20% of patients treated in early studies (pre-5HT3-antagonist) suffered severe vomiting. Furthermore, as carboplatin is cleared through the kidneys unchanged, individually appropriate doses may be calculated using a simple formula, based on the desired patient exposure, as defined by area under concentration/time curve (AUC)? 9This dose may then be titrated up or down in 10% increments, against the nadir blood count, as it appears that doses sufficient to induce a modest degree of myelosuppression improve the outcome of treatment. 2° Put another way, myelosuppression may be used as a surrogate pharmacodynamic endpoint.

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IS CARBOPLATIN AS GOOD AS CISPLATIN IN OVARIAN CANCER? For many years carboplatin and cisplatin have been thought to have equivalent activity in ovarian cancer, but most comparative trials have been too small to discriminate clinically significant differences in outcome. The AOCTG has recently addressed this question in overview, and reported that any differences in survival curves cannot be resolved at 4 yearsY However, this analysis neglects one potentially confounding factor, the influence of 'crossover': most patients treated with carboplatin first line will have been retreated with cisplatin. Meta-analysis showed an identical median time to disease progression (14 months). = However, one French randomized trial, reported in 1992, compared cisplatin (75 mg/m 2) based triple therapy with carboplatin (300 mgJm~) in the same (4-weekly combination, but specifically forbade crossover, and reported significantly improved pathological OR (33% versus 15%), the overall response was (73% versus 47%) and median survival was 27.9 versus 20.6 months in the cisplatin limb, albeit without any significant difference in progression-free survival? 3 Toxicity differences were interesting; contrary to expectations, there was no significant difference with respect to neuro or ototoxicity, but the cisplatin combination induced more anaemia, thrombocytopenia, renal impairment, nausea and anorexia. It seems plausible that the inferior results of carboplatin in this study may reflect its use at an inadequate dose: carboplatin 300 mg/m 2every 28 days may not be enough. In summary, when appropriate doses are compared, any difference in efficacy is trivial in relation to their differences in toxicity and practical convenience. Cost comparisons are difficult to generalize given cisplatin's requirement for expensive inpatient care.

THE ROLE OF ANTHRACYCLINES

Single-agent doxorubicin given 3-weekly at 75 mg/m 2 has a response rate of 40% in previously untreated patients with advanced ovarian carcinoma, and overviews suggest that cyclophosphamide, doxorubicin, and cisplatin CAP has some modest advantage over cisplatin and cyclophosphamide CR 21 However, whilst the toxicity of CAP is considerable, the dose of cisplatin (50 mg/m 2) used in the comparitor limb (P, or CP) in many of the trials included in this analysis is lower than that commonly used off-study (75 mg/m2), so qualifying their conclusion. The AOCTG (administered through the MRC Gynaecological Cancer Working Party in the UK) has recently sponsored a very large multicentre prospective randomized trial (ICON-2) comparing single-agent carboplatin AUC 5 with CAP (cyclophosphamide 500 mg/m 2, doxorubicin 50 mg/m 2, and cisplatin 50 mg/m2). The trial is essentially pragmatic in

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Table 1 ICON-2interim results- toxicity

Grade 3 or 4 leukopenia Nausea and vomiting Mucositis Alopecia Cardiac toxicity

CAP %

Carboplatin %

34 19 21 72 2

10 9 0 4 0

intent 24 and assumes acceptance of carboplatin's reduced toxicity and its ease of use in an out-patient setting. The AOCTG took the view that should the overview results be confirmed, then a modest 5-10% improvement in survival with CAP has the potential to prolong thousands of lives per year world-wide. Alternatively, should a null result arise, then it might have important implications for the more widespread substitution of carboplatin. Accrual has closed with 1526 patients randomized, and the full results will be submitted for publication in 1997. Interim results were presented at ASCO in May 1996, 25and have been updated by the MRC trials office in September. 26 As expected there were some differences in both type and severity of toxicity (Table 1). By September 1996, 740 patients had progressed or died. The hazard ratio is 0.88, implying a 12% reduction in the risk of progression or death with CAR The 95% confidence intervals (CI) run from 0.76 to 1.02, with a p value of 0.07, approaching significance. 498 patients had died by September 1996; the hazard ratio was 0.94, 95% confidence intervals run from 0.79 to 1.12, with a p value of 0.47 (Table 2). In conclusion, it is possible that the relatively toxic CAP regimen may improve progression-free survival marginally, but there is no evidence yet of any overall survival benefit. However, there is some concern that the choice of the traditional CAP regimen, utilizing cisplatin at a relatively low-dose intensity of 50 mg/m 2, may have prejudiced the outcome.

PLATINUM DOSE INTENSITY/RESPONSE RELATIONSHIPS

Dose intensity is a measure of drug dose per unit time and is conventionally expressed in mg/m~/week. Retrospective studies have related dose intensity to treatment outcome in ovarian cancer. However, comparisons based on these figures alone may conceal important differences in total dose, schedule and Table 2 ICON-2interim results- progression-freesurvivaland overall survival CAP% Carboplatin% Abs. DifP/0 95% CI% Progression-free survival 54 Overall survival 52

50 50

+4 +2

(+9--1) (+8~4)

duration of treatment. Furthermore, the validity of retrospective studies is inevitably undermined by the vagaries of patient selection, and the potential implications of 'performance status' for both prognosis, susceptibility to treatment toxicity, and dose reduction. Dose intensity calculations become further complicated in the face of combination chemotherapy, and retrospective analyses often make uncomfortably arbitrary assumptions about the therapeutic equivalence of individual component drugs. Such an approach has been shown to be over simplistic for ovarian cancer: when measures of response are plotted against the relative dose intensity (RDI) of individual component drugs across a series of randomized trials, a stronger relationship is seen for cisplatin, than for doxorubicin. Cyclophosphamide RDI has no impact in multivariate analysis. 27 Unfortunately, interstudy differences between projected and delivered dose intensity may vary systematically, and confound comparisons based on dose intent. These considerations have prompted prospective randomized trialsY 9 Since cytotoxic drugs are conventionally prescribed close to maximum tolerated dose, the technical success of such studies in delivering significantly different intensities depends on either one trial arm being treated at sub-standard dose intensity or, alternatively, the successful development of some novel means of raising threshold for dose limiting toxicity. Direct comparison of six cycles of cisplatin 50 mg! m ~versus six cycles of cisplatin 100 mg/m 2 (each with cyclophosphamide 750 mglm 2 3-weekly) showed a significant survival benefit for patients treated with higher dose intensity, who achieved a median survival 28.5 months, as opposed to 17 months for low-dose cisplatin? 8 However, the difference in 4-year survival rates was less impressive at 32.4% versus 26.6%, respectively?° It seems likely that further follow-up will see the survival curves meet, consistent with Goldie and Coldman's view that the impact of dose intense regimens may be limited to an increase in partial and complete response rates since these reflect the fate of sensitive cells, with quantitatively smaller effects on long-term survival and mortality, as this will ultimately be dictated by the presence of even very small numbers resistant cellsY Criticism of the Scottish study has centred on the low-dose cisplatin used as comparitor, and the absence of direct implication for standard treatment with cisplatin 75 mg/m 2. However, the choice of cisplatin 50 mg!m 2 was in keeping with that evaluated in at least two other large randomized studies, and it is clear that 100 mg/m 2 is associated with an unacceptable level of toxicity: of 35 patients who stopped treatment early on the highdose arm, 25 did so because of side effects, 19 with ototoxicity or neurotoxicity. The authors concluded that standard treatment with cisplatin 75 mg/m 2 remains a reasonable compromise, pending more effective means of preventing neurotoxicity.

Chemotherapy in epithelial cancer Another prospective randomized trial of dose intensity has produced even less impressive results, but the design differed in two important respects: first, it compared eight cycles of cyclophosphamide 500 rag/ m 2 and cisplatin 50 mg/m 2 with four cycles of cyclophosphamide 1000 mg/m ~ and cisplatin 100 mg/ m ~, thereby maintaining the same total dose in each arm; second, it limited recruitment to sub-optimally debulked patients. 32 This trial showed no significant difference in median survival (20.7 versus 23.9 months), but any conclusion about the relative importance of total dose and dose intensity must be qualified by reference to trials that examine the impact of total dose, and hold dose intensity constant. TM Whilst five cycles may be as good as ten, it is a widely held view that four is inadequate. Other platinum intensification studies have employed carboplatin dose escalation and/or schedule interval reduction to avoid the irreversible neuropathic side effects inevitable with high cumulative doses of cisplatin. Whilst the practicalities of carboplatin intensification seem less forbidding, the rationale is rather more doubtful. On one hand high-dose carboplatin appears inactive in patients whose disease is refractory to conventional dose cisplatin, 33 and on the other hand retrospective analyses of carboplatin dose/response relationships in previously untreated patients have revealed no advantage for supranormal doses, despite taking a sophisticated pharmacokinetic perspective in which estimated drug exposure (as AUC) ~9is analysed in relation to outcome. No advantage is seen retrospectively for an AUC of greater than 5-6. 34However, this analysis may be flawed in several respects: firstly, relatively few patients were exposed to a high carboplatin AUC; secondly, as delivered AUC was 'back-calculated' from total dose prescribed and renal clearance, many patients with a high AUC had a poor clearance, a possible indication of poor performance status or massive disease burden, themselves independently adverse prognostic factors; thirdly, only data relating to the first cycle of chemotherapy were presented; and fourthly, dose, rather than dose intensity, was the parameter analysed. The London Gynaecological Oncology Group has tried to resolve these difficulties in a prospective randomized trial that compared six cycles of carboplatin AUC 6 (Calvert formula), with four cycles at AUC 12, with 28 day treatment intervals. Despite significantly increased toxicity in the high-dose arm, there was no significant difference in response rate, progression free or overall survival, even on subgroup analysis for residual disease volume. 35Although this must be seen in the context of the failure of the high-dose arm to deliver full protocol doses, reaching just 22% above control, rather than the 33% projected. The consensus view is that relatively modest differences in delivered dose or dose intensity, typified by those achieved here, are unlikely to make significant impact on the outcome of treatment in this disease. Interest now focuses

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on the use of peripheral stem cell support to deliver doses in order of magnitude above standard.

INTRAPERITONEAL CHEMOTHERAPY

Intraperitoneal (IP) chemotherapy is another attempt to improve the therapeutic index of chemotherapy for ovarian cancer, promising enhanced delivered dose intensity to the peritoneum with some reduction in systemic exposure. Phase I and phase II trials have shown that any pharmacokinetic advantage is determined by a drug's fat solubility and peritoneal and systemic clearances; these factors provide a 10-fold advantage for cisplatin, and 1000-fold improvement for mitoxantrone and paclitaxel. However, the evaluation of IP/chemotherapy has been difficult and protracted. Randomized trials have been slow to recruit, and the technical limitations are clear. Early work established that there is no role for IP chemotherapy in patients with > 2 cm residual disease, as tumour drug penetration is too poor. Doubts have also been raised by the finding that 30-40% of patients with stage III disease may have retroperitoneal lymph node involvement, and that this may be a potential sanctuary site. 36 Early studies reveal that IP chemotherapy has been shown to convert microscopic or minimal residual peritoneal disease after first-line chemotherapy to pathological CR. 37The results of one large randomized SWOG-GOG-ECOG intergroup trial are now available. 38 This randomized patients with optimally debulked, newly diagnosed epithelial ovarian cancer to either six cycles of cisplatin 100 mglm 2 IP, with cyclophosphamide 600 mg/m 2 3-weekly, versus both drugs using the same doses and schedule. 654 patients were randomized between June 1986 and July 1992, and stratified by residual disease, performance status and centre. Seventeen point six per cent of patients were ineligible on surgical or pathological review. Median survival was 48 months for IP treatment (95% CI, 43-55 months) versus 41 months for iv (95% CI 34-47 months), p=0.03. Clinically evident hearing loss and neutropenia were significantly more frequent in the iv arm.

CHEMOTHERAPY TIMING AND DOSE INTENSITY IMPLICATIONS

The theoretical basis of any relationship between dose intensity and response has received relatively little attention. Coldman and Goldie have modelled the relationship between dose intensity and fractional cell kill for sensitive cells and, assuming somatic cell mutation as the rate limiting step for the generation of resistant clones, examined the implications of delay in treatment initiation. 31 They have suggested that the time of maximum risk for the emergence of drug resistant cells is when cell number is maximal.

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Accordingly, they postulate that dose intensity should logically be calculated from the time of tumour staging. This might have two sequelae: first, small differences in overall dose intensity so calculated could then have disproportionate importance; second, early dose intensity could significantly reduce the time-dependent risks of acquired drug resistance. Others have speculated about the potential of perioperative chemotherapy for exploiting surgically triggered tumour cell repopulation to achieve kinetic sensitization. Multivariate analysis has certainly identified early initiation of chemotherapy in ovarian cancer as significantly favourable to survival, 5,6 and these questions now require randomized prospective studies.

PACLITAXEL'S DEVELOPMENT AND SECOND-LINE ACTIVITY Paclitaxel's activity was first discovered in extracts from the bark of the Pacific Yew in P388 murine lymphocytic leukaemia screens in 1971, but its poor solubility led to formulation difficulties, and early appraisals ignored the implications of its unique structure, and viewed the drug as just another mitotic inhibitor. Synthetic problems were anticipated and it was accordingly afforded low priority for early clinical trials. Appreciation of its novel mechanism of action in deregulating tubulin synthesis was slow in coming, but eventually prompted phase I trials in 1982. However, serious acute hypersensitivity reactions were encountered, and fatalities led to a halt in clinical development, pending reappraisal in the light of some early indication of activity against platinum-resistant ovarian cancer. This prompted a successful attempt to empirically circumvent the anaphylactoid problems with an extended 24 h infusion time, .and steroid and antihistamine premedication. Phase II trials confirmed modest activity in platinum-resistant disease, at a range of relatively low doses reflecting their subjects' heavy pre-treatment. 39 A large randomized '2 x 2' bifactorial study has compared 3 h and 24 h infusions at both 135 mg/m 2 and 175 mg/m2: the 3-h infusion proved just as safe, and caused less neutropenia. 175 mg/m ~ showed a trend towards a higher response rate, and significantly longer progressionfree survival? ° Side effects at 175 mg/m 2include alopecia 89%, neutropenia 50% grade 4 (but only 18% with a 3-h infusion), myalgia 67%, and peripheral neuropathy 52%. However, only 1% suffered grade 3 neurotoxicity or worse, and many of these are likely to have been sensitized by prior exposure to cisplatin, with varying degrees of pre-existing subclinical neuropathy. Bradycardia also occurs during paclitaxel infusions but is very rarely symptomatic. Premedication reduces the incidence of serious acute hypersensitivity reactions to less than 5%. Paclitaxel was licensed for second-line use in 1994, but with a response rate as low as 14% in the platinum refractory

Table 3 GOG 111 trial: cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer

Cisplatin and Cisplatin and cyclophosphamide paclitaxel Eligible patients 202 Patients with measurable disease 116 Overall response% 60 Median progressionfree survival 13 months Median survival 24 months 95% CI 21-30 months

184 100 73

p = 0.01

18 months p
disease, 41 it has yet to achieve widespread use in this context in the UK. Work is underway to try and identify those factors predicting response, with the hope of facilitating more effective treatment targeting.

PACLITAXEL AND CISPLATIN COMBINATIONS IN FIRST-LINE CHEMOTHERAPY Paclitaxel's modest second-line activity has encouraged investigators to explore its use first-line, both as a single agent and in combination with cisplatin. Phase I dose escalation studies have defined maximum tolerated doses in combination as 75 mg/m 2 for cisplatin (infused at 1 mg/min) and in the range 135-170 mg/m 2 for paclitaxel (over 24 h). These doses are individually "clinically relevant' and reversible neutropenia, rather than cumulative neurotoxicity, has proved dose limiting. Paclitaxel is less myelotoxic if given prior to cisplatin, a finding possibly related to a 20% reduction in clearance rate if paclitaxel is given second. The first trial to compare cisplatin and paclitaxel with standard cisplatin and cyclophosphamide in first-line therapy was the GOG 111 phase III protocol (GOG protocol # 111), which opened in 1990. This utilized a 24 h paclitaxel 135 mg/m 2 infusion with cisplatin 75 mg/m 2 and recruited patients with suboptimally debulked stage III and IV ovarian cancer. Preliminary results were reported in 1993, and more mature data in January 1996.42 The analysis was performed on the basis of confirmed eligibility, rather than intention to treat. The paclitaxel/cisplatin combination was more toxic, with grade IV neutropenia in 79% of patients versus 61%, and febrile events in 20% versus 11%. Overall, the response rate was 73% versus 60%. However, there was no significant difference in the pathological complete response rate. Furthermore, the median progression-free survival was 18 months (95% CI, 16-21 months) for cisplatin/paclitaxel versus 13 months (95% CI, 11-15 months) for cisplatin/cyclophosphamide, a relatively modest 5 month improvement (Table 3).

Chemotherapy in epithelial cancer Against this background, the 14 month difference in median survival, which became apparent as the data matured, was somewhat surprising. Cisplatin/ paclitaxel provided a median survival of 38 months (95% CI, 3 2 4 4 months), and cisplatin/ cyclophosphamide 24 months (95% CI, 21-30 months). This difference between progression-free and median survival is almost unprecedented and is not yet fully explained. If anything, it implies a systematic difference in duration of response to secondline therapy between each limb. Unfortunately, GOG has made little information available about this, but it appears that most patients in both limbs were retreated with carboplatin at relapse, as paclitaxel availability was limited during the study period. The authors have suggested that only 25% of patients in the control arm were retreated with paclitaxel. This prompts the question as to whether the substantially improved median survival seen in patients who received a first-line paclitaxel-containing combination, in part relates to an increased chance of a better response to second-line platinum. A large EORTC phase III trial evaluating another first-line cisplatin/paclitaxel combination completed accrual in 1995. This utilized a 3-h paclitaxel infusion, at a dose of 175 mg/m 2 and will report in 1997. Mindful of standard U K practice, generally based on single agent carboplatin, the MRC have compared carboplatin, or CAP should the investigator prefer (pending ICON-2 results), with a combination of carboplatin and paclitaxel (175 mg/m 2 as a 3-h infusion) in both optimally and sub-optimally debulked patients. The trial (ICON-3) was designed with a target accrual of at least 600, and a 2:1 randomization, platinum to carboplatin/paclitaxel. Carboplatin was given at the same dose in either limb, AUC 5 using the Calvert formula on a measured renal clearance, or AUC 6 were the Cockcroft calculation to be employed instead. Recruitment has been extremely rapid, reaching the provisional target by October 1996. Carboplatin has been used as control in 65% of U K patients. The first interim analysis, based on 434 patients randomized by 30th April 1996, was reviewed by an independent data-monitoring committee in July 1996. Their conclusions were that the design of the trial was appropriate and did not require modification; the levels of toxicity encountered were acceptable; there were no relevant external data available from other trials to influence its continuation, and that efficacy data were too immature to provide meaningful information. They recommended that the sample size for ICON-3 be increased to tighten CIs, and whilst they were aware of the cost implications of extending the trial, it was felt that these were cheap by comparison with the off protocol use of paclitaxel, ahead of survival evidence being available. A similar 1:1 designed trial in Italy is also recruiting well. A trial comparing cisplatin and paclitaxel with carboplatin and paclitaxel is underway in Europe. Ironically, carboplatin and

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Table 4 Gemcitabine, Topotecan and paclitaxel; response rates

(RR), median response duration (MRD), and time to progression (TTP) Endpoint

Gemcitabine (n : 42)

Topotecan (n : 96)

Paclitaxel (n : 105)

RR% MRD TTP

19 32 weeks 11 weeks

23 32 weeks 23 weeks

14 20 weeks 14 weeks

paclitaxel have already become the standard first-line therapy in North America. At present, there is a consensus that further phase Ill trials in design stage should utilize cisplatin and paclitaxel as the standard comparator, and this is underscored by paclitaxel being granted a first-line licence within this combination in Europe in October 1996. In the UK, within the Health Service, physicians are constrained by an unsophisticated and fragmented 'internal market', which is unlikely to take on funding for first-line paclitaxel-containing regimens prior to contracts negotiated for the 1997 financial year. However, in the U K private sector, insurance companies have formally authorized first-line paclitaxel from January 1996.

OTHER NEW DRUGS FOR OVARIAN CANCER

Several other drugs have recently demonstrated activity in phase II clinical trials, and are now being evaluated in combination, prior to further larger comparative studies in 1996/1997. These include, a number of conventional cytotoxics, including docetaxel (Taxotere), a taxoid whose lack of schedule-specificity offers simpler administration; gemcitabine, an antimetabolite, which looks particularly promising in the platinum-refractory context, ~3 and Topotecan, a topoisomerase I inhibitor 4~ (Table 4). The activity of gemcitabine and paclitaxel is also being cautiously explored in previously untreated patients. Marimastat (BB2516) is a novel matrix metalloproteinase inhibitor that has recently completed phase I trials in patients with ovarian cancer in the U K and North America. Reversible soft tissue and arthropathic side effects have proved dose-limiting. Some reduction in serum CA125 levels, and their rate of rise, was also seen, and the significance of these observations is to be further explored in a pivotal randomized trial of carboplatin versus carboplatin and marimastat in platinum sensitive recurrent disease.

MANAGEMENT OF RELAPSED OVARIAN CANCER

Second-line chemotherapy at relapse can sometimes afford worthwhile palliation, and depending on interpretation of the GOG 111 data, may in itself

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affect survival. Until recently, re-exposure to platinum has been more effective than other 'off the shelf' drugs, and most clinicians would prefer single-agent carboplatin after a first-line cisplatin-based combination, as it is generally better tolerated, and minimizes the risk of cumulative neurotoxicity. Response rates to platinum re-treatment demonstrate a clear relationship with time elapsed since completion of first-line chemotherapy, and stage at presentation. Overall response varies from just over 25% at between 5 and 12 months, to 33% between 13 and 24 months, and reach nearly 60% after 24 months? 4 These figures are consistent with two mutually compatible hypotheses: firstly, that the degree of platinum resistance determines number of cells surviving primary treatment, and hence time to relapse; secondly, that away from the selective influence of treatment, tumour cells may spontaneously lose platinum resistance. Certainly, acquired in vitro resistance to other DNA cross-linking drugs is phenotypically unstable during passage away from their selective influence. 45 That first-line treatment has not simply failed to clear a rump of sensitive cells is suggested by these patients' ultimate incurability, and their poorer duration of response second time around. It is now generally accepted that platinum re-exposure is generally best avoided in patients developing symptoms or signs of relapse within 6 months of completing platinum-based first-line chemotherapy. Throughout much of Europe and North America, paclitaxel is now routinely offered in this setting. Although licensed for second-line use, paclitaxel has made little impact in the UK, given its modest activity and duration of response, information that is germane to discussions with the patient and his/her family about the prospects of benefit from further treatment, in relation to continued simple symptomatic care. 46 The response rate to paclitaxel in patients less than 6 months from their last therapy is probably just 12-13%. 40Within the academic centres, the poverty of these options is used to justify offering such patients treatment within phase II clinical trials. Over the last 5 or 6 years wider cognisance of these practical and ethical considerations has led to patients being characterized by time to first relapse, and reduced the otherwise inevitable biological heterogeneity of small study groups, with the benefit of clarifying the significance of phase II trial response rates. 47Randomized phase II trials represent a further refinement, and may permit the operation of other selection factors to be inferred, by reference to the response rate obtained by a standard drug. This approach is being taken in ICON-4, a randomized trial of single-agent platinum versus paclitaxel and platinum in patients 6 months and more out from first-line treatment. Recent data from North America suggest that CAP may be better than paclitaxel alone in patients whose disease has relapsed from complete remission > 12 months from completing first-line platinum chemotherapy? 8

However, there remains considerable uncertainty about the optimal timing second-line chemotherapy in individual patients, heightened by the increasing use of the CA-125 ovarian tumour marker in followup. The standard approach is symptom-driven, in recognition of relapsed patients' incurability, and the 'palliative' nature of subsequent endeavour. However, disease burden and performance status are the main determinants of success in chemotherapy across a range of diseases and clinical contexts, and the available evidence suggests relapsed ovarian cancer is no exception: multivariate analysis of the results of the European-Canadian second-line Taxol study revealed tumour bulk greater than 5 cm diameter as a significant poor prognostic determinant. 4° Furthermore, the first symptom at relapse may often be bowel obstruction, all too often a grave and disabling complication, in which many would be wary of using chemotherapy. Hence, the MRC have commenced a prospective randomized evaluation of whether the 3-4 month warning of impending symptomatic relapse, typically afforded by the CA-125 tumour marker, can provide a window for more effective and less toxic chemotherapy (Trial OV 05).

GENETHERAPY

In the mid 1980s, the discovery of tumour suppressor genes led to suggestions that recombinant viral vectors might be used to direct gene therapy for cancer. However, although tumour cells had long been recognized as defective cells, with restoration of 'lost properties' by gene therapy a notion of beguiling simplicity, the difficulties implicit in directing efficient vector expression in each and every cell within a tumour were all too obviously insuperable. Virus-directed enzyme prodrug therapy (VDEPT) is a development of gene therapy that avoids this all too stringent condition by creating and exploiting transcriptional differences between tumour cells and normal tissues. 49A recombinant viral vector is used to selectively express the gene for an 'exotic' enzyme, whose substrate is an otherwise inert pro-drug and whose product is a cytotoxic metabolite, in tumour cells. It is hoped that the 'amplification' afforded by the enzyme's activity and the short-range cytotoxic effect of the (ideally) unstable metabolite, will obviate the requirement that every tumour cell be transduced. Like antibody-directed enzyme prodrug therapy (ADEPT), the concept of VDEPT arose from study of those curiously rare instances where single cytotoxic drugs yield complete regression of advanced transplanted rodent tumours. Three such examples have been identified, and in each case the remarkably enhanced therapeutic index is attributed serendipitous differences in the levels of expression of particular enzymes in tumour cells and normal tissue2 ° Whilst sensitivity to asparaginase in the Gardner

C h e m o t h e r a p y in epithelial cancer

l y m p h o s a r c o m a is a function o f its relative deficiency o f L-asparagine synthetase, in the two other examples, aniline m u s t a r d in the PC-5 plasma cell t u m o u r and Aziridinyl-dinitrobenzamide (CB1954) in the Walker tumour, the advantage arises because the drugs are activated selectively by tumour-specific enzymes. I n the case o f CB1954, high concentrations o f D T diaphorase within the t u m o u r convert the prodrug, a relatively weak non-toxic m o n o - f u n c t i o n a l alkylator, to a m u c h m o r e p o t e n t difunctional alkylating agent. In abrogating the requirement for enzyme expression in every t u m o u r cell, the V D E P T proposal is based on the susceptibility o f 'bystander cells' to active cytotoxic metabolite diffused from transduced cells. The short half-life o f such metabolites limits their systemic exposure and m a y reduce their propensity for collateral damage to n o r m a l tissues, so further enhancing the therapeutic index. However, success in this respect depends on the pro-drug not being a substrate for endogenous enzymes in n o r m a l tissues and also the successful incorporation o f efficient t u m o u r specific promoters into recombinant viral vectors, and the demonstration that such constructs are able to differentially regulate enzyme expression in infected n o r m a l tissues and tumours. A variety o f promoters cloned f r o m t u m o u r marker genes have been evaluated for this role, and a n u m b e r o f candidate enzymep r o - d r u g combinations have been proposed. With regard to ovarian cancer, a m a j o r effort is now underway to clone the C A 125 promoter. Pharmacological approaches to m o d u l a t i o n o f t u m o u r suppressor gene dysfunction are also being investigated. For example, the development o f screens for small molecules that might selectively inhibit the interaction between tumour-suppressor gene proteins and their pathological ligands, particularly those transcription factors that play i m p o r t a n t roles in cell cycle regulation. Alternatively, it m a y prove possible to mimic the effects o f P53 on transcription using D N A binding drugs targeted to P53-responsive elements. Yet another a p p r o a c h might be to develop drugs that bind m u t a n t P53 and, t h r o u g h allosteric effects, induce a change to a wild type conformation.

ANTIBODY-DIRECTED E N Z Y M E PRO-DRUG THERAPY The development o f m o n o c l o n a l antibody-enzyme conjugates offers a means by which tumour-specific enzyme 'expression' might be 'artificially' conferred at therapeutic will, to enable systemic therapy with biologically inert pro-drugs, and so improve therapeutic index. These approaches carry the promise o f localized a n t i - t u m o u r activity and reduced systemic toxicity, and have become k n o w n as antibody-directed enzyme p r o - d r u g therapy strategies. Initial work has utilized colorectal cancer as a developmental model,

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but the m e t h o d o l o g y seems equally applicable to advanced ovarian and cervical tumours.

CONCLUSION C h e m o t h e r a p y has come a long way in the last 50 years or so, but its propulsive force is changing; rational drug development and the h u m a n solid t u m o u r screen promise b o t h advantage and challenge. Blindman's-buff has become enlightened empiricism. REFERENCES 1. Poole C, Kerr D. The clinical evaluation of novel chemotherapeutic agents. In: Kerr D, Workman P (eds). New molecular targets for cancer chemotherapy. Boca Raton, Anne Arbor: CRC Press. 1994:195-212 2. Calman. The provision of cancer care in the UK: report by an expert working party. Department of Health 1995 3. Bolis G, Columbo N, Favelli Get al. Randomised multicentre clinical trial in stage I epithelial ovarian cancer. Proc Am Soc Clin Oncol 1992; 11:225 4. Kaern J, Trope C. Adjuvant treatment of stage I ovarian cancer: how can we prevent overtreatment? Proc ASCO 1992; 11:225 5. Omura G, Bundy B, Berek J et al. Randomised trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma. J Clin Oncol 1989; 7:457465 6. Warwick J, Kehoe S, Earl H. Long term follow-up of patients with ovarian cancer involved in clinical trials - important prognostic features. Br J Cancer 1995; 72(6): 1513-1517 7. Griffiths R, Cummins C, Kirk A et al. Cancer and Health: joint report of the West Midlands Regional Director of Public Health and the West Midlands Cancer Registry. West Midlands Regional Health Authority 1995 8. Hunter R, Alexander N, Soutter W Meta-analysis of surgery in advanced ovarian carcinoma: is maximum cytoreductive surgery an independent prognostic factor? Am J Obstet Gynecol 1992; 166:504-511 9. Hacker N, Berek J, Lagasse Let al. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983; 61: 413420 10. Hoskins W, Bundy B, Thigpen Jet al. The influence of cytoreductive surgery on recurrence-freeinterval and survival in small volume stage III epithelial ovarian cancer, a Gynaecologic Oncology Group Study. Gynae Oncol 1992;47:159-166 11. Heintz A, van Oosterom A, Trimbos J. The treatment of advanced ovarian carcinoma (1) clinical variables associated with prognosis. Gynecol Oncol 1988; 30:347-358 12. Webb M. Cytoreduction in ovarian cancer: achievability and results. In: Burghardt E, Monagham J (eds). Operative treatment of ovarian cancer. London: Bailti~re Tindall. 1989: 83-94 13. Van der Burg M, Van Lent M, Buyse Met al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995; 332:629-634 14. Redman C, Warwick J, Leusley D et al. Intervention debulking surgery in advanced epithelial ovarian cancer. Br J Obstet Gynaecol 1994; 101:142-146 15. Young R. Chemotherapy of ovarian cancer: past and present. Sem Onc 1975; 2:267-276 16. Masterson J. Management of ovarian cancer: surgery, irradiation, and chemotherapy. Am J Obstet Gynecol 1967; 98:374-386 17. Lambert H, Berry R. High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): report from the North Thames Cooperative Group. Br Med J 1985; 290:889-892 18. Hakes T, Hoskins W, Jones Wet al. Randomised prospective trial of 5 versus 10 cycles of cyclophosphamide doxorubicin, and cisplatin (CAP) in stage III and IV ovarian cancer. Proc ASCO 1990; 9:156

60

Current Obstetrics & Gynaecology

19. Calvert A, Newell D, Gumbrell Let al. Carboplatin dosage: prospective evaluation of a simple fm-mula based on renal function. J Clin Oncol 1989; 17(11): 1748-1756 20. Rankin E, Mill L, Kaye Set al. A randomised study comparing standard dose carboplatin with chlorambucil and carboplatin in advanced ovarian cancer. Br J Cancer 1992; 65: 275~81 21. Advanced Ovarian Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Br Med J 1991; 303:884-893 22. Rozencweig M, Martin A, Beltangady Met al. Randomised trials of carboplatin versus cisplatin in advanced ovarian cancer. In: Bunn P, Canetta R, Ozols R, Rozencweig M (eds). Carboplatin (JM8), Current Perspectives and Future Directions. Philadelphia: WB Saunders, 1990:175-192 23. Belpomme D, Bugat R, Rives Met al. Carboplatin vs cisplatin in association with cyclophosphamide and doxorubicin as first line therapy in stage IIl IV ovarian cancer - results of an ARTAC trial. Proc ASCO 1992; 11:227 24. Ghersi D, Parmar M, Guthrie D, Williams C. High versus low dose cisplatin in epithelial ovarian cancer. Lancet 1992 Sept; 340:678-679 25. Torri V. Studies -obotICON. Randomised study of cyclophosphamide doxorubicin & cisplatin (CAP) vs single agent carboplatin in ovarian cancer patients requiring chemotherapy: interim results of ICON-2. Proceedings of ASCO 1996; 15:280 26. MRC Cancer Trials Office. ICON-2 interim results. Gynaecological Cancer Newsletter September 1996 27. Levin L, Simon R, Hryniuk W The importance of multiagent chemotherapy regimens in ovarian carcinoma - dose intensity analysis. JNCI 1993; 85:1732-1742 28. Kaye S, Lewis C, Paul Jet al. Randomised study of two doses of cisplatin with cyclophosphamide in epithelial ovarian cancer. Lancet 1992; 340 (8815): 329-333 29. Murphy D, Crowther D, Rennison Jet al. A randomised dose intensity study in ovarian carcinoma comparing chemotherapy given at four week intervals for six cycles with half dose chemotherapy for twelve cycles. Annals of Oncology 1993; 4(5): 377-383 30. Kaye S. Causes of clinical drug resistance. In: Sharp F, Blackett T, Leake R (eds). Ovarian Cancer. London: Chapman and Hall Medical. 1996; 4:215~20 31. Coldman A, Goldie J. Impact of dose-intense chemotherapy on the development of permanent drug resistance. Sere Onc 1987; 14(4): 29-33 32. McGuire W, Hoskins W, Brady M, Homesley H, ClarkePearson D. A phase III trial of dose intense versus standard dose cisplatin and cytoxan in advanced ovarian cancer. Proc Am Soc Clin Oncol 1992; 11:226 33. Ozols R. High dose carboplatin in the treatment of ovarian cancer. In: Bunn E Canetta R, Ozols R, Rozencweig M (eds). Carboplatin (JM-8). Philadelphia: WB Saunders. 1990:147-152 34. Jodrell D, Egorin M, Canetta R et al. Relationship between carboplatin exposure and turnout response and toxicity in patients with advanced ovarian cancer. J Clin Oncol 1992; 10(4): 520-528

35. Gore M, Mainwaring P, Macfarlane Vet al. A randomised trial of high versus standard dose carboplatin in patients with advanced epithelial ovarian cancer. Proceedings of ASCO 1996:15 36. Parker B, Castellino R, Fuks Z et al. The role of lymphangiography in patients with ovarian cancer. Cancer 1974; 31:100-105 37. Markman M. Intraperitoneal chemotherapy. Semin Onc 1991; 18:255~69 38. Alberts D, Liu P, Hannigan E et al for the SWOG-GOGECOG intergroup. A phase III study of ip cisplatin and iv cyclophosphamide vs iv cisplatin and iv cyclophosphamide in patients with optimal disease stage III ovarian cancer. Proceedings of ASCO 1995; 14: 273, 760 39. McGuire W, Rowinsky E, Rosensheim N. Taxol a unique antineoplastic agent with significant activity in advanced ovarian neoplasms. Ann Intern Med 1989; 111: 273~79 40. Eisenhauer E, ten Bokkel Huinink W, Swenerton K et al. European-Canadian randomised trial of paclitaxel in relapsed ovarian cancer: high versus low-dose and long versus short infusion. J Clin Oncol 1994; 12:2654-2666 41. Carmichael J, Gordon A, Malfetano Jet al. Topotecan, a new active drug, vs paclitaxel in advanced epithelial ovarian carcinoma: International Topotecan Study Group. Proceedings of ASCO 1996; 15:283 42. McGuire W, Hoskins W, Brady Met al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334:1-6 43. Lund B, Hansen O, Theilade K, Hansen M, Neijt J. Phase II study of Gemcitabine (2,2-Diftuorodeoxycytidine) in previously treated ovarian carcinoma patients. J Natl Cancer Inst 1994; 86:1530-1533 44. Markman M, Rothman R, Hakes T et al. Second line platinum chemotherapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991; 9(3): 389-393 45. Bellamy W, Dalton W, Gleason M, Crogan T, Trent J. Development and characterisation of a melphelan-resistant human multiple myeloma cell line. Cancer Res 1991; 51(3): 995-1002 46. Cody M, Slevin M. Treatment decisions in advanced ovarian cancer. Br J Cancer 1989; 60:155-156 47. Blackledge G, Lawton F, Redman C, Kelly K. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and design of phase II trials. Br J Cancer 1989; 59(4): 650-653 48. Columbo N, Marzola M, Parma Get al. Paclitaxel vs CAP (Cyclophosphamide, Adriamycin, Cisplatin) in recurrent platinum sensitive ovarian carcinoma. Proceedings of ASCO 1996; 15:279 49. Huber B, Richards C, Krenitsky T. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. Proc Natl Acad Sci USA 1991; 88:8039-8043 50. Connors T. Antibody directed enzyme prodrug therapy. Cancer Cells 1990; 2(2): 56-57