This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Articles by Baker, M. Search for Related Content PubMed PubMed Citation Articles by Markman, M. Articles by Baker, M. Social Bookmarking                            What's this?

Phase II Trial of Weekly Single-Agent Paclitaxel in Platinum/Paclitaxel-Refractory Ovarian Cancer

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We wished to critically examine the level of activity of weekly paclitaxel in a patient population with well-characterized platinum/paclitaxel-resistant (3-week schedule) ovarian cancer.

PATIENTS AND METHODS: Eligibility criteria for this phase II trial included the following: ovarian and fallopian tube cancers or primary carcinoma of the peritoneum; prior initial therapy with platinum/paclitaxel; and failure to respond to treatment (progression or stable disease as best response), or a response duration of less than 3 months, or if the response was more than 3 months, retreatment with both agents required and failure to respond a second time or the response duration was less than 3 months. Measurable or assessable disease (CA-125 response criteria) was required. Patients received weekly paclitaxel (80 mg/m²) until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment.

RESULTS: Fifty-three patients (52 assessable for toxicity and 51 for response) were entered onto this multi-institution trial. Of 248 total cycles (887 doses), only 13 (1%) were modified (dose reduction or treatment delay) because of side effects. Therapy was discontinued in five patients because of toxicity (four because of peripheral neuropathy, and one because of painful fingernail beds). Thirteen patients (25%; 95% confidence interval, 13.5% to 37.5%) achieved an objective response (four by CA-125 criteria, and nine by 50% reduction of measurable disease).

CONCLUSION: Weekly paclitaxel (80 mg/m²) is generally well tolerated and is an active second-line regimen against ovarian cancer that has demonstrated resistance to platinum/paclitaxel delivered on an every-3-week schedule.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PACLITAXEL IS RECOGNIZED as one of the most active cytotoxic agents in the treatment of ovarian cancer^1-3 and has been incorporated as a component of initial therapy of the malignancy.^4,5 Despite considerable clinical experience with paclitaxel in ovarian cancer, investigators continue to evaluate alternative methods of administering the drug to optimize its therapeutic potential.^6-10

As paclitaxel is known to be a cell-cycle–specific agent,^11,12 it has been suggested that increasing the duration of tumor exposure to the drug might enhance cytotoxicity. For example, a 24-hour paclitaxel infusion schedule has been shown to increase bone marrow toxicity, compared with a 3-hour delivery regimen.⁷

Thus, it is possible that the administration of paclitaxel in ovarian cancer on a weekly schedule, rather than the standard every-3-week schedule, might demonstrate greater tumor-cell kill. In one previously reported trial, a weekly paclitaxel (1-hour infusion) regimen produced objective tumor regressions in patients previously treated with paclitaxel on an every-3-week program.⁹

To explore further the potential for this more dose-dense weekly paclitaxel regimen in patients with ovarian cancer refractory to platinum and paclitaxel (3-week schedule), we initiated a phase II trial of the weekly administration of the agent in women with disease well defined clinically as being resistant to their prior chemotherapy program. We report here the results of this study.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Patients had to meet the following criteria to be eligible for entry onto this multi-institution, nonrandomized, phase II trial: (1) Histologic confirmation of epithelial ovarian cancer, primary carcinoma of the peritoneum, or fallopian tube cancer. (2) Patients must have received and not responded (progressive or stable disease as best response) to an initial chemotherapy regimen that included a platinum agent (cisplatin or carboplatin) and a taxane; or, if the patient had responded (complete or partial) to a platinum agent plus a taxane, the disease had recurred within 3 months of completion of therapy; or, if the patient had responded but progressed more than 3 months after completing therapy, the patient must have received at least one additional course of a platinum/taxane program and not responded, or recurred within 3 months of discontinuation of the second-line treatment program. (3) No other prior cytotoxic agents were permitted. (4) The patient’s prior taxane therapy must have been administered on a 3-week schedule. (5) Eastern Cooperative Oncology Group performance status 2. (6) Age 18 years. (7) Life expectancy 3 months. (8) Laboratory values must have been as follows: absolute neutrophil count 1,500/µL; platelet count 100,000/µL; total bilirubin 2.0 times institutional upper normal limit; serum creatinine 2.0 mg/dL; and serum AST or ALT 2.5 times institutional upper limit of normal. (9) Disease must have been measurable or assessable. Assessable disease for entry onto this trial was defined by CA-125 criteria as follows: The minimum CA-125 level at the time of entry must have been more than 70 U/mL. This CA-125 level must have at least doubled from a baseline determination to demonstrate evidence of disease progression from a previous treatment regimen (with the value having been confirmed by at least two separate blood samples obtained 4 weeks apart or other clinical evidence of progressive disease). (10) Patients were also required to sign an informed consent statement indicating they understood the experimental nature of this treatment program.

Patients were ineligible for entry onto this study for any of the following indications: (1) Major surgery 3 weeks before study entry. (2) Radiotherapy 3 weeks before study entry or radiotherapy to more than 30% of the bone marrow. (3) Treatment with chemotherapy, hormonal therapy, or immunotherapy 3 weeks before study entry. (4) New York Heart Association class III or IV heart disease. (5) History of serious cardiac disease not adequately controlled: documented myocardial infarction within 6 months preceding enrollment onto the study, congestive heart failure, unstable angina, clinically significant pericardial effusion or arrhythmia. (6) An active serious infection or serious underlying medical condition that would otherwise impair the ability to receive protocol treatment, including prior significant allergic reactions to drugs containing Cremophor. (7) Existing peripheral neuropathy of any cause more than grade 1.

Treatment Regimen
Patients were to receive paclitaxel 80 mg/m² intravenously in 250 mL normal saline over 1 hour every 7 days. One cycle consisted of 4 weeks of therapy. Treatment was to be given on an outpatient basis unless hospitalization was required for other indications. The dose of paclitaxel was to be calculated on actual weight at the first dose of each cycle. Doses were rounded to the nearest 5 mg.

Standard prophylaxis for paclitaxel-associated hypersensitivity reactions were used, with only a single dose of dexamethasone administered 30 to 60 minutes before each paclitaxel treatment. Although the initial protocol design called for dexamethasone to be administered at a dose of 20 mg, this was subsequently reduced to a dose of 10 mg with each treatment.

Palliative and supportive care for disease-related symptoms was offered to all patients on the study. The requirement for radiation therapy while the patient was on study was considered evidence of disease progression and the patient was removed from the trial.

Treatment with weekly paclitaxel was to continue in patients experiencing an objective response (complete or partial), or those with stable disease, until evidence of disease progression or unacceptable toxicity. Patients experiencing intolerable toxicity at any time point during the trial were to be removed from the treatment program.

Dose Modifications
The dose of paclitaxel was reduced one level (to 70 mg/m²) for the following indications: (1) on the day of treatment, absolute neutrophil count 800/µL or platelet count 50,000/µL; (2) grade 2 motor or sensory neuropathy; or (3) any other toxicity grade 2. If, after the initial dose reduction, the patient continued to experience unacceptable toxicity (as defined above), subsequent weekly paclitaxel treatments were administered at a dose of 60 mg/m².

Treatment was to be held for patients experiencing these toxicities until they had recovered to a level where treatment was permitted. If therapy had to be delayed for more than 2 weeks, the patient was to be removed from the study.

The use of bone marrow colony-stimulating factors was discouraged on this protocol. In cases of myelotoxicity, dose reduction was performed. However, if a patient experienced severe (grade 4) bone marrow suppression, use of a bone marrow colony-stimulating factor was permitted for the individual event.

Evaluation During the Study
Patients had a complete blood count, platelet count, and toxicity assessment performed before each dose of paclitaxel. At the end of each 4-week cycle, a CA-125 level was to be determined. Tumor measurements in patients with measurable disease were to be obtained every three cycles. After 1 year of therapy, measurements were to be evaluated every 6 months. In an individual who experienced an objective response to treatment, tumor measurements were repeated after 4 weeks to confirm the response. Information regarding the status of patients was obtained every 3 months until death or they were lost to follow-up.

Criteria for Response

Measurable disease: tumor measurable in two dimensions by physical examination or radiographic investigations and the tumor is at least 1 x 1 cm.

Complete response: disappearance of all clinical evidence of tumor, determined by two observations not less than 4 weeks apart.

Partial response: 50% or greater decrease in the sum of the products of measured lesions compared with baseline, determined by two observations not less than 4 weeks apart. No simultaneous increase ( 25%) in the size of any lesion or the appearance of a new lesion could occur. Nonmeasurable lesions had to remain stable or regress for this category.

Stable disease: no significant change in disease status for at least 4 weeks. A lesion could show a less than 50% decrease in the sum of the products of measured lesions or an increase of less than 25%. There could be no new lesions for the patient to be considered to have stable disease.

Progressive disease: a 25% increase in the area of any malignant lesion greater than 2 cm² or in the sum of the products of the individual lesions in a given organ site. If only one lesion was available for measurement, a 50% increase in size if the areas of the lesion was 2 cm². Appearance of new lesions also constituted progressive disease. Comparison of tumor size was made with the previous smallest measurement in patients who had attained a partial response or unconfirmed partial response or with baseline measurements in patients with stable disease or progressive disease. Tumor progression was also defined as significant clinical deterioration that could not be attributed to treatment or other medical conditions.

CA-125
A 75% response occurred when there had been a serial decrease of serum CA-125 over three samples of more than 75%. In each case, the subsequent sample had to have been 28 days after the previous sample.^13,14

For progressive disease, the serum CA-125 level must have been at least 70 U/mL and have doubled from the previous value. This had to be repeated 28 days later and have met the same criteria. The date of progression was the date of the level confirming the doubling of the CA-125 value and at least 70 U/mL. The occurrence of a new pleural effusion or ascites was also considered progressive disease if substantiated by positive cytology.

Patients were required to have completed at least one scheduled evaluation of their disease (excluding baseline) to be considered assessable for response. Patients removed from study before this time point were not considered assessable for response unless there was clear evidence of disease progression.

Study Quality Control
An independent radiology review was conducted of all patients where an objective response of measurable disease was claimed on the basis of the results of abdominal/pelvic computed tomographic (CT) scan findings. Theradex (Princeton, NJ) collected patient and treatment information from the sites participating in the multi-institution study and provided data management quality control.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
A total of 53 patients were entered onto this multi-institution phase II trial. Characteristics of the patient population are listed in Table 1.

In general, the treatment regimen was reasonably well tolerated (Table 2). Only five patients discontinued therapy because of toxicity (four because of peripheral neuropathy, and one because of painful fingernail beds).

Responses
A total of 51 patients were assessable for response (one patient never received treatment on this protocol, and one patient had neither measurable nor assessable disease). Of the 15 patients whose only evaluation was by CA-125 criteria, four (27%) achieved at least a 75% decline in this tumor marker. Of the 36 patients with measurable disease, nine (25%) experienced an objective response (one complete response and eight partial responses). Seven of the nine responses were demonstrated by findings on CT scan. All seven responses were confirmed by independent radiographic review. Thus, the overall objective response rate (by measurable disease and CA-125 criteria) on this phase II trial was 25% (95% confidence interval [CI], 13.5% to 37.5%).

Of note, several additional patients achieved a decrease in the size of measurable mass lesions that would have been classified as partial responses, but a follow-up examination 4 weeks after the initial evidence of response (whether by CT scan or physical examination) was not performed. These individuals are considered to be nonresponders to the treatment protocol.

Table 3 outlines the relationship between observed responses (combining both measurable disease and CA-125 response criteria) and the patients’ prior treatment history. Of note, responses were observed in patients who had previously progressed, or failed to respond (ie, stable disease as best response) to initial platinum/paclitaxel (3-week regimen) chemotherapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this multi-institution phase II trial, we have demonstrated that the weekly administration of paclitaxel produces objective antitumor responses in patients with ovarian cancer and primary carcinoma of the peritoneum previously shown to be resistant to both a platinum agent and paclitaxel (delivered on an every-3-week schedule).

Furthermore, this report confirms the relative safety of this therapeutic strategy in individuals previously treated with paclitaxel and a platinum drug. Of note, only seven patients (13%) treated on this trial developed grade 2 to 4 peripheral neuropathy, with only five women (10%) forced to discontinue therapy because of excessive toxicity.

The overall objective response rate (measurable disease only or including CA-125 determinations) observed on this trial (25%) was surprisingly high for a population of individuals whose disease was more resistant than that included on most trials of second-line therapy of ovarian cancer. For example, in its phase II trials of new agents in platinum-resistant ovarian cancer, the Gynecologic Oncology Group will enter patients whose disease has recurred up to 6 months after the completion of initial chemotherapy,^2,15 in contrast to the more stringent 3-month time limit used in the current trial.

It is possible the overall response rate observed in this study was influenced by unrecognized favorable characteristics of the patient population. Thus, it will be important for other groups to attempt to confirm (or refute) the results of this trial. In addition, in the absence of data from well-designed randomized trials, it is inappropriate to conclude that this or any other second-line treatment strategy in platinum/paclitaxel-refractory ovarian cancer is superior to another with regard to its ability to improve disease-related symptoms and favorably impact progression-free or overall survival.

However, on the basis of the results of this relatively large multi-institution phase II trial, it is reasonable to conclude that single-agent weekly paclitaxel is a rational therapeutic option for women with platinum/paclitaxel-resistant (3-week schedule) ovarian cancer. For many patients, this approach will be appealing because of the ease of administration of the agent (1-hour weekly infusion) and their prior knowledge of, and experience with, the toxicity profile of paclitaxel. Conversely, for patients who must travel long distances to receive weekly treatment, or where prior paclitaxel-associated toxicity has been excessive (eg, peripheral neuropathy, severe treatment-related arthralgias), this strategy will be less attractive.

A precise mechanism to explain the level of activity of a weekly paclitaxel regimen in patients with ovarian cancer, or other malignancies, who have progressed on a less frequent paclitaxel dosing schedule remains to be defined. The observation may simply reflect the increased exposure of cycling (but nonresistant) cancer cells to the agent when it is delivered on a weekly program.

However, alternative explanations are certainly possible. For example, it has been shown in experimental systems that specific chemotherapeutic agents are capable of interfering with tumor growth and progression by disrupting the cancer’s blood supply (antiangiogenesis).¹⁶ If the weekly delivery of lower doses of paclitaxel exhibited greater interference with the process of angiogenesis than the less frequent every-3-week schedule, this could help to at least partially explain the results observed in this trial.

Finally, assuming the level of activity of weekly paclitaxel demonstrated in this study can be documented by others, it will be important to examine this dose-dense paclitaxel schedule as a component of initial chemotherapy of ovarian cancer (along with a platinum agent), to determine the impact of this approach on the response rate, progression-free survival, and overall survival in this clinical setting. An assessment of the superiority of a weekly paclitaxel regimen, compared with an every-3-week schedule, in the initial management of ovarian cancer will require an appropriately designed and conducted randomized trial.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273-279, 1989

2. Thigpen JT, Blessing JA, Ball H, et al: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group study. J Clin Oncol 12: 1748-1753, 1994[Abstract/Free Full Text]

3. Trimble EL, Adams JD, Vena D, et al: Paclitaxel for platinum-refractory ovarian cancer: Results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11: 2405-2410, 1993[Abstract/Free Full Text]

4. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334: 1-6, 1996[Abstract/Free Full Text]

5. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92: 699-708, 2000[Abstract/Free Full Text]

6. Arbuck SG: Paclitaxel: What schedule? What dose? J Clin Oncol 12: 233-236, 1994[Medline]

7. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High dose versus low-dose and long versus short infusion. J Clin Oncol 12: 2654-2666, 1994[Abstract/Free Full Text]

8. Markman M, Rose PG, Jones E, et al: Ninety-six hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens. J Clin Oncol 16: 1849-1851, 1998[Abstract]

9. Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187-192, 1997[Abstract/Free Full Text]

10. Markman M, Rowinsky E, Hakes T, et al: Phase I trial of intraperitoneal taxol: A Gynecologic Oncology Group study. J Clin Oncol 10: 1485-1491, 1992[Abstract/Free Full Text]

11. Rowinsky EK, Donehower RC, Jones RJ, et al: Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res 48: 4093-4100, 1988[Abstract/Free Full Text]

12. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 32: 235-242, 1993[CrossRef][Medline]

13. Rustin GJS, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 14: 1545-1551, 1996[Abstract/Free Full Text]

14. Bridgewater JA, Nelstrop AE, Rustin GJS, et al: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17: 501-508, 1999[Abstract/Free Full Text]

15. Markman M, Blessing JA, DeGeest K, et al: Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial. Gynecol Oncol 75: 444-446, 1999[CrossRef][Medline]

16. Browder T, Butterfield CE, Kraling BM, et al: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60: 1878-1886, 2000.[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				Q. Sun, C. Liu, H. Zhong, B. Zhong, H. Xu, W. Shen, and D. Wang Multi-center Phase II Trial of Weekly Paclitaxel Plus Cisplatin Combination Chemotherapy in Patients with Advanced Gastric and Gastro-esophageal Cancer Jpn. J. Clin. Oncol., April 1, 2009; 39(4): 237 - 243. [Abstract] [Full Text] [PDF]

				N. Penel, B. N. Bui, J.-O. Bay, D. Cupissol, I. Ray-Coquard, S. Piperno-Neumann, P. Kerbrat, C. Fournier, S. Taieb, M. Jimenez, et al. Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study J. Clin. Oncol., November 10, 2008; 26(32): 5269 - 5274. [Abstract] [Full Text] [PDF]

				M. Markman New, Expanded, and Modified Use of Approved Antineoplastic Agents in Ovarian Cancer Oncologist, February 1, 2007; 12(2): 186 - 190. [Abstract] [Full Text] [PDF]

				A. A. Kamat, T. J. Kim, C. N. Landen Jr., C. Lu, L. Y. Han, Y. G. Lin, W. M. Merritt, P. H. Thaker, D. M. Gershenson, F. Z. Bischoff, et al. Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer Cancer Res., January 1, 2007; 67(1): 281 - 288. [Abstract] [Full Text] [PDF]

				H. S Sano, J A. Waddell, D. A Solimando Jr, P. Doulaveris, and R. Myhand Study of the effect of standardized chemotherapy order forms on prescribing errors and anti-emetic cost Journal of Oncology Pharmacy Practice, March 1, 2005; 11(1): 21 - 30. [Abstract] [PDF]

				S. A. Cannistra Cancer of the Ovary N. Engl. J. Med., December 9, 2004; 351(24): 2519 - 2529. [Full Text] [PDF]

				T. J. Herzog Recurrent Ovarian Cancer: How Important Is It to Treat to Disease Progression? Clin. Cancer Res., November 15, 2004; 10(22): 7439 - 7449. [Abstract] [Full Text] [PDF]

				V. Hess, M. W. Verrill, C. C. Bomphray, M. M. Vaughan, M. Allen, and M. E. Gore Phase I study of carboplatin, doxorubicin and weekly paclitaxel in patients with advanced ovarian carcinoma Ann. Onc., April 1, 2003; 14(4): 638 - 642. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Articles by Baker, M. Search for Related Content PubMed PubMed Citation Articles by Markman, M. Articles by Baker, M. Social Bookmarking                            What's this?