A dose escalating study of topotecan preceding cisplatin in previously untreated patients with small-cell lung cancer

Annals of Oncology 11: 829-835, 2000. © 2000 Kluwer Academic Publishers. Primed in the Netherlands.

Original article A dose escalating study of topotecan preceding cisplatin in previously untreated patients with small-cell lung cancer M. Sorensen,1 P. B. Jensen,1 I Herrstedt,2 F.R. Hirsch1 & H. H. Hansen1 x

2

Department of Oncology, Copenhagen University Hospital Herlev, Copenhagen, Denmark

Summary Background: The aim was to define the MTD of topotecan (TPT) given before cisplatin in patients with previously untreated SCLC. Patients and methods: Alternating cycles A and B to a total of 6 cycles were given. Cycle A: TPT days 1-5 and cisplatin (50 mg/m 2 ) day 5. Cycle B consisted of teniposide, carboplatin, vincristine, and cisplatin. TPT was escalated at doses 0.75, 1.0, 1.25, and 1.5 mg/m 2 . DLT was defined for the first cycle as grade 4 neutropenia with fever or when lasting > 7 days, or grade 4 thrombocytopenia. Results: Fifteen patients with limited disease and six patients with extensive disease were included. No episodes of DLT were

recorded in the first cycles A and consequently 1.5 mg/m was defined as MTD. At 1.5 mg/m 2 (11 patients, 30 cycles), four and three episodes of grade 4 thrombocytopenia and neutropenia lasting more than seven days occurred in subsequent cycles A. Thrombocytopenia and anaemia were cumulative as more cycles were administrated. Non-hematological toxicity was mild. The response rate was 86% (95% confidence interval (95% CI): 64%-97%) with 33% (95% CI: 15%-57%) achieving CR. Conclusions: 1.5 mg/m 2 TPT can be delivered safely with 50 mg/m 2 cisplatin on day 5 in patients with previously untreated SCLC. Key words: cisplatin, combination chemotherapy, phase I, phase II, small-cell lung cancer, topotecan

approximately half of the recommended single agent dose. Initially, Miller et al. recommended a dose of Topotecan belongs to a novel class of anticancer drugs, 1.0 mg/m2 topotecan in combination with 50 mg/m2 the camptothecins. The sodium salt of camptothecin cisplatin on day 1 without growth factor support [10], was evaluated in early clinical trials in the 1970s, but but later, the same group reported that 3 out 12 patients further clinical development was suspended due to un- died of treatment related neutropenic sepsis using this predictable toxicity including haemorragic cystitis [1, 2]. schedule [11]. In order to increase the dose delivery of Later, it was discovered that the camptothecins have a topotecan we chose to examine the alternate sequence of unique mechanism of action. These drugs kill cells by the drugs, i.e., cisplatin on day 5 preceded by five-day freezing an essential enzyme, topoisomerase I in a tem- topotecan based on data by Rowinsky et al. indicating porally state in which the topoisomerase I is bound to a that cisplatin following topotecan was significantly less broken piece of single-strand DNA [3]. When the DNA myelosuppressive than cisplatin given before topotecan replication machinery encounters these topoisomerase [12]. However, the latter study was not designed to I-bound DNA strand breaks they are converted to per- establish the MTD of the alternate sequence. In the manent and lethal DNA double-strand breaks [4, 5]. As present study, the topotecan-cisplatin based courses a consequence, topotecan cytotoxicity is dependent on were given every second cycle. The alternate cycles conintracellular levels of topoisomerase I and the fraction of sisted of a combination of cisplatin, carboplatin, teniposide and vincristine, corresponding to one of the arms in cells undergoing DNA synthesis. Among the many new agents which underwent clin- the most recent phase III trial at the participating ical evaluation in small-cell lung cancer (SCLC) in the institutions [13]. The rationale for this alternating last decade, topotecan was found to be one of the most schedule was two-fold. Firstly, topotecan-cisplatin as active drugs [6, 7], indicating a future role for topotecan front-line treatment must be considered experimental in combination with established drugs in this disease therapy and we wanted to ensure that established treatentity. Preclinical studies indicated a synergistic tumor ment was delivered in reasonable doses early in the cell kill when cisplatin and topotecan are used in combi- course of the treatment. Secondly, preclinical data nation [8, 9]. This combination has been tested in a indicate that sequential treatment with topoisomerase-I number of clinical trials showing that administration of (topotecan) and -II (teniposide) inhibitors could prove 50-75 of mg/m2 cisplatin on day 1 only allows a dose beneficial, based on tumor cell studies showing that escalation of topotecan to a dose corresponding to resistance towards one type of drug often confers hyperIntroduction

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The Finsen Centre, Rigshospitalet;

830 sensitivity to the other drug type [8, 14, 15]. The mechanism behind this pattern might be that tumor cells in response to topotecan induced topoisomerase I downregulation compensate by up-regulating the target of teniposide-topoisomerase II [16-18]. Patients and methods Eligibility

Treatment A total of six cycles of chemotherapy was scheduled for each patient. Cycles 1, 3 and 5 consisted of topotecan on day 1-5 in combination with cisplatin 50 mg/m2/d on day 5 (cycle A). Topotecan was infused following completion of the cisplatin infusion on day 5. Cycles 2,4 and 6 consisted of vincristine 1.3 mg/m2/d (maximally 2.0 mg) on day 1, cisplatin 35 mg/m2/d on day 2 and 3, carboplatin AUC = 4 on day 1, and teniposide 50 mg/m2/d on day 1-5 (cycle B). All drugs were administered intravenously. Intervals between the treatment cycles were 21 days following cycle A and 28 days following cycle B. After the completion of chemotherapy, chest- and prophylactic cranial irradiation were allowed according to the guidelines at the participating institutions. Chest radiation was not performed concomitantly with chemotherapy to avoid radiation induced toxicity as the study aimed exclusively at assessing the toxicity of the combination of topotecan and cisplatin.

Drug administration Topotecan was supplied as a lyophilized cake in 4 mg vials by SmithKline Beecham Pharmaceuticals, Welwlyn Garden City, UK. The drug was reconstituted with 2 ml of sterile water, diluted in 50 or 100 ml of normal saline and infused over 30 minutes. Cisplatin was infused over 30 minutes. A standard hydration regimen was used. Carboplatin was dosed according to Calverts equation using GFR monitored by Cr-EDTA clearance. Teniposide was infused over 30 minutes. Vincristine was given as a bolus. In cycles A, prophylactic antiemetics included 30 mg metoclopramide or metopimazine orally 3-4 times daily day 1-4. On day 5 and the following morning, 8 mg oral ondansetron was administered twice

Criteria for dose reductions

Dose reductions

Leucocyte count ^ 1000/ul or neutrophil count ^ 500/ul > 7 days or with fever » 38 5 °C or infection or platelet count i£25,000/ul or grade 3 non-hematological toxicity except nausea, vomiting, fever, alopecia or anorexia (only for topotecan)

Topotecan: reduction by one dose level Teniposide: 75% of planned dose Carboplatin: AUC = 3

Renal toxicity > grade 3

Cisplatin: 75% of planned dose

Neuropathy > grade 3

Discontinuation of vincristine Cisplatin: 75% of planned dose

Criterias for treatment delay

Delay

Leucocyte count on day 1 < 3000/ul or neutrophil count on day I < 1500/ul or platelet count on day < 75,000/ul

One week delay Failure to recover after one week required dose reductions as outlined above

daily in combination with a single oral dose of 50 mg prednisolone. In cycles B, the prophylactic antiemetic regimen was identical to that used on day 5 of cycles A. Dose escalation Only the doses of topotecan were escalated and no dose escalation in individual patients was allowed. All other drugs were given in a fixed dose unless toxicity required individual dose reductions. Cohorts of three patients were included at dose levels 0.75, 1.0, 1.25, and 1.5 mg/m2/d. If no patient experienced dose limiting toxicity (DLT), accrual was continued at the next dose level. If two out of three patients at a given dose level had DLT, accrual was to be discontinued and the dose level below was considered the maximal tolerable dose (MTD). If one out of three patients at a given dose level had DLT, an additional cohort of three patients had to be included at this dose level. If one or more patients in the second cohort had DLT, accrual was stopped and the dose level below was considered MTD. If none of the patients in the second cohort had DLT, dose escalation proceeded to next dose level. Decisions regarding dose escalation were based on toxicity data derived from the first course of topotecan/cisplatin. A minimum of six patients was to be treated at the dose level defined as MTD. When MTD was defined, we planned to transform the study to a phase II study with the aim of treating a total of 25 patients at MTD. The results of the latter trial will be reported later. Toxicity was graded according to Guidelines for Reporting of Adverse Drug Reactions, Bethesda, Division of Cancer Treatment, National Cancer Institute, 1988. Dose limiting toxicity (DLT) was defined as toxicity after the first cycle of topotecan-cisplatin including one of the following: grade 3 or 4 non-hematological toxicity other than nausea, vomiting, fever, alopecia or anorexia; grade 4 neutropenia (^500/ul) lasting more than seven days or complicated with fever > 38.5 *C and/or infection; grade 4 thrombocytopenia (< 25,000/ul) of any duration; failure to recover neutrophil count 3= 1500/ul or platelet count 3= 75,000/ul by day 28.

Dose modifications Dose reductions and decisions for treatment delay were based on the criteria outlined in Table 1.

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Patients with histologically verified SCLC (WHO type II) or mixed histology (WHO type V) regardless of disease extent were candidates for the trial provided that they had measurable or evaluable disease, age between 18 and 70 years, WHO performance status of 0-2, and had not received prior radio- or chemotherapy. The following laboratory values were required at entry: hemoglobin level 3*6.0 mmol/1 (9.6 g/dl), white blood cell count SOOOO/ul, neutrophil count 3:1500/ul, platelet count ~z 100,000/ul, serum creatinine level <133 mmol/1 (1.5 mg/dl), slCr-EDTA clearance 5=60 ml/min, serum bilirubin level ^34 mmol/1 (1.4 mg/dl), transaminases and alkaline phosphatase < 2 times the upper limit of normal or ^ 3 times the upper limit of normal in the presence of liver metastases. The protocol was approved by the local ethical committee. All patients gave written informed consent. Patients were ineligible if they had a history of prior or present malignancies other than SCLC except for carcinoma of the skin or CIS of the cervix, active non-controlled infection, a concurrent medical problem unrelated to their lung cancer which could significantly limit full compliance with the study or expose the patient to an undue risk of decreased life expectancy. Further, treatment with an investigational drug within 30 days prior to study entry was not allowed. No concurrent chemotherapy, immunotherapy, or investigational therapy for the treatment of SCLC were allowed. Radiotherapy could be administered if the clinical condition demanded it. Pregnant or lactating females were not allowed to enter the study.

Table I. Guidelines for dose modifications.

831 Patient evaluation and follow-up

Criteria for evaluation of tumor response and toxicity Tumor response evaluation was done according to the WHO criteria.

Statistics A multiple regression analysis with backward stepwise elimination was used to evaluate if toxicity increased as more cycles were administered. The cut off value for elimination was a significance level of 0.05. For the comparison of toxicity in cycles A and B non-parametric statistics were applied due to the small sample sizes. The Wilcoxon matched pairs test was used for continuous data and the McNemar test for binomial data. Cycles were compared in pairs as follows: cycle 1 to 2, cycle 3 to 4, and cycle 5 to 6. All p values are based on two-sided tests.

Hematological toxicity following cycles B was as follows: Grade 4 neutropenia and thrombocytopenia Between November 1996 and July 1998, 22 patients occurred in 66% (Table 2a) and 50% (Table 2b) of entered the study at Finsen Centre, (n = 20) and as of cycles. Grade 3 and 4 anemia were observed in 6% of April 1998 at Department of Oncology, Herlev (n - 2), cycles (not shown). Seven episodes of grade 4 neutroboth Copenhagen. One patient assigned to dose level penia lasting more than seven days were recorded 1.5 mg/m2 died suddenly before receiving any protocol (Table 2a). No episodes of either treatment related specified treatment and was excluded for further analysis. deaths or sepsis occurred. Of the remaining 21 patients, 15 had limited and 6 had Paired non-parametric analyses were performed extensive disease. Patients were equally balanced be- comparing toxicity following cycles A and B in the 11 tween sexes (11 males and 10 females), and the majority patients receiving 1.5 mg/m2 topotecan (Tables 2a and b, had performance status (PS) one (PS 0, n - 2; PS 1, footnotes 1-5 and Table 3). The incidence of fever n = 16; PS 2, n - 3). Three, four and three patients were (P - 0.06, 0 of 30 vs. 5 of 30) and grade 4 thrombocytoentered at dose levels 0.75, 1.0 and 1.25 mg/m2 while penia (P = 0.07, 4 of 30 vs. 11 of 30) as well as the need eleven patients were treated at the highest dose level of for platelet transfusions (P - 0.06, 2 of 30 vs. 8 of 30) 1.5 mg/m2. As the first patient on dose level 1.0 mg/m2 were borderline significantly less frequent after cycles A suffered an early death due to tumor progression, addi- compared to cycles B. The next treatment cycle had to be tionally three patients were included on this dose level. postponed after 60% of cycles A compared to 13% of Sixteen patients completed all six scheduled cycles of cycles B (P = 0.001) (Table 3). therapy. The remaining five patients discontinued treatment due to tumor progression (n - 3) and toxicity Non-hematological toxicity in = 2). Generally, non-hematological toxicity was manageable Hematological toxicity and mild, i.e., mainly grade 1 and 2 (Table 4). Seven cases of grade 3 or 4 toxicities were recorded. One At dose levels 0.75 and 1.0 mg/m2, no grade 4 neutrope- episode of grade 3 and 4 hypomagnesemia, respectively, nia was observed. At dose levels 1.25 and 1.5 mg/m2 followed cycles B. One patient experienced grade 3 grade 4 neutropenia was recorded in approximately half haematuria after the first cycle of topotecan-cisplatin. Results

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Pretreatment evaluation included complete history, physical examination, WHO performance status, chest X-ray, chest, brain and abdominal CT scans, bronchoscopy including endobronchial biopsy, bilateral bone marrow aspirates and biopsies from the iliac crest, routine laboratory tests including hemoglobin, differential WBC, platelet count and chemistries (electrolytes, creatinine, albumin, prothrombin time, lactate dehydrogenase, alkaline phoshpatase, total bilirubin, alanine aminotransferase), electrocardiograms, urinanalysis, 5l Cr-EDTA clearance, and audiometry. Complete blood cell count were performed on days 11 and 15. 51 Cr-EDTA clearance was performed before carboplatin based cycles. Chest X-ray and routine laboratory tests as outlined above were repeated before each treatment cycle. Tumor evaluation by CT scans of involved regions were repeated every second treatment cycles, i.e., every 7 weeks during treatment and hereafter every 4 months for 24 months.

of the delivered cycles (Table 2a). No episodes of grade 4 neutropenia lasting more than seven days or grade 4 thrombocytopenia were observed after the first cycles A and accordingly 1.5 mg/m2 was denned as MTD. However, grade 4 neutropenia of more than seven days duration occurred after the fifth cycle at dose level 1.5 (n - 3) and 1.25 (n = 1) mg/m2 (Table 2a). Seven episodes of grade 4 thrombocytopenia followed cycles 3 and 5 (1 at 1.0 mg/m2; 2 at 1.25 mg/m2; 4 at 1.5 mg/m2) (Table 2b). Grade 3 anemia was observed in one case (not shown). No patients experienced sepsis, and neutropenia was associated with fever in one patient treated at 1.25 mg/m2 following the last topotecan/cisplatin treatment cycle. No patients required dose reductions of topotecan. To determine if hematological toxicity increased with the number of cycles delivered, a multiple regression analysis was performed on hemoglobin values, neutrophil counts, and platelet counts at the time of nadir using dose, renal function (51Cr-EDTA clearance) and cycle number as covariates. With respect to anemia and thrombocytopenia the dose could be eliminated in the model at a significance level of 0.05 whereas the number of cycles and renal function were independent predictors of nadir counts. In contrast, the number of cycles delivered was not an independent predictor of the nadir neutrophil count, indicating that the degree of neutropenia did not increase as more cycles were delivered to each patient. Similar analysis were performed for cycles 2, 4 and 6 (teniposide based cycles) showing that hematological toxicity did not increase with number of cycles administered.

3 4 3 lod

n

Cycle I

0 0 3 5

G4

Cycles A

0 0 0 0

>7d

2.6 1.5 0.33 0.55

Mean

3.90-0.75 3.50-0.50 0.40-0.30 1.20-0.17

Range 3 2 3 11

n

0 0 0 5

G4

Cycle 3

0 0 0 0

>7d 3.2 0.8 0.62 0.66

Mean 4.30-1.40 1.004.60 0.754.51 1.574.30

Range tr

3 2 3 9

0 0 1 3

G4

Cycle 5

0 0 1 2

> 7d 1.80 0.90 0.55 0.59

Mean

3 4 3 10"

n

Cycle I

Cycles A

0 0 0 0

G4

145 94 76 97

Mean

175-61 175-45 97 -53 176-41

Range 3 2 3 I1

n

Cycle 3

0 0 0 1

G4 88 86 56 67

Mean 123-45 96-75 63-50 135-24

Range tr

3 2 3 9

Cycle 5

0 1 2 3

G4

51 45 33 45

Mean

91-26 67-23 85-4 109-10

Range

2.30-1.10 1.004.80 0.89-0.07 1.704.10

Range 9 8 9 30

11

Total

9 8 9 30

11

Total

0 0 4 15"

G4

0 1 2 4b

G4

0 0 1 3b

> 7d

100 80 55 70C

Mean

2.5 1.2 0.50 0.60'

Mean 7 5 7 17"

9 7 8 30

4.3-0.75 3.5-0.50 0.89-0.07 1.7-0.10

II

9 7 8 30

Range 175-26 175-23 97-4 176-10

Total

I lh

6 3 7

G4

2 1 2 2b

> 7d

Cycles B

G4

rr

Total

Cycles B

Range

C'yclcs A includes topotec;~nand cisplatin; cycles B includes teniposide, carboplatin, cisplatin and vincristine. Abbreviations: secTable 2a. "All I I patients treated at 1.5 mg/m2 completed cycle I; however, one patient missed nadir counts; b~ = 0.065; 'P = 0.22 in paired analyses comparing cycles A and B at dose level 1.5 mglm2.

0.75 1 .O 1.25 1.5

Dosc (ms/m2)

Ttrhkc 2h. Platelet counts a t nadir ( x 10'1~1).

-

Cycles A includes topotecan and cisplatin; cycles B includes teniposide, carboplatin, cisplatin and vincristine. Abbreviations: 11 number of trcatment cycles; G4 - grade 4 neutropenia; > 7d - grade 4 neutropenia lasting more than seven days. 'I P 1.00, h~ = 1.00; ' P = 0.30 in paired analyses comparing cycles A and Bat dose level 1.5 mglm2. All I I patients treated at 1.5 mg/m2 completed cycle I; however, I patient missed nadir counts.

0.75 1 .O 1.25 1.5

Dose (mg/m2)

T d l e 20. Neutrophil counts a t nadir (x 10'/pl).

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25 52 13 62'

Mcnn

0.41 0.35 0.20 0.84'

Mean

53-6 118-5 47-4 203-6

Range

2.00-0.00 1.00-0.00 0.79-0.00 3.00-0.00

Range

833 Table 3. Comparison of cycles A with B at dose level 1.5 mg/m 2

RBC transfusions3 Platelet transfusions" Fever bc IV antibiotics'" Next cycle delayed*5

Cycles A

Cycles B

/•-value

19/29 2/30 0/30 0/29 18/30

36/29=1.24 8/30 = 0.27 5/30= 17% 3/29 = 10% 4 / 3 0 = 13%

0.27 0.06 0.06 0.25 0.001

= 0.66 = 0.07 = 0% = 0% = 60%

a

In this patient, the bladder mucosa appeared normal without evidence of bladder stones as judged by cystoscopy, but a small lesion in the mucosa of the urethra was observed. The patient was retreated with topotecancisplatin in cycles 3 and 5 according to the protocol and haematuria did not reappear. One patient was taken off study after three cycles of therapy due to a decrease in renal function. Prior to treatment 51Cr-EDTA clearance was 78 ml/min which decreased to 46 ml/min. One patient entered at dose level 1.25 mg/m2 experienced an episode of grade 3 constipation after the fourth treatment cycle including vincristine. The patient refused cycle 6 to avoid the reappearance of constipation. One case of grade 3 diarrhea and one case of grade 3 nausea followed cycle A and B, respectively.

Grade 1-2 (% of cycles)

Neuropathy Stomatitis Hearing Dermatological Pain Bleeding Constipation Diarrhea Fever Fatigue Nausea Vomiting Alopecia Dizziness Hypomagnesaemia Anorexia Hematuria

Grade 3-4 (% of cycles)

Cycles A

Cycles B

Cycles A

Cycles B

19 7 5 5 16 9 11 4 5 42 28 11 61 5 7 4 0

20 7 6 4 15 11 6 7 11 33 24 11 55 11 2 2 0

0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 2

0 0 0 0 0 0 2 0 0 0 2 0 0 0 4 0 0

day 1. However, severe toxicity including treatment related deaths has been reported using this schedule [10-12, 20]. The current study is the first to report the MTD of the alternate schedule, i.e., five-day topotecan with single dose cisplatin on day 5. Out of 11 patients treated at 1.5 mg/m2 no patients experienced DLT defining the MTD as 1.5 mg/m2 which corresponds to the recommended single-agent dose of topotecan. A previous study has evaluated the sequence of topotecan Efficacy and cisplatin [12]. Treatment cycles alternated between Tumor responses were evaluated after every second cisplatin given on day 1 and 5 in each individual patient treatment cycle. Overall 18 (86%, 95% confidence inter- with the aim of determining the MTD of topotecan in val (95% CI): 64%-97%) had a response with 11 (52%, combination with cisplatin on day 1. Similar to the 95% CI: 30%-74%) and 7 (33%, 95% CI: 15%-57%) present study, they found no episodes of grade 4 neutroexperiencing partial and complete responses, respec- penia at the two lowest dose levels tested (0.75 and 1.0 tively. Three patients had progressive disease during mg/m2), but grade 4 thrombocytopenia appeared at treatment (n - 2, dose level 1.0 mg/m2; n = 1, dose level dose level 1.0 mg/m2. Both mean neutrophil and platelet 1.5 mg/m2). One of these patients treated at dose level counts were comparable to the figures reported here. 1.0 mg/m2 presented with brain metastases and suffered It is important to emphasize that the definition of an early death after receiving his first cycle of treatment. DLT used in this study accepted a rather long duration Death occurred at day 25 and was preceded by haema- of grade 4 neutropenia (> 7 days). Further, only epitologic recovery but the patient had deterioration in sodes occurring following the first course of topotecanbrain metastases related symptoms including frank psy- cisplatin were included in the definition of DLT and thus chosis. Intracranial responses were observed in two out only first course toxicity had implications for decisions of three patients presenting with brain metastases. regarding dose escalation. In fact, in subsequent cycles grade 4 thrombocytopenia and prolonged neutropenia were recorded even at dose level 1.0 and 1.25 mg/m2. At 1.5 mg/m2 grade 4 thrombocytopenia and prolonged Discussion neutropenia were seen in 4 of 30 and 3 of 30 cycles, Topotecan is among the most active new chemothera- respectively (Tables 2a and b). In a single-agent topotecan peutic agents in SCLC. Its activity with respect to tumor study, Rowinsky reported that the onset of nadir occurred response and survival has proven to be at least equal to as early as day 8-12 [21], indicating that the duration of standard treatment in relapsed SCLC [19]. Further, top- nadir could be underestimated in the present study as otecan and cisplatin in combination display synergy in blood samples were drawn at day 11 and 15. Patients preclinical model systems. Focus has been on a five-day treated at 1.5 mg/m2 seemed to tolerate cycles B better topotecan schedule preceded by single-dose cisplatin on than all other cohorts as they achieved the highest mean

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Indicated as number of transfusions/total number of cycles. Indicated as number of incidences/total number of cycles. c Fever refers to temperature above 38.5 °C regardless of neutrophil count. Information were missing for one pair of cycles with respect to RBC transfusions and IV antibiotics. b

Table 4. Non-hematological toxicity.

834 patients [20]. Thus, toxicity of this drug combination is highly sequence dependent. Similar observations have been reported previously by Rowinsky et al. [12] who proposed that the increased toxicity of cisplatin preceding topotecan could be caused by a decrease in renal excretion of topotecan due to subclinical cisplatin induced nephrotoxicity. This notion was based on pharmacokinetic data indicating that administration of cisplatin on day 1 seemingly increased systemic exposure to topotecan. However, analyses were performed on a quite small sample size. Alternatively, the sequence dependence could be a result of various cellular mechanisms. A role for topoisomerase I in DNA repair has been suggested and camptothecin has been reported to inhibit DNA repair [22]. Thus, topotecan might inhibit the repair of cisplatin induced DNA damage. Indeed, in cultured tumor cells, 9-amino-camptothecin slows down the reversal of cisplatin induced DNA inter-strand cross-links [23]. Further, the lethality of topoisomerase I mediated cleavable complexes is highly dependent on active DNA replication [5]. Thus, hypothetically, upregulation of DNA replication in association with cellular repair of cisplatin induced DNA adducts might make cells more susceptible to topotecan induced cleavable complexes. Irrespective of the mechanism behind the pronounced sequence dependence, the main goal is to achieve the maximal tumor response and ultimately optimal survival with a manageable level of myelotoxicity. The data available to date can not determine which sequence is the optimal. It appears that cisplatin preceding topotecan leads to synergistic bone marrow cytotoxicity whereas this is not the case when cisplatin is delivered after topotecan. It is an open question whether the cytotoxicity on tumor cells is also sequence dependent, and thus it would be difficult at present to favor one sequence over the other. Of major concern is however the reported toxic deaths on the cisplatinbefore-topotecan schedule [11]. Further, the low doses of topotecan on the cisplatin-before-topotecan schedule might result in insufficient delivery of topotecan. Based on these considerations we plan to further explore the cisplatin-after-topotecan schedule. This will include studying the feasibility of incorporating concomitant radiotherapy. The future role of this strategy needs to be evaluated in large comparative randomized trials using survival as primary end-point. Acknowledgements

Research nurses Mr P. Knoblauch and Ms U. Sorensen are thanked for their expert assistance. Statistician Mr K. Nilausen is acknowledged for the establishment of the data base. This work was supported by a grant from the Faculty of Health, Copenhagen University, Copenhagen, Denmark and an educational grant provided by SmithKline Beecham, Harlow, Essex, UK.

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nadir counts, possible reflecting that all 11 patients had limited disease and most had performance status one. Thus, the recommended dose of 1.5 mg/m2 should be used with caution in patients who display features that could influence their tolerance to chemotherapy. The severity of both thrombocytopenia and anemia increased as more cycles were administered. This is in contrast to the non-cumulative toxicity of single agent topotecan as well as topotecan in combination with cisplatin (except for one case of progressive anemia [10]). Presumably, the cumulative toxicity is due to an interaction with the alternating cycles B and carboplatin is a plausible drug candidate for this effect as thrombocytopenia is a prominent feature of the toxicity profile of carboplatin. A progressive impairment of renal functions resulting in increased exposure to topotecan is a less likely explanation as neutropenia did not increase as more cycles were administered. The alternate cycle B consisting of teniposide, carboplatin, cisplatin and vincristine was part of one of the arms in the most recent randomized study for the treatment of limited and extensive disease SCLC at the participating institutions [13]. Accordingly, it was relevant to compare toxicity of the two alternating cycles A and B. It seems that the toxicity of topotecan/cisplatin at the MTD is no more severe than that of cycle B. On the contrary, there was a tendency towards more severe thrombocytopenia following cycles B requiring more platelet transfusions. These data should however be interpreted with caution due to the small sample size. Failure to retreat at the planned day were significantly more common following cycles A than cycles B. This difference reflects that treatment intervals were 21 days and 28 days for cycles A and B, respectively. In 60% of cycles A, the next cycle had to be postponed due to low neutrophil counts at day 21. Similarly, Miller reported that only in 27% of cycles, retreatment could be administered at the planned 21-day interval using a schedule with cisplatin given on day 1 [10]. Thus, it appears that adding cisplatin either before or after topotecan hampers the feasibility of 21 days treatment intervals. Non-hematological toxicity was mild with alopecia, fatigue, nausea, and peripheral neuropathy among the most frequent (Table 4). No episodes of sepsis or treatment related deaths were recorded. As haemorragic cystitis were found to be dose limiting in the early trials of the parent compound camptothecin [1, 2], we thoroughly investigated one case of grade 3 haematuria. No endoscopic evidence of cystitis was observed and the incidence did not reappear upon retreatment. Tumor response rates were similar to that expected in this disease entity but the small number of patients including patients with both limited and extensive disease impede meaningful conclusions with respect to the efficacy of the regimen. The present study indicates that topotecan with cisplatin on day 5 is tolerated in approximately double the recommended dose for topotecan when given in combination with cisplatin on day 1 in chemotherapy-naive

835 References

Received 28 February 2000; accepted 22 May 2000.

Correspondence to: Dr M. Sorensen The Finsen Centre Rigshospitalet 9, Blegdamsvej DK-2100 Copenhagen O Denmark E-mail: [email protected]

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