Paclitaxel (Taxol) in heavily pretreated ovarian cancer: Antitumor activity and complications

Annals of Oncology 5: 827-833, 1994. O 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Paclitaxel (Taxol) in heavily pretreated ovarian cancer: Antitumor activity and complications

University of Southern California, Los Angeles, CA, U.SA. Summary

tients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia Objective: To analyze the efficacy and toxicity of Taxol in and its complications occurred primarily during the first two patients with ovarian cancer who had failed at least two pre- cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a vious chemotherapy treatment regimens. Patients and methods: Sixty-eight patients with advanced higher incidence than in prior series. pretreated ovarian cancer, with either measurable or evaluConclusions: Taxol as a single agent has modest activity in able disease who were shown to have disease progression heavily pretreated ovarian cancer patients but appears to be were entered on a National Cancer Institute sponsored 'com- useful and is subjectively well tolerated by many. The high passionate' treatment referral center protocol and received incidence of infection in comparison with other series of intravenous infusion of Taxol over 24 hours 135 mg/m2, patients with ovarian cancer treated with chemotherapy sug(after steroid-containing premedication) repeated every 3 gests this pretreated patient population has enhanced susweeks and continued while showing no evidence of progres- ceptibility to develop complications from neutropenia. Safer sion. treatment in this advanced setting should include more agResults: Of the 68 patients enrolled, 10 patients (15%) gressive use of cytokines and/or less myelosuppressive regihad a partial response and one assessable by marker only mens (e.g. shorter Taxol infusions). had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 Key words: chemotherapy complications, ovarian cancer, patients with elevated baseline CA-125s. Twenty-seven pa- taxol

Introduction

The task of improving the outlook of advanced ovarian cancer and identifying new active agents in this disease during the past decade has been challenging. Cisplatinor carboplatin-based chemotherapies used widely since 1980 in newly diagnosed patients have yielded overall major response rates around 80% with median time free from progression of disease (progression-free survival) exceeding 1 year. However, after relapse, few drugs surpass the modest activity of platinum for retreatment. For example, the Gynecologic Oncology Group (GOG) has tested a large number of drugs during the past two decades, and only ifosfamide and paclitaxel (Taxol) have had moderate activity after such platinum-based chemotherapy [1]. In the landmark GOG phase II study of Taxol, responses were reported in both platinum-refractory and platinum-sensitive patients [2] who had only received one prior regimen. Moreover, the responses were achieved with reason-

ably subjective tolerance. We report here the response and complications in a much more heavily pretreated population with platinum-resistant ovarian cancer. The study was part of the Treatment Referral Center (TRC) protocol sponsored by the National Cancer Institute (NCI) to permit patients with advanced pretreated ovarian cancer to receive Taxol, while awaiting its approval by the Food and Drug Administration. This country-wide 'compassionate' experience was published in the Journal of Clinical Oncology in December of 1993 [3]. The analysis of 1000 patients showed 4% complete responses (CRs) and 18% partial responses (PRs) for an overall objective response rate of 22%. Fifty-four percent had stable disease and 24% had disease progression. The main toxicity was neutropenia and fever occurring in 33% [3], with infections being documented in some. We are now reporting our own experience with special emphasis on analysis of factors which may have predisposed to response as well as treatment complications.

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B. Uziely, S. Groshen, S. Jeffers, M. Morris, C. Russell, L. Roman, L. Muderspach & F. Muggia

828 Material and methods

Eligibility

To be eligible for the study patients had to have had histologically documented epithelial ovarian cancer, and have failed at least three (up to July 1992) and subsequently at least two prior chemotherapy regimens (from August 1992 through December 1992). Resistance to platinum compounds (i.e., growth during or treatment failure within 6 months of platinum-containing regimens) was a prerequisite. Eligibility allowed for entry of patients with performance status 3 by ECOG scale (or Karnofsky 40) or better. Prior to entry, all patients had a complete history and physical examination with documentation of clinical sites of disease. Initial laboratory data included CBC, serum electrolytes, glucose, creatinine, total protein, albumin, phosphorus, bilirubin, SGOT, SGPT, and CA-125 levels. Baseline chest X-ray, ECG, and abdominal pelvic computerized tomography (CT) scans or magnetic resonance imaging (MRI) were also performed within two weeks of treatment Patients with potential cardiac risk factors such as myocardial infarction within the past 6 months, angina pectoris, congestive heart failure, or evidence of a cardiac conduction defect were excluded. Patients taking medications known to affect the cardiac conduction system (beta-blockers, digoxin, calcium channel blockers) were also initially excluded, but subsequently allowed after discussion with the study coordinator (FM). Taxol was supplied by the National Cancer Institute and administered at a dose of 135 mg/m2 as a 24-hour infusion repeated every 21 days. All patients were premedicated in cycle 1 as previously described, but in those with steroid-related side effects, dexamethasone was reduced by 8 mg decrements to a minimum of 4 mg per dose (total 8 mg) as long as no hypersensitivity reactions were documented [5]. Treatment continued until progression or unacceptable side effects. All laboratory studies and a physical examination were performed prior to each treatment, whereas the blood counts were repeated weekly. For patients with measurable or evaluable tumor, formal documentation of disease response was required at three months after start of the Taxol and every three months thereafter, additional x-rays, scans and/or MRIs were performed as needed to document the duration of response. For patients with measurable disease, a complete response (CR) was defined as complete disappearance of all evidence of tumor and return of abnormal tests to normal for a minimum of 4 weeks. Partial response (PR) was defined as a decrease of at least 50% in the sum of the products of the perpendicular diameters of all measured lesions, without appearance of new lesions or increase in evaluable lesions or markers for a minimum of 4 weeks. Patients with stable disease (SD) had changes in measurable disease that did not meet the criteria for partial response, and no new lesions for a minimum of 4 weeks after the first reassessment at 2 months; and no appearance of new lesions. For patients with evaluable disease, a PR was

Statistical methods Toxicity and response to Taxol were summarized by constructing tables with numbers and percents. The response rate was estimated as the percent of patients experiencing a partial response or improvement All patients were evaluable for toxicity; and all but three patients were assessable for disease response. The three patients not assessable for response died prior to receiving a second course of Taxol: two due to toxicity and one due to tumor-related metabolic complications secondary to bulky disease and intestinal obstruction. One other patient was taken off-study prior to the second course of Taxol because of progressive disease; she was counted as a 'progression'. Exact binomial confidence intervals were constructed for the response rate (6] the demoninator used was 68. Responders and non-responders were compared using the Wilcoxon test for continuous baseline variables and the Pearson's chi-square test for categorical baseline variables (or Fisher's exact test, if the expected number of observations per cell was small). Stepwise exact logistic regression was used for multivariate analysis [7). The probability of progression and of surviving after start of Taxol was estimated using the product-limit Kaplan-Meier method [8, Section 3.2). All p-values reported are two-sided. To compare the survival of patients with PR, I, or SD to those who did not respond to treatment, the landmark method was used [9]. The survival of all patients alive and responding at 3 months was compared to the survival of those patients who had progressed prior to three months. Survival was measured from 3 months after start of Taxol; the logrank test was used to compare the survival of the three groups. A significant difference between two survival curves would not necessarily imply a cause-and-effect relationship (i.e. that Taxol has prolonged the life of the responding and stable patients) but would reinforce the conclusion that after three months, such responses or stability might be associated with prolonged survival.

Results Sixty-eight patients were entered on this study. Patients characteristics are shown on Table 1. The one patient receiving 9 prior regimens has a 10-year history of endodermal sinus tumor of the ovary and multiple

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This trial of Taxol for recurrent or persistent ovarian cancer was initiated as part of the NCI-TRC protocol, patients were to be treated with Taxol 135 mg/m2 as a 24-hour infusion after premedication with dexamethasone 20 mg, 12 and 6 hours before, and dephenhydramine 50 mg and cimetidine 300 mg, just prior to Taxol. All patients were hospitalized at the Norris Cancer Center and monitored continuously for cardiac arrhythmias during cycle 1. Following an episode of febrile neutropenia, the same dose was given, but G-CSF (5 (ig/kg) was started prophylactically on day 2 and continued until the granulocyte counts was >2000/uL. Dose adjustment to 110 mg/m2 was mandated whenever grade 3 or 4 neutropenia occurred in spite of G-CSF prophylaxis neutropenia. [NCI toxicity criteria [4]]. Dose reduction was also mandated for grade 3 or 4 thrombocytopenia and, grade 3 and 4 non-hematologjc toxicities, such as neuropathy. The trial was initiated in September 1991 and the last patient in our institution was enrolled in December 1992 after an accrual of 68 patients.

defined as a definite improvement in evaluable malignant disease estimated to be in excess of 50%, lasting at least four weeks and agreed upon by two independent investigators (FM & BU). For patients with disease measured by CA-125, improvement (I) was defined as a decrease of the serum marker (CA-125) to at least 50% of the starting value for a minimum of 4 weeks while not exhibiting either objective progression or subjective deterioration. In evaluable disease, stable disease was defined as no significant changes and no increase in size of any known malignant disease, and no appearance of new lesions. Development of any new site of disease, an increase of more than 25% in the sum of the products of the diameters of measured lesions or increase in any evaluable disease, constituted progression (PD). Patients were to go off study when criteria of progression were met Duration of response was defined from the date that the complete or partial response or improvement criteria were first met until the first documentation of clinical progression. The time to disease progression was the time from the first treatment until tumor progression was noted. Patients were to continue on Taxol treatment until disease progression or unacceptable toxicity. Patients who suffered from neutropenic fever within day 15 of treatment were treated with G-CSF during the following cycle. Beginning January 1993, patients who had been stable, had their dose escalated to 175 mg/m2. G-CSF (300 u.g) was added beginning on day 2 whenever these patients manifested febrile neutropenia or were neutropenic <500/mm 3 for more than 5 days.

829 Table 1. Patients characteristics. Age: Median - 5 8 years (Range: 35-75). Karnofsky Performance Status: Median - 80 (Range 40100). Median interval from diagnosis to study entry: 2.0 years, range (0.4-17.7 years). Feature

(%)

61

7

(90%) (81%) (4%) (1%) (3%) (10%)

B. Prior therapies Two chemotherapy regimens Three chemotherapy regimens More than three (4-9) Prior radiation Prior intraperitoneal therapy

9 22 37 15 28

(14%) (31%) (55%) (22%) (41%)

C. Prior treatment response Initial platinum sensitive Primary platinum resistant Inadequate information

55 9 4

(81%) (13%) (6%)

D. Site of involvement at start of Taxol Peritoneum Lymph nodes Ascites Liver Brain Palpable abdominal mass Palpable subcutaneous mass

46 29 13 24 3 17 10

(68%) (44%) (19%) (35%) (4%) (25%) (15%)

55 3 1 2

recurrences. A median number of 4 treatments reflects in part a large number entered into institutional intraperitoneal protocols and in part the initial requirement for patients to have received three or more prior regimens. Most patients who were referred had received two platinum containing regimens, and then 5-Fluorouracil + leucovorin or hexamethylmelamine. As of February 1994, 68 patients had received 1 to 30 courses of Taxol with a median of 5 courses. Four patients died during cycle 1: a clinical course suggestive of sepsis complicating two with neuropenia, and two (one with progression) following recovery from toxicity. Sixty-seven patients are off study and only 1 patient (with a minimally abnormal CA-125 and residual pleural thickening) is still receiving treatment on study as of September 1994. Two patients were removed from study because of toxicity, and five others for either practical considerations or for having achieved surgically documented CRs in two instances. Fourteen patients remain alive 8 to 24 months from on study. Fifty patients received four or more cycles and 34, six or more cycles of treatment with one patient still receiving drug after 30 cycles changing to a modified dose schedule of 175 mg/m2 3-hour infusion every four weeks in the past 6 months. Of the 68 patients enrolled, 38 patients had measurable disease, 27 patients had evaluable disease and 3 patients were not evaluable. There were no CRs; but in two patients the treatment with Taxol converted then-

Table 2. Disease outcome. Response

%

Months to progression

Partial response 5 Measurable 5 Evaluable 1 Improvement* 27 Stable disease

7 7 1 40

Progression

40

8.3,11.2,11.2,14.0,15.9 9.9, 17.5, 18.3, 18.9, 23.4+ 9.2 Median-6.0 months (26 pts. have eventually progressed — range 2-17.7 mo.) Median-2.1 months (range 1.1-8.9 mo.)b

Non-evaluable

# of pts

27 3

1

Marker assessment only (see text). Two patients with a mixed response were considered progressive disease but did not go immediately off study as prescribed. b

We evaluated the relation between response (PR, I versus SD, PD) and 33 pretreatment factors including age, interval from diagnosis, months from last laparotomy, last chemo, prior debulking, findings at last laparotomy, organ involvement(s), palpable abdominal/any masses, number of prior chemotherapy regimens, initial sensitivity to platinum therapy, pleural effusions, CA-125 and baseline laboratory tests. Only Karnofsky Performance Status (KPS) at baseline, lymph node involvement, palpable abdominal/any masses, baseline albumin, and baseline LDH had a p<0.10 and were subjected to stepwise exact logistic regression analysis. Only baseline KPS (p-0.009) and the presence of palpable masses (either in the abdomen or subcutaneously) (p-0.006) were still significant (Table 4). We realize that with the number of variables examined, some significant associations may be observed by random chance alone; and because of the relatively small numbers, some important associations could have been missed. Therefore, caution must be used in interpretation of these findings. Survival of the 68 patients is shown in Fig. 1: the median survival was 11.4 months for the overall group. For those on study after three months, the survival of patients responding to treatment (PR + I) was significantly better (p< 0.001) than the survival of patients who progressed while on treatment or compared to patients who had stable disease. The CA-125 was a marker for response for patients

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A. History Epithelial - Papillary - Endometroid - Clear cell - Unclassified Other or unknown

# of pts

disease from non-operable to operable and became CRs after a subsequent debulking operation. Ten patients (16%) had a partial response (5 measurable PR, 5 evaluable PR) and one had improvement of her disease on Taxol after failing multiple prior chemotherapies [95% confidence interval for both PR and I: 10% to 27%; and for PR alone: 8% to 25%]. The individual duration of these responses are listed in Table 2. One patient is maintaining a stable response 17.5 months from start of treatment. Twenty-seven patients were stable on Taxol treatment with median duration of 6.4 months. Twenty-seven patients progressed while on treatment.

830 Table 3. Disease response compared to CA-125 'response'.

68 Patients 53 Oe»d

CA-125 'response'1

Median Survival • 11.4 Month*

Elevated1 CA-125 at baseline (n - 46)

Normal CA125 b at baseline (n - 6) 3 0.60

2 0.25

0.00

0

2

4

6

8

10

12

14

16

18 20 22 24

26 28 30

Months From First Taxol Treatment

Fig. 1. Kaplan-Meier estimate of the probability of survival (in months) following start of Taxol treatment based on all 68 patients registered onto the study.

with elevated serum levels in whom no other measurable or evaluable disease was present. Table 3 shows the changes (or 'response') of CA-125 during Taxol treatment for all patients that were studied. In addition to patients with PR, patients with stable disease often showed declines in CA-125. Most of the hematologjcal toxicities during Taxol protocol were noticed during the first cycle (Table 5). Granulocytopenia was the predominant toxicity and was accompanied by fever in 28 patients (41%). Hospitalization for this complication took place in 23, whereas 30 received antibiotics. G-CSF was administered to a total of 35 patients during the first 2 cycles. Infections, none of which were fatal, were documented in 19 patients: of these, 7 patients had urinary tract infections (Escherichia coli, Klebsiella, p-Streptococcus, Gram-negative organism unidentified), 8 suffered from disseminated infections originating in venous access lines (Staphylococcus epidermidis, Enterobacter, Pseudomonas maltophilia, Klebsiella pneumonia,

Total

t by 50% or greater

Incr.

1 2 1

0 1 0

4 6 1

0 9 5

0 1 2

0 1 0

0 0 0

4 2 2

1 4 1

0 1 2

0

0

1

0

0

5

1

20

20

6

1

Excluded are 16 patients who were not evaluable for CA-125 'response' (13 of these progressed without additional determinations and 3 initially normal did not have repeat determinations). b < 35 units/ml. c 36-48,500 units/ml (Median: 423).

Table 4. Response (PR or I) according to baseline parameters. KPS

Palpable abdominal or subcutaneous mass

#Pts.

# Responders (%)

40-60

Yes No

6 11

0 0

70-80

Yes No

11 15

0 4 (27%)

90-100

Yes

6 16

0 7 (44%)

No

Table 5. Cycle 1 and cumulative toxicities. Type of side effect

Granulocytopenia Leukopenia Thrombocytopenia Alopecia Cardiac (Any) Bradycardia only Other arrhythmias Paresthesias Myalgia Stomatitis Fatigue Diarrhea Nausea and vomiting

Toxicity during cycle 1 ( n - 6 8 ) # of patients with grade 0

1

1 1 31 4 51 56 63 62 49 55 51 63 58

2 3 24 7 17 12 5 3 16 11 7 3 6

2 5 7 20 0 0 0 3 3 2 3 2 2

na — not available or not assessable. • Differential not done on 8 patients during cycle 1. b Pre-existing alopecia.

12 42 3 0 0 0 0

Overall worst toxicity (n-68) # of patients with grade

43 17 2 0 0 0

0

1

8" 0 1 37b

2 1 19 4 44 49 63 36 27 42 27 49 45

1 1 22 5 24 19

0 0 0

0 0 0 0

1

0

0 0

0 0 7

na

0 0 0 0

1

0

na 1 5 9 22 0 0 5

25 29 19 15

0

9 5 16

0 0

0 0

7 3 2 10 9 5

50 24 3 -

0 0

7 16

9 37 5 -

0 0 0 0 0

3 1

0 1

5' 0 1 37" 0 0 0 0 0 0 0 0 0

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Measurable disease PR Stable Progression Evaluable disease PR Stable Progression Marker evaluation only

I by Stable 50% or greater

Stayed normal

831

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lyzed our initial experience with this drug in a heavily pretreated population of patients with ovarian cancer. Our major objective response rate (PR + Improvement) was 16% which is less than expected according to previous phase II trials reported by McGuire [12], Thigpen [2] and Einzig [13] who showed 22%-30% objective responses. This response rate being just slightly lower to the overall response rate in the TRC study of 22% (4% CR and 18% PR), is not unexpected given our patient characteristics. Nevertheless, we did observe other suggestive evidence of benefit such as durable responses and survival benefit for patients responding, and those showing improvements in CA125. The patients who responded or those who had stable disease did better and lived significantly longer than patients who had no response. At the 3 month evaluation, the median survival of non-responders is 2.4 months; the median survival was 12.6 months for patients who had stable disease under Taxol therapy while for the patients who responded, the median survival after 24.5 months has not yet been reached. Einzig et al. [13] suggested a similar survival benefit for patients who responded. In our series the overall median survival is 11.4 months. It compares favorably the the TRC-103 study with an overall median survival of 9 months, and is consistent with the finding that patients with stable disease and response experienced prolonged survival [3]. The likelihood of response in our patients correlated with better performance status and lesser bulk of disease, this appears reasonable, but the number of variables examined could lead to some chance associations. Neutropenia is the principal dose limiting toxicity of Taxol and - as will be described - its incidence is closely related to schedule [14]. Other toxicities are peripheral neurotoxicity, myalgias, cardiac (bradycardia) [12, 15, 16] and total alopecia. Mucositis has been described with high doses in patients with leukemia [17]. Hypersensitivity reactions [18, 19] have not been a major problem since the introduction of routine premedication, even with the wide adoption of short infusion schedules. The optimal dose and schedule of Taxol remain to be determined. Responses in ovarian cancer have been observed over a broad range of doses including 135 Discussion mg/m2. A response rate of 50% was observed in preTaxol, an antimicrotubule agent, is a diterpene plant treated patients receiving Taxol 250 mg/m2 by 24-hour product derived from the needles and bark of the West- infusion with G-CSF [20]. Ongoing studies by the ern Yew, Taxus brevifolia. The drugs blocks cells in G2 GOG coupled with other groups under NCI sponsorand M phases of the cell cycle. It blocks the cell cycle ship are comparing different doses of Taxol and difby enhancing the rate and yield of microtubular assem- ferent schedules in patients with ovarian cancer. The bly and prevents microtubular depolymerization [10, National Cancer Institute of Canada (NCIC) and the Cancer Treatment Group (CTG) of Bristol-Myers 11]. Since 1990 Taxol has been known to be an effec- Squibb in Europe compared in a two by two factorial tive treatment for women failing their initial plati- design (to permit efficient testing of efficacy and safety) num-based chemotherapy for ovarian cancer [2]. two Taxol doses (135 mg/m2 versus 175 mg/m2) and However, detailed information about its overall impact two schedules (24- versus 3-hour infusions). The toxicon this disease, its spectrum of activity and toxicities ity data were presented at the second National Cancer is still wanting. We have, therefore, thoroughly ana- Institute Workshop on Taxol and Taxus; neutropenia Gram-negative organisms), 2 had peritoneal infections (Staphylococcus aureus, and one unidentified), one patient had sepn'cemia without specific origin, and one had a liver stump tube infected (Staphylococcus aureus). In addition, two patients died with neutropenic sepsis and no documented infection during cycle 1. Ten patients required transfusion of red blood cells because of increasing anemia. Patients who had no hematological toxicity during the first two cycles usually did not suffer from these side effects later in the course of the treatment. Other toxicities - stomatitis, cardiac toxicity, neurotoxicity, myalgias and other gastrointestinal symptoms - were generally mild. Paresthesias, myalgias, diarrhea and fatigue increased somewhat in incidence with additional courses. Vomiting was rare and in some instances clearly attributed to anticipatory conditioning from prior treatments, and it gradually improved during Taxol. We explored eleven predictors of toxicity (presence or absence of: central catheters, prior stem-cell depleting chemotherapies, prior radiation, prior liver involvement, pleural effusions, prior infections, prior IP therapy, and prior parenteral nutrition; baseline KPS, and the number of prior therapies <3, 4-9) and looked for associations with 7 toxicity related issues (antibiotics given, hospitalization, neutropenic fever, grade of neutropenia, grade of thrombocytopenia, grade of all nonhematologic toxicities, and the latter without alopecia). Five associations with p values <0.05 were documented: as expected antibiotic administration significantly related to central catheters and parenteral nutrition; hospitalizations related to KPS and parenteral nutrition, and non-hematologic toxicities excluding alopecia related to prior IP therapy. Surprisingly neither neutropenic fever, nor thrombocytopenia were predicted by any prior therapy or baseline characteristic. However, as with response, the numbers are small for firm conclusions in multivariate analyses; and the number of variables examined might lead to chance associations. In other words, there may be predictive factors for either response or toxicity but our sample size is too small for firm conclusions.

832

Undoubtedly, the 24-hour schedule contributed to the high incidence of neutropenic fever. The incidence of neutropenic fever in our study is greater than other Taxol studies cited above, and far exceeds the number documented in a retrospective review of patients with this disease treated with various drug regimens by one gynecologic oncology service [23]. In that review, 56 episodes of neutropenic fever from platinum-containing regimens, and 12 positive cultures for infection including one death were documented among 416 patients. The potential of G-CSF to avoid neutropenic complications was studied at the National Cancer Institute (NCI) [24] in a previously untreated population. The study showed that with G-CSF support Taxol doses of 250 mg/m2 24 hour infusion were safe and the neutropenia was brief. More recently, widespread use of 3 hour infusions have resulted in even fewer neutropenic events and complications [20, 25]. Since our study did indicate some benefit from Taxol in this pretreated patient cohort, what might be done to render such treatment safer? Use of cytokines, particularly under circumstances of considerable pretreatment could be considered. The shortened infusion schedules may avoid these complications and be associated with perhaps similar activity. Furthermore, identifying patients likely to respond in the future by their absence of p-glycoprotein overexpression in their tumors [26] may lead to better patient selection. On the other hand, since Taxol's future role is in combination with cisplatin as initial treatment of ovarian cancer, such treatment issues in a pretreated population will become less pressing. Efforts at continuing to treat patients with drug-

resistant solid tumors are periodically questioned as being futile. We did not formally assess quality of life, but clearly the responses achieved with relatively good subjective tolerance encouraged referral, enrollment and continued treatment. On the other hand, we observed that heavy pretreatment carried with it an enhanced risk of early complications. Only active programs with reasonable therapeutic indices are likely to benefit the population treated in this trial. Taxol appears to fulfill these requirements in patients with ovarian cancer already failing two or more therapies, but a reduction in the frequency of complications must be sought. Acknowledgements D. Deauna, MJD.; R Dikranian, Medical Student Supported in part by GRC 9103. PHS Grant CA14089. References 1. Thigpen JT, Vance RB, Khansur T. Second-line chemotherapy for recurrent carcinoma of the ovary. Cancer 1993; Suppl 71: 1559-64. 2. Thigpen T, Blessing J, Ball H et al. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinumbased chemotherapy: A Gynecologic Oncology Group Study. J Clin Oncol 1994; 12:1748-53. 3. Trimble EL, Adams JD, Vena D et al. Paclitaxel for platinumrefractory ovarian cancer Results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 1993; 11: 2405-10. 4. NCI, Investigator's Handbook, 1986. 5. Uziely B, Jeffers S, Muggia FM. Low doses of dexamethasone protect against paclitaxel (Taxol)-related hypersensitivity reactions following cycle 1. (Letter) Ann Oncol 1994; 5(5): 474. 6. Murty VN. Binomial and Poisson probabilities with an HP-28S scientific advanced calculator. J Appl Stat 1990; 17:411-5. 7. Hirji KF, Mehto CR, Pater NR Computing distributions for exact logistic regression. J Am Statist Assoc 1987; 82:1110-7. 8. Miller RG Jr. Survival Analysis. New York: John Wiley & Sons, Inc. 1981. 9. Anderson JR, Cain KC, Gelber RD et al. Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials. Cancer Treat Rep 1985; 69: 1139-44. 10. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature 1975; 22: 665-7. 11. Schiff PB, Horwitz SB. Taxol stablized microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 1980; 77:1561-5. 12. McGuire WP, Rowinsky EK, Rosenstein NB et al. Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273-9. 13. Einzig Al, Wiernik PH, Sasloff J et al. Phase II study and longterm follow-up of patients treated with Taxol for advanced ovarian adenocarcinoma. J Clin Oncol 1992; 10:1748-53. 14. Sarosy G, Kohn E, Stone EK et al. Phase I study and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 1992; 10:1165-70. 15. Lipton RB, Apfel SC, Dutcher JP et al. Taxol produces a predominantly sensory neuropathy. Neurology 1985; 39: 368-73. 16. Rowinsky EK, Burke PJ, Karp JE et al. Phase I and pharmacodynamic study of Taxol in refractory acute leukemias. Cancer Res 1989; 49: 4640-7.

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was more common and severe in the 24-hour arms and showed little relation to dose [21]. Consistent with this, febrile neutropenia was noted only in the 24-hour arms. On the other hand, distal peripheral neuropathy appears dose-related and has been a prominent manifestation in subsequent dose-escalation trials [22]. With Taxol, at the dose level employed in our study, non-hematologic toxicities such as cardiac, neurologic, and gastrointestinal in origin were not a problem. Hypersensitivity reactions even with reduction in the amount of dexamethasone were rare and mild. The major toxicity observed in our patients was leukopenia and this resulted in complications and hospitalization during the first 2 cycles. Forty-one percent of our patients manifested neutropenic fever with 28% having a proven infection. The substantial number of episodes of infection and sepsis with a positive culture requiring antibiotic treatment is likely contributed by a large group of heavily pretreated patients with central venous and peritoneal ports. In addition, there were 2 drug-related deaths, both during cycle 1. Complications were rare after these two cycles. We treated many patients for extended periods and 6 patients had 16 or more courses. These patients responded or had a stable disease for a long period of time without major side effects.

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