Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: A Gynecologic Oncology Group study

Gregory P. Sutton, MD," John A. Blessing, PhD,b William P. McGuire, MD; Thomas Patton, MD,d and Katherine Y. Look, MD"

Indianapolis, Indiana, Baltimore, Maryland, Buffalo, New York, and Duarte, California

OBJECTIVE: Our objective was to determine the activity of ifosfamide and mesna in women with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy. STUDY DESIGN: This is a phase II drug study in which the starting dose of ifosfamide was 1.5 gm/m2

daily intravenously for 5 days. The starting dose of ifosfamide was reduced to 1.2 gm/m2 daily in patients who had received prior radiotherapy. The uroprotector mesna was given intravenously with, and at 4 and 8 hours after, the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. RESULTS: Fifty-six patients were placed in the study; 52 were evaluable for toxicity and 51 for response. Twenty-eight (54.9%) patients had previously undergone surgery and 46 (90.2%) had received radiotherapy before this trial. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in 7 (13.5%) patients, and 2 (3.9%) had grade 3 thrombocytopenia. Six (11.5%) patients had grade 3 or 4 neurotoxicity. Complete response was observed in 2 (3.9%) patients and partial responses in 6 (11.5%) patients, for a total response rate of 15.7% (95% confidence interval 7.02% to 28.59%). CONCLUSIONS: This response rate is higher than that reported by the Gynecologic Oncology Group in patients with previously treated squamous carcinoma of the cervix. Our findings fail to confirm that ifosfamide is a highly active agent in patients with squamous carcinoma of the cervix as reported by others; nonetheless, the observed activity of this drug deserves further study in combination therapy of squamous carcinoma of the cervix. (AM J OSSTET GVNECOL 1993;168:805-7.)

Key words: Ifosfamide, advanced or recurrent squamous carcinoma of the cervix

Previous studies conducted by the Gynecologic On­cology Group (GOG) have demonstrated the antineo­plastic effectiveness of ifosfamide in epithelial ovarian cancer, 1 mixed mesodermal tumors of the uterus,2 and uterine leiomyosarcomas." Coleman et at< and Mean­well et aI. 5 reported response rates of 40% and 33%,

From the Section of Gynecologic Oncology, a and the Department of Obstetrics and Gynecology,' Indiana University School of Medicine; the Gynecologic Oncology Group, Roswell Park Cancer Instituteb

; the Department of Oncology, Johns Hopkins Oncology Center'; and the Department of Gynecologic Oncology, City of Hope National Medical Center. d A complete list participating institutions is shown at the end of the article.

respectively, in patients with advanced or relapsed squa­mous carcinoma of the cervix who had never received chemotherapy and were treated with ifosfamide. How­ever, ifosfamide treatment resulted in partial responses in a disappointing 11.1 % of 27 patients with drug­resistant squamous cell carcinoma of the cervix in a recent GOG triaI.6 Our study was designed to determine the activity of ifosfamide given in a dose of 1.5 gm/m2 daily for 5 days in patients with squamous carcinoma of the cervix who had not received prior chemotherapy.

Supported by Walter Reed Army Medical Center (GA 23501), Georgetown University Hospital (GA 16938), University of Texas Health Science Center at Dallas (GA 28160), Indiana University Medical Center (GA 21720), University of California Medical Center at Irvine (GA 23765), Tufts New England Medical Center (GA 37569), and the Illinois Cancer Council (GA 27806). Received for publication June 15, 1992; revised September 10, 1992; accepted October 21, 1992. Reprint requests: GOG Administrative Office, Suite 1945, 1234 Market St., Philadelphia, PA 19107. 6/1/43666

Material and methods

Patients were entered into this GOG study from January 1988 to February 1990. All patients had squa­mous carcinoma of the cervix confirmed histologically by review of the Group Pathology Committee. Pa­tients were not candidates for curative therapy and were eligible for this study if they had not received chemotherapy and if their primary surgical therapy, radiation therapy, or both had failed. In addition, eligibility requirements included white blood cell

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806 Sutton et al.

Table I. Patient characteristics

Cases

Characteristics No. %

Age (yr) Median 45.0 Range 20-84

Performance status 0 17 33.3 1 21 41.2 2 13 25.5

Grade 1 3 5.9 2 31 60.8 3 17 33.3

Prior radiotherapy 46 90.2 Prior surgery 28 54.9 Courses

Median 3.0 Range 1-12

count ~ 3000/mm2, platelets ~ 100,000/mm", creati­

nine :s 2.0 mg/dl, bilirubin, serum glutamate oxaloace­tate transaminase (SGOT), and alkaline phosphatase :s 2 x upper normal limit, GOG performance grade of o to 2, one or more lesions measurable in perpendicu­lar diameters by physical examination or radiographic study, and :s 10 red blood cells per high-power field on pretreatment urinalysis. Informed consent was obtained from all patients before entry on study.

Pretreatment evaluation included assessment of per­formance grade, measurement of the indicator lesion or lesions, physical examination (including pelvic exami­nation), complete blood count and differential, serum electrolytes, bilirubin, serum glutamate oxaloacetate transaminase, alkaline phosphatase, creatinine, blood urea nitrogen, chest radiograph, and microscopic uri­nalysis. Complete blood count and differential was re­peated weekly and hematologic toxicity was based on nadir counts. The pretreatment evaluation was re­peated every 3 weeks with the exception of chest radio­graph (unless pulmonary metastases were present), and urinalysis was repeated daily in the initial portion of the study. Because microhematuria was rarely observed, this monitoring was later changed to a single urinalysis before each course of chemotherapy.

The inital dose of ifosfamide was 1.5 gm/m" daily for 5 days and the dose escalated by 0.3 gm/m2 increments if no toxicity was encountered. Mesna was given intra­venously in three doses daily. The first dose was given on completion of ifosfamide and the other two at 4 and 8 hours after ifosfamide administration. Each dose was 20% of the total daily dose of ifosfamide. Dose reduc­tion for grade 3 or 4 toxicity was carried out in 20% increments, with two such reductions being allowed before removal of the patient from study. Pretreatment hydration with 1 L of normal saline solution was

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encouraged; antiemetics were given at the discretion of the institutional investigator.

Because of evidence of activity in the first cohort of patients, accrual was extended to determine with accu­racy the activity of this agent.

Results

Fifty-six patients were entered in this trial. Two pa­tients were ineligible for the study (one had the wrong cell type, the other had the wrong primary site), and two were inevaluable (one with an inadequate trial of ther­apy, and the other with inadequate data). Fifty-two patients were evaluable for toxicity, and all but one of these were evaluable for response. Patient characteris­tics are detailed in Table I. A median of three courses of ifosfamide was administered (range I to 12 courses). All but five (90.2%) patients had prior pelvic radiotherapy, and 28 (54.9%) had had surgery.

Toxicity in this trial included grade 3 and 4 neutro­penia in 3 (5.8%) and 4 (7.7%) patients, respectively. The median nadir for 37 patients with leukopenia was l500/mm2 (range 200/mm" to 3300/mm"). Only 2 (3.8%) instances of grade 3 thrombocytopenia were observed. Other toxicity included 2 cases of grade 4 and 4 cases of grade 3 neurotoxicity. Only 3 (5.8%) patients experienced grade 3 gastrointestinal toxicity, and no patient had grade 3 or 4 nephrotoxicity. Alopecia was universal. Mucositis, phlebitis, and extravasation injury were not noted.

Two (3.9%) patients had complete responses to che­motherapy, with a median number of 9 courses to response (range 6 to 12 courses). Six (11.8%) patients had partial responses after receiving a median 4.5 courses of chemotherapy (range 2 to 8 courses). Median response duration was 14.1 + months (range 2.2 to 26.0+ months) for complete and 3.1 months (range 1.4 to 4.6 months) for partial responders, respectively. Complete responses were seen in pelvic sites in 2 patients; in the 6 patients with partial responses, 3 were seen in pelvic and 3 in extrapelvic sites. The 2 complete responders were GOG performance status 0 and 2; half of the partial responders were performance status 1, and 2 were performance status O. Both complete re­sponders had received radiotherapy and surgery, and all of the partial responders had received radiotherapy. Both patients with complete responses to therapy had grade 2 tumors; partial responders were equally divided between grades 2 and 3.

Comment

Ifosfamide administered over 5 days possesses activity in this group of patients with advanced squamous carcinoma of the cervix. The total response rate of 15.7% is less than that reported by other authors, however. In 1986 Coleman et al. 4 treated 41 patients

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with advanced carcinoma of the cervix with I.S gm/m" ifosfamide daily for S days every 3 weeks. Nine had received prior chemotherapy and three had nonsqua­mous histologic types. Response rates of 31 % and 40% were reported for all patients and for those who had not received previous chemotherapy, respectively. The me­dian time to response in this study was 12 weeks; the median response duration was > 20 weeks.

Meanwell et aI." used infusional ifosfamide (S gm/m2 per 24 hours) and mesna (9.2 gm/m" per 36 hours) to treat 30 patients with relapsed squamous carcinoma of the cervix. These authors reported one complete and nine partial responses (response rate 33%) with a median response duration of 6.S months for the partial responders. In addition, Cervellino et aI. 7

reported a SO% rate of response (S partial and 4 complete responses) among 18 patients with advanced cervical cancer.

The response rate in our present trial is low when compared with the rates discussed above. In addition, the mean performance status in our present study is relatively low; Bonomi et aI." demonstrated a very strong inverse correlation between performance status and response to cisplatin chemotherapy in patients with advanced cervical cancer.

Ifosfamide is an agent with activity in advanced or metastatic squamous carcinoma of the cervix that can be incorporated into combination therapy with other active drugs such as cisplatin. The GOG is presently conducting a phase III study to evaluate the combina­tion of ifosfamide and cisplatin and cisplatin and dibro­modulcitol in comparison with cisplatin alone in this patient population.

Sutton et al. 807

The following institutions participated in this study: Walter Reed Army Medical Center, Georgetown Uni­versity Hospital, University of Texas Health Science Center at Dallas, Indiana University Medical Center, State University of New York at Syracuse, University of California Medical Center at Irvine, Tufts New England Medical Center, Illinois Cancer Council, and The Johns Hopkins Oncology Center.

REFERENCES 1. Sutton GP, Blessing .lA, Homesley HD, Berman ML, Mal­

fetano J. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 1989;17:1672-7.

2. Sutton GP, Blessing .lA, Rosenshein N, Photopulos G, Di­Saia P. Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). AM J OBSTET GY:-IECOL 1989;161:309-12.

3. Sutton GP, Blessing JA, Barrett RJ, McGehee R. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. A\I J OBSTET GYNECOL 1992; 166:556-9.

4. Coleman RE, Harper PG, Gallagher C, et al. A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 1986;18:280-3.

5. Meanwell CA, Mould JJ, Blackledge G, et al. Phase II study of ifosfamide in cervical cancer. Cancer Treat Rep 1986; 70: 727-30.

6. Sutton GP, Blessing JA, Adcock L, Webster KD, DeEulis T. Phase II study of ifosfamide and mesna in patients with previously treated carcinoma of the cervix. Invest New Drug 1989;7:341-3.

7. Cervellino JC, Araujo CE, Pirisi C, et al. Ifosfamide and mesna at high doses for the treatment of cancer of the cervix: a GETLAC study. Cancer Chemother Pharmacol 1990;26:s1-s3.

8. Bonomi P, Brady M, Blessing J, et al. Prognostic factors related to response and to survival in women with advanced squamous cell carcinoma of the cervix treated with cis­platin. A Gynecologic Oncology Group trial. Proc Am Soc Clin Oncol 1988;29:824.