A phase II trial of three sequential doublets for the treatment of advanced müllerian malignancies☆

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Gynecologic Oncology 91 (2003) 293–298

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A phase II trial of three sequential doublets for the treatment of advanced mu¨llerian malignancies夞 U. Matulonis,a S. Campos,a L. Duska,b A. Fuller,b R. Berkowitz,c S. Gore,b M. Roche,d T. Colella, a H. Lee, a M.V. Seiden,d,* representing members of the Gynecologic Oncology Research Program at Dana Farber/Partners Cancer Care and the Dana Farber–Harvard Cancer Center a

Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA Division of Gynecologic Oncology, Massachusetts General Hospital, Boston, MA 02114, USA c Division of Gynecologic Oncology, Brigham and Women’s Hospital, Boston, MA 02115, USA d Division of Medical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA

b

Received 25 September 2002

Abstract Objective. In an effort to improve the results of primary chemotherapy for mu¨llerian malignancies a novel chemotherapy program was piloted that delivered three sequential chemotherapy doublets. The primary endpoints were surgically defined response rates and evaluation of toxicity. Methods. After primary cytoreductive surgery patients were treated with three sequential doublets including three initial cycles of carboplatin and paclitaxel (doublet 1) and then two cycles of cisplatin (day 1) and gemcitabine (days 1 and 8; doublet 2), and finally two cycles of doxorubicin (day 1) and topotecan (days 3,4, and 5; doublet 3). Cycles 4 through 7 were given with G-CSF (Neupogen) support at a dose of 5 mcg/kg/day. After therapy, all women were clinically staged and evaluated by second-look laparoscopy/laparotomy (SLO) if clinical staging was negative for residual disease. Results. A total of 49 eligible patients were enrolled with a median age of 52 (SD 9). Forty-four women had either ovarian cancer or primary peritoneal carcinoma with 3 women diagnosed with fallopian tube carcinoma and 2 with papillary serous carcinoma of the uterus. Eighty-four percent of patients had stage IIIc/IV tumors, with 29% having ⬎1 cm residual disease after primary cytoreductive surgery. Thirty-nine of 49 (80%) patients completed therapy. A total of 283 cycles of chemotherapy were delivered with acceptable toxicities. There were no toxic deaths. Five women were withdrawn from trial (3 for Taxol hypersensitivity, 1 for gemcitabine pulmonary hypersensitivity, and 1 for serious line infection). Neutropenia, typically without fever, was relatively frequent in the first doublet. Nausea and thrombocytopenia were the predominant toxicities in doublet 2. Thirty-nine women completed all cycles of treatment. Thirty-six women had restaging results consistent with a clinical complete response (CR) and underwent SLO. The pathologic CR rate of the patients undergoing SLO was 38%. Conclusions. Treatment with this sequential doublet regimen is feasible with a 38% pathologic CR rate. © 2003 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Topotecan; Gemcitabine; Adriamycin; Paclitaxel; Cisplatin; Neupogen treatment

Introduction Ovarian cancer remains the most lethal of gynecologic malignancies. Typically, patients present with advanced in夞 Funding provided by Eli Lilly Pharmaceutical Company and Amgen. * Corresponding author. Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, MA 02114, USA. Fax: ⫹1-617-724-3166. E-mail address: [email protected] (M. Seiden). 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0090-8258(03)00496-7

traperitoneal disease. While current surgical and chemotherapeutic techniques are effective at cytoreducing the tumor and palliating intraabdominal symptoms, the vast majority of these women eventually relapse and die of chemotherapy-resistant tumor [1]. A newer approach for the treatment of this malignancy is needed. Current standard therapy for newly diagnosed epithelial ovarian cancer is the combination of carboplatin with pac-

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litaxel [2,3] although several other agents demonstrate activity in this disease and are safe in combination with platinum agents. Recently, gemcitabine and topotecan have demonstrated activity in recurrent epithelial ovarian cancer that has been defined as resistant to platinum and paclitaxel [4 –7]. Furthermore, the combination of gemcitabine with platinum has demonstrated activity in epithelial ovarian cancer and currently is being evaluated in the treatment of women with both recurrent and newly diagnosed ovarian epithelial ovarian cancer [8,9]. Finally, the combination of topotecan, a topoisomerase I inhibitor, with Adriamycin, a topoisomerase II inhibitor, allows the potential for synergy in women with platinum/Taxol-resistant tumors [10 –12]. In an attempt to maximize tumor cytoreduction with a goal of improving remission rates and potentially long-term survival, we piloted the administration of three sequential doublets to women with high-risk mu¨ llerian malignancies in a phase II trial. Initial therapy included standard paclitaxel and carboplatin with the second doublet of gemcitabine and cisplatin. Finally, the third doublet combined topotecan and Adriamycin extending from a phase I trial that demonstrated both clinical activity and acceptable tolerability [12]. Specific aims of the study included evaluating both the efficacy and the toxicity of this treatment regimen. To refine response information all patients demonstrating an excellent clinical response were restaged surgically at the conclusion of therapy.

Table 1 Schedule and doses of triple doublets Doublet 1—three cycles, each cycle 21 days Taxol Carboplatin

175 mg/m2 AUC ⫽ 5

IV IV

3h 1h

Day 1 Day 1

Doublet 2—two cycles, each cycle 21 days Gemcitabine Cisplatin G-CSF

1250 mg/m2 75 mg/m2 5 ␮g/kg

IV IV SQ

60 min 60 min

Days 1 and 8 Day 1 Days 9–18

Doublet 3-two cycles, each cycle 21 days Adriamycin Topotecan G-CSF

25 mg/m2 1.75 mg/m2 5 ␮g/kg

IV IV SC

10 min 30 min

Day 1 Days 3, 4, and 5 Days 6–15

near normal bone marrow, hepatic, and renal function were also required. Exclusion criteria included a history of prior chemotherapy for mu¨ llerian malignancy, ECOG performance status of 3 or 4, a history of recent myocardial infarction or congestive heart failure, or a concurrent invasive malignancy. Patients with concurrent endometrial carcinoma were eligible if their endometrial carcinoma was superficial or invaded less than 50% of the thickness of the myometrium. Treatment guidelines

Patients and methods This was a multi-institutional open-labeled phase II trial that was reviewed and approved by the Scientific Review Committee and Institutional Review Board (IRB)1 of the Dana Farber/Partners CancerCare (DF/PCC). The DF/PCC IRB has oversight responsibility for all cancer trials open at the Massachusetts General Hospital, Brigham and Women’s Hospital, and the Dana Farber Cancer Institute. Patients Eligible patients had a newly diagnosed mu¨ llerian malignancy including epithelial ovarian carcinoma, fallopian tube cancer, primary peritoneal carcinoma, or other tumors of mu¨ llerian origin such as papillary serous carcinoma of the endometrium. All patients must have undergone an attempt at aggressive surgical debulking. Patients with surgically defined stage II, III, or IV disease who were debulked to have no evidence of disease, microscopic disease, or gross residual disease were all eligible. In addition, patients were required to consent to second-look staging laparotomy and provide written informed consent. Normal or 1 Abbreviations used: CR, complete response; DF/PCC, Dana Farber/ Partners CancerCare; G-CSF, Granulocyte colony stimulating factor; IRB, institutional review board; SLO, second-look operation.

Table 1 reviews the treatment schedule and drug doses for the sequential doublets. All cycles were planned to be 21 days in duration. Patients who achieved ⱖ1000 neutrophils/ mm3 and ⱖ100,000 platelets/mm3 at the planned start of the next cycle received full doses of the chemotherapy. During cycles 2–3, patients with 60,000 –99,000 platelets on day 21 received carboplatin at an AUC of 4, while patients who had experienced either fever during a period of neutropenia or a neutrophil count of 750 –999/mm3 on day 21 had Neupogen added to subsequent cycles at a dose of 5 mcg/kg rounded to the nearest vial size. For cycles 4 and 5, the gemcitabine dose was reduced to 800 mg/m2 on day 1 or 8 if platelet counts were between 60,000 and 99,000/ mm3 or the neutrophil count was 500 to 999/mm3. On day 8 gemcitabine was held if platelets were below 60,000/ mm3 or neutrophils were below 500/ mm3. For cycles 6 and 7, the topotecan dose was reduced to 1.25 mg/m2 for days 3 through 5 and Adriamycin to 22.5/m2 for day 1 if the platelet count was between 60,000 and 99,000/ mm3. For a neutrophil count of 500 to 999/mm3 topotecan was delivered at 1.5 mg/ m2 and Adriamycin at 22.5 mg/ m2. If grade 2 mucositis occurred during cycle 6 then Adriamycin was reduced to 22.5 mg/ m2 for the final cycle. Final evaluation of clinical response was performed approximately 3 weeks after the seventh cycle of chemotherapy. Second-look laparoscopy/laparotomy was scheduled

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between 4 and 8 weeks from the last cycle of therapy. Reassessment laparoscopy/laparotomy was to conform to the standards described by the Gynecologic Oncology Group [13]. Laparoscopic evaluation of the peritoneal cavity was acceptable as a second-look procedure if histologically confirmed persistent disease was confirmed by biopsy. If no disease was discovered by laparoscopy then conversion of the procedure to exploratory laparotomy was required.

Table 2 Patient characteristics Age (median) Primary tumor site Ovary Primary peritoneum Fallopian tube Uterine papillary serous Grade Well differentiated Moderately differentiated Poorly differentiated Histology Serous Endometrioid Clear cell Other/mixed Initial stage Stage IIIC Stage IV Stage II Stage III A/B Ascites present Yes No Extend of postdebulking diseasea Microscopic ⬍1 cm ⬎1 cm

Response definitions Pathologic complete response (PCR) required the absence of tumor on exam, CXR, and a normal laparotomydirected inspection of the peritoneal cavity. Patients with a PCR were required to have negative biopsies and cytology. Patients with only microscopic foci of tumor on directed or blind biopsies or alternatively on peritoneal wash were considered as having microscopically positive responses. Statistical consideration The trial was designed to include 40 patients evaluable for response by laparotomy and perhaps a few additional patients who would be evaluable for toxicity. The study had a one-stage design. Patients with either a microscopically positive or a pathologic negative SLO were considered to have had positive responses. The regimen was to be deemed worthy of further study if at least 25 positive responses were observed in the 40 patients. This figure was derived with the a priori assumption that 66% of patients entered onto the trial would have had optimal cytoreduction.

Results Fifty-one women were accrued to the trial between March 1999 and March 2001. Two women were in ineligible; 1 woman proved to have colon cancer metastatic to an ovary and was removed after cycle 1 and a second women was found on final review to have stage I ovarian cancer. Table 2 provides the patients’ characteristics. The median age on the trial was 52 years, with approximately 90% of patients having ovarian cancer or primary peritoneal tumor. Approximately 75% of women had high-grade tumors and papillary serous histology. In general most women presented with high-risk disease with 42 of 49 (86%) women presenting with stage IIIC/IV disease. Final residual tumor after surgical debulking was categorized into no visible disease (microscopic or NED), ⬍1 cm residual disease, and ⬎1 cm residual disease and was 31, 40, and 29%, respectively. Fig. 1 highlights the outcome of the 49 women started on the triple doublet therapy. Thirty-nine of 49 (80%) women completed therapy. Five women came off early for toxicity including 3 women with paclitaxel hypersensitivity on cycle

295

a

52 34 10 3 2 3 9 37 36 5 1 7 33 9 5 2 37 12 15 19 14

One case not available.

1 who were excluded from further analysis. One woman developed gemcitabine pulmonary toxicity on cycle 4 and was withdrawn from the protocol and a second women developed a serious line infection and was withdrawn after cycle 6. These later 2 women are excluded from efficacy analysis (both are currently alive and 1 is without evidence of disease recurrence). Five women withdrew consent, 3 after Taxol and carboplatin and 2 after cycle 4. Including the 2 women who had “unacceptable” gastrointestinal toxicity at cycle 4, 7 of 49 could not complete the therapy secondary to toxicity. All 5 women who withdrew consent had a normal CA-125 at the time of discontinuing the trial. Forty-nine women had a total of 283 cycles of therapy. Detailed hematologic toxicity per doublet is reviewed in Table 3. Neutropenia was most severe in the first triplet (not Neupogen supported) and thrombocytopenia and gastrointestinal toxicity were most severe in doublet 2. Grade 3– 4 neutropenia rates were 58, 35, and 11% for doublets 1, 2, and 3, respectively, while rates for grade 3– 4 thrombocytopenia were 3, 45, and 38% for these doublets. There were 6 episodes of fever and neutropenia with 5, 0, and 1 episode in doublets 1, 2, and 3, respectively. This represented 4, 0, and 1% of cycles in each of the respective doublets. Grade 3– 4 nonhematologic toxicities, in general, occurred with less than a 10% incidence (reviewed in Table 4); however, gastrointestinal toxicity (nausea, vomiting, and anorexia) and fatigue were more frequent and at times severe with the cisplatin-containing doublet. Neuropathy in

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Fig. 1. Outcome of patients on triple doublets.

this treatment program, which included only 5 cycles of a platinum agent and 3 cycles of a taxane, was infrequent and not severe. Other toxicities included three deep venous thrombosis, two episodes of transient ischemic events (in a single patient), one renal stone complicated with abscess, one perirectal abscess, and two pelvic abscesses. One woman presented with hypotension, renal dysfunction, and gastrointestinal bleed in the setting of an acute bowel obstruction that required surgical exploration. There were no deaths on trial. Thirty-nine women were evaluable for response at the conclusion of the three doublets. No formal assessment of response was performed between doublets. CA-125 data were collected on each cycle and are reviewed in Table 5. CA-125 data demonstrate progressive drops in CA-125 with each doublet. At the conclusion of therapy, 3 women had

Table 4 Nonhematologic toxicities Toxicity

Grade 2

Grade 3

Grade 4

Doublet 1 (N ⫽ 138 cycles) Nausea Vomiting Anorexia Constipation Diarrhea Mucositis Neuropathy Myalgia Fatigue

10 4 5 9 6 1 4 6 15

1 2 1 3 3

1 2

1 1

Doublet 2 (N ⫽ 83 cycles) Table 3 Hematologic toxicities Toxicity

Grade 2

Grade 3

Grade 4

Doublet 1: cycles 1–3, n ⫽ 138 cycles Hemoglobin Neutrophils/granulocytes Platelets

25 10 1

2 25 3

0 33 0

Nausea Vomiting Anorexia Constipation Diarrhea Mucositis Neuropathy Myalgia Fatigue

57 28 10

7 22 37

1 13 8

Doublet 3: cycles 6–7, n ⫽ 79 cycles Hemoglobin Neutrophils/granulocytes Platelets

52 17 22

9 5 34

7 4 30

6 7 2 1

1

6

Doublet 3 (N ⫽ 79 cycles)

Doublet 2: c ycles 4–5, n ⫽ 83 cycles Hemoglobin Neutrophils/granulocytes Platelets

14 7 10 7 7

1 6 4

Note. Incidences of toxicity are stated as percentages. Total number of cycles evaluated includes 138 for doublet 1, 83 for doublet 2, and 79 for doublet 3.

Nausea Vomiting Anorexia Constipation Diarrhea Mucositis Neuropathy Myalgia Fatigue

4 3

1 1

8 4 3 1 11

1

Note. Incidences of toxicity are stated as percentages. Total number of cycles evaluated includes 138 for doublet 1, 83 for doublet 2, and 79 for doublet 3. Blank boxes represent 0%.

U. Matulonis et al. / Gynecologic Oncology 91 (2003) 293–298 Table 5 Mean and median CA-125 Timepoint

N

Mean

Median

On-study End of cycle 3 End of cycle 5 End of cycle 7

49 42 38 36

929 39 31 13

283 24 15 12

either progressive or residual disease and were not assessed surgically. Thirty-six women underwent surgical exploration of whom 15 women demonstrated a pathologic complete response (38%), with 6 additional women having a microscopically positive second look (15%). No specific treatment protocol was recommended for women with positive second looks and many of these women were treated with various protocols before evidence of disease progression and therefore progression-free survival data are not meaningful. Fig. 2 demonstrates current overall survival with 29 of 39 women alive with a median follow-up of 6 to 31 months as of June 2002. Eight of 15 women who had a pathologic complete response remain in first remission with a median follow-up of 35 months.

Discussion This study demonstrates that three sequential doublets incorporating six different active agents in epithelial ovarian cancer can be delivered with acceptable toxicity. Each of the doublets was based on a prior clinical trial that demonstrated activity of the doublet in ovarian epithelial malig-

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nancies. The final doublet, Adriamycin and topotecan, was added at the conclusion of five cycles of platinum-based therapy. This doublet combines a topoisomerase I and II toxin as previously defined in a phase I clinical trial that demonstrated both tolerability and activity in a wide variety of tumors including ovarian cancer [12]. Timing of the topotecan administration (48 h after Adriamycin delivery) was based on in vitro studies that demonstrated upregulation of topoisomerase I level in cell lines approximately 48 h after exposure to Adriamycin [10]. The seven-cycle triple doublet therapy was in general well tolerated with no unusual toxicities directly related to the administration of sequential doublets. Principal toxicities included myelosuppression and fatigue. Gastrointestinal toxicity and fatigue were most prominent and occasionally severe with cisplatin-based therapy in doublet 2 and neutropenia and fever were most common in the first three cycles (not Neupogen supported). Thrombocytopenia was most notable in doublet 2; however, there was no evidence of cumulative or refractory myelosuppression with this regimen. Since many patients had no measurable disease after primary debulking surgery, formal evaluation of clinical response in not feasible. Thirty-six of 39 women had no evidence of disease by noninvasive evaluation and were eligible for second-look surgery. The negative second-look rate was 38% in the women who completed therapy. Median survival has not yet been reached but will be in excess of 36 months. The 38% negative second-look rate compares favorably with several other large trials. For example, in GOG 111, women assigned to the Taxol/ cisplatin arm had a negative second-look rate of 25% [14]. Several other studies have

Fig. 2. Kaplan—Meier overall survival curve.

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reported negative second-look rates between 20 and 40% with a variety of platinum-based regimens [15–18]. Our 53% rate of negative second-look plus microscopic positive second-look also compares favorably to the 61% rate reported with the cisplatin, Taxol, cyclophosphamide regimen as described by investigators at the National Cancer Institute by Kohn and colleagues [19] but with much less neurotoxicity. The feasibility of a sequential doublet regimen has been described by Hoskins et al. including cisplatin and topotecan followed by a cisplatin and paclitaxel regimen [20]. This trial, done in chemotherapy-naive women with mu¨ llerian malignancies with high-risk features, paralleled the current study in many respects. There was no unusual or idiosyncratic toxicity associated with juxtaposing the two doublets. Clinical response rates were seen in 78% of patients although surgical restaging was not performed. Similar results were also reported by Gordon and colleagues with the carboplatin-containing sequential doublets [21]. Since the completion of this trial, gemcitabine and carboplatin regimens have been described with less gastrointestinal and systemic toxicity then the gemcitabine and cisplatin doublet. This has allowed modification of the triple doublet regimen [22,23]. This “modified” triple doublet regimen is currently under study as a phase II trial at our institutions. The potential utility of sequential doublet therapy requires direct comparison to the standard Taxol and carboplatin regimen. Such a trial is underway by the Gynecologic Oncology Group (GOG 182) [24].

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