A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: A Gynecologic Oncology Group study

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Gynecologic Oncology 107 (2007) 274 – 279 www.elsevier.com/locate/ygyno

A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: A Gynecologic Oncology Group study Peter G. Rose a,⁎, Koen DeGeest b , Scott McMeekin c , Nancy Fusco d a

Case Western Reserve University and Cleveland Clinic Foundation, Cleveland, OH 44195, USA b University of Iowa, Iowa City, IA, USA c University of Oklahoma, Oklahoma City, OK, USA d Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA Received 2 April 2007 Available online 3 August 2007

Abstract Purpose. To determine the maximum tolerated dose (MTD) of gemcitabine followed by cisplatin that can be administered weekly during pelvic radiation therapy in patients with locally advanced cervical cancer. Methods. A phase I and feasibility study with dose escalation of gemcitabine in cohorts of three to six patients to determine the MTD (the dose level at which no more than one of six patients experienced a acute dose-limiting toxicity) was conducted. Results. Thirteen patients were entered on the phase I trial. Acute dose-limiting toxicity occurred with weekly cisplatin at a dose of 40 mg/m2 and gemcitabine at a dose of 100 mg/m2. The study was modified, decreasing the dose of cisplatin to 30 mg/m2 in an effort to dose escalate gemcitabine. Acute dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/m2 and gemcitabine at a dose of 75 mg/m2 (dose level 3). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 and 4 GI and GU toxicities have occurred in two of six patients at dose level 3. Twelve of thirteen patients remained disease-free following treatment. Conclusion. The MTD found in this chemoradiation study was weekly gemcitabine 50 mg/m2 followed by cisplatin 40 mg/m2. The alternative drug sequence has been reported by others to allow higher doses of gemcitabine. However, at this dose level chronic toxicity was observed. Further expansion of the feasibility cohort of this study was suspended pending the efficacy and toxicity results of a large trial which has recently been completed. © 2007 Elsevier Inc. All rights reserved. Keywords: Gemcitabine; Cisplatin; Cervical cancer

Introduction Cisplatin-based chemoradiation has been demonstrated to be superior to radiation therapy alone in five randomized trials [1– 5]. In 1999 cisplatin-based chemoradiation therapy was formally recommended by the NCI as a new standard for locally advanced cervical [6]. However, despite concurrent cisplatin-based radiation, failure of tumor control within the ⁎ Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, A81, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Fax: +1 216 444 8551. E-mail address: [email protected] (P.G. Rose). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.06.012

radiation field continues to represent a therapeutic problem. Since cisplatin-based combination therapy has demonstrated increased response rates, progression-free and overall survival advantages in cervical cancer patients with advanced or recurrent cervical cancer, it seems reasonable to see if these combinations can be delivered with concurrent radiation therapy [7,8]. A recent randomized chemoradiation trial by the Gynecologic Oncology Group (GOG) compared weekly cisplatin with a non-platinum containing regimen, 5-fluorouracil infusion. That study was stopped when on interim analysis the risk of disease progression was increased with a hazard ratio of 1.33 and it was evident that 5-FU infusion would not be superior to cisplatin [9]. Because of this, it was our intent to

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develop new chemoradiation regimens that would include cisplatin to further build on the current success of cisplatin chemoradiation. Gemcitabine is a deoxycytidine analog antimetabolite structurally related to cytosine arabinoside and inhibits DNA synthesis. There is an accumulation of dFdCTP, which leads to DNA polymerase inhibition and chain termination, triggering apoptosis [10,11]. Several dosing schedules were tested in various phase I trials. The weekly administration of gemcitabine permitted better drug delivery than did twice-weekly or daily ×5 schedules [12–17]. Gemcitabine has been studied as a second line agent in cervical cancer with an 8.4% response rate [18]. However, the known synergy of cisplatin and gemcitabine makes the combination attractive [19,20]. Several studies of the combination have been performed in first line therapy of recurrent disease with response rates ranging from 41 to 75% and collectively 62% [21–23]. Gemcitabine has demonstrated radiosensitization of HeLa cervical cancer cells [24]. When used as a radiation sensitizer with concurrent pelvic radiation, gemcitabine at a dose of 300 mg/m2 weekly resulted in a complete response in 89.5% of patients with IIIB disease [25]. This study was planned with two parts, first, a dose finding study and second, a feasibility study. The primary endpoint for the first part was assessment of acute toxicity to identify the MTD of gemcitabine followed by cisplatin when given concurrently with whole pelvic radiation. For the second part of the study, further assessment of acute and chronic treatment toxicity was to be accomplished as well as the progression-free survival and overall survival at the established MTD. Methods Eligible patients had previously untreated, histologically confirmed, primary invasive carcinoma of the uterine cervix (any cell type). Clinical stages were IB2, IIA, IIB, IIIB, and IVA with negative para-aortic lymph nodes by radiologic evaluation or biopsy-negative para-aortic nodes if CT scan suspicious for adenopathy. Patients must have had adequate bone marrow, renal and hepatic function defined as absolute neutrophil count ≥1500/mcl; platelet count ≥100,000/mcl; creatinine b2.0 mg%; bilirubin ≤1.5 times normal; and SGOT ≤3 times normal. Patients with ureteral obstruction must be treated with stent or nephrostomy tube to maximize renal function. Additionally, patients were required to have a GOG performance status of 0, 1, or 2, no history of prior malignancy evident within the last 5 years and no prior chemotherapy or radiation therapy. Lastly, patients had to sign an appropriate written informed consent consistent with all federal, state and local institution requirements prior to receiving protocol therapy and be entered on study within 8 weeks of diagnosis. Ineligible patients had disease that was less extensive than stage IB2 or had clinical evidence of disease outside the pelvis. Also ineligible were patients with severe infection, patients who were pregnant and did not wish pregnancy termination prior to initiation of treatment, patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal transplantation, that would require modification of radiation fields, and patients whose circumstances did not permit completion of this study or the required follow-up. Staging was performed by standard FIGO criteria although cystoscopy, proctoscopy, and barium enema were optional. Additionally, all patients were required to undergo an abdominal and pelvic CT scan with intravenous contrast, while lymphangiography or ultrasound was considered optional. Those patients who have positive or suspicious para-aortic nodes on lymphangiography, CT scan, or ultrasound examinations were required to

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undergo a fine needle aspiration (FNA) or extraperitoneal lymph node biopsy to exclude metastasis. Those patients with negative radiologic evaluation for para-aortic adenopathy were not required to have cytologic or histologic confirmation.

Radiation therapy Radiation therapy consisted of both external and intracavitary radiation therapy. External radiation therapy consisted of 45 Gy external beam delivered homogeneously to the pelvis in 25 fractions of 180 cGy utilizing a four-field box technique. A CT scan or MRI was used in pre-treatment planning. External radiation therapy was to be completed in 5 weeks and 3 days. If external pelvic radiation therapy exceeded 38 days, the reason for the delay was to be documented. Either low-dose rate or high-dose rate brachytherapy was allowed and had to be specified upon enrollment. For patients receiving low dose rate brachytherapy, a dose of 40.0 Gy to point A by intracavitary implant with radium or its equivalent in one or two applications was planned. The first implant was to be performed immediately following external radiation therapy and, if two implants were contemplated, the second implant was completed within 3 weeks of the completion of external radiation therapy. High-dose rate brachytherapy consisted of five fractions of 600 cGy per fraction for a total dose of 30 Gy to point A. High-dose rate brachytherapy was scheduled to begin on week four, with at least one implant per week with no external radiation therapy given on the day of the insertion. Two implants per week were allowed but were required to be separated by at least 72 h. If intracavitary RT could not be performed, shrinking field technique was performed to bring gross tumor volume with adequate margins to a minimum of 65 Gy. Interstitial brachytherapy was not permitted and, if delivered, was considered a major treatment deviation.

Chemotherapy Chemotherapy was planned on days 1, 8, 15, 22, 29 and 36 of external radiation therapy (preferably Mondays), approximately 4 h prior to radiation. Gemcitabine at the protocol specified dose (Table 1) was to be administered as a 30-minute continuous infusion. Cisplatin at a dose of 40 mg/m2 (maximum total dose of 70 mg/week) was to be administered immediately after gemcitabine. Dose modification CBC was to be obtained weekly during radiation therapy and, if the WBC fell below 2000 mm3 or platelet count below 100,000 mm3, a CBC was to be obtained twice weekly. Radiation therapy was to be interrupted for ANC b500/ mm3 or platelets b20,000 mm3 or if the patient developed febrile neutropenia or bleeding. Counts were to be obtained twice weekly and radiotherapy resumed when above these levels. Chemotherapy was to be interrupted if the absolute neutrophil count was b500/mm3, the platelet count was b50,000/mm3, or if the patient developed febrile neutropenia or bleeding. Patients experiencing acute dose-limiting toxicity at dose level ≥2 were to undergo a one dose level reduction for the remaining cycles. If on dose level 1, the patient was to be taken off study. Patients with prolonged Grade 4 neutropenia or Grade 3–4 thrombocytopenia lasting more than 7 days past the interruption of chemotherapy (14 days since the last dose received) should restart radiation therapy alone (when the ANC N500 mm3 and platelets N20,000 mm3) without

Table 1 Dose escalation planned Dose level

# of patients

Cisplatin mg/m2 (max 70 mg)

Gemcitabine mg/m2

Level 1 starting dose 2 3 4 5 6

3 3 3 3 3 3

40 40 40 40 40 40

50 100 150 200 250 300

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Table 2 Patient characteristics

Table 4 Dose escalation studied

Age—median Age—range Race White Black Performance status 0 1 Stage IB2 IIA IIB IIIB Histology Squamous Non-Squamous Undifferentiated Grade 1 2 3 Courses Median Range

41 25–62

Dose level

# of patients

Cisplatin mg/m2 (max 70 mg)

Gemcitabine mg/m2

12 1

1 2 3

3 3 7

40 40 30

50 100 75

10 3 2 2 6 3 10 2 1 0 6 7 6 4–6

further chemotherapy. Additionally, cisplatin doses were to be held for persistent (N24 h) grade 3 or 4 nausea and vomiting or renal failure defined as a creatinine level of N2.0 mg% or creatinine clearance less than 50 ml/min and reduced to 30 mg/m2 (maximum dose = 60 mg) when nausea and vomiting resolved and the creatinine clearance exceeded 50 ml/min.

limiting acute toxicities were defined by hematologic toxicities including grade 4 neutropenia lasting more than 7 days, grade 3 or 4 neutropenia with associated fever or sepsis, grade 4 thrombocytopenia or symptomatic grade 3 or 4 thrombocytopenia. Acute dose-limiting toxicities also included any grade 3 or 4 non-hematologic toxicity (except nausea and vomiting lasting less than 24 h or diarrhea resulting in delays of therapy lasting less than 6 days) or delays of therapy of greater than 2 weeks for any reason. In addition to acute toxicities, chronic dose-limiting toxicities included any grade 3 or 4 toxicity occurring more than 30 days after radiation therapy completion. Patients were evaluated in cohorts of size three. In the absence of any acute dose-limiting toxicity, patients were accrued to the next dose level. Toxicity data and the ability of the patient to complete all of her radiation therapy within 8 weeks were reviewed prior to advancing to the next dose level. A mandatory 30-day evaluation of all enrolled patients was required before advancing to the next dose level. If dose level 1 was determined to have exceeded the MTD, the study would have closed without evaluation of regimen feasibility. For each dose level, if one of the first three patients experienced an acute dose-limiting toxicity, the cohort on that dose level was expanded up to six patients to better define the toxicity. If any of these additional patients experienced a DLT, then the dose level was considered to be too toxic. There were no intra-patient dose escalations allowed. The MTD was defined as the highest dose level at which no more than one of the six patients experienced an acute dose-limiting toxicity.

Statistical design Toxicity assessment For the purpose of this study, toxicity was defined as acute toxicity occurring within 30 days of radiation therapy completion and late toxicity occurring more than 30 days after radiation therapy completion. Acute dose-

A feasibility trial was to be conducted with the established MTD for the combination therapy to further evaluate the acute and chronic toxicity in an additional 20 to 40 patients. The chronic toxicity will be evaluated by the following formal decision rule based on the number of patients experiencing a

Table 3 Grade 3 or 4 acute adverse events (worst per patient) Toxicity

Hematologic Leukopenia Neutropenia Neutropenia with fever Thrombocytopenia Anemia Non-hematologic Diarrhea Nausea and vomiting Fatigue PE Dyspnea Neurologic WT loss C = course. ⁎ = acute dose-limiting toxicity.

Dose level 1 Cisplatin 40 mg/m2 Gemcitabine 50 mg/m2

Dose level 2 Cisplatin 40 mg/m2 Gemcitabine 100 mg/m2

Grade 3

Grade 3

1 (C2) 1 (C6)

1 (C3)

Grade 4

1 (C2) 2 (C5) 2 (C5) 1 (C2)∗ 1 (C5) 1 (C5), 1 (C6) 1 (C5)

Dose level 3 Cisplatin 30 mg/m2 Gemcitabine 75 mg/m2 Grade 4

Grade 3

Grade 4

1 (C3) 1 (C3) 1 (C3) 1 (C3) 1 (C3)∗

1 (C3)

1 (C6)

1 (C1)

1 (C3) 1 (C4)

1 (C2 Cdiff)∗ 1 (C4)∗ 1 (C5)∗ 1 (C2)

1 (C3)∗ 1 (C5)∗

1 (C5) 1 (C4), 1 (C6) 1 (C4)

P.G. Rose et al. / Gynecologic Oncology 107 (2007) 274–279 chronic dose-limiting toxicity: if one or less patients out of 20 experience chronic dose-limiting toxicities (CDLT) then the study was stopped and the regimen was declared tolerable. If five or more patients out of 20 experienced CDLTs, then the study was stopped and the regimen was declared intolerable. If between two and four patients experienced CDLTs, then the study was opened to a second stage to further evaluate the regimen. If a cumulative of six or less patients out of 40 experienced CDLTs, then the regimen was declared tolerable. If seven or more out of 40 experienced CDLTs, then the regimen was declared intolerable. This group sequential design had an 89% probability of declaring the regimen tolerable if the true probability of a CDLT was 10%. The design had a 90% probability of declaring the regimen intolerable if the true probability of a CDLT was 25%. The acute toxicity was to be evaluated in a less formal way by calculating a 90% conditional likelihood-based confidence bound.

Results This trial accrued 13 patients from 4/2/04 to 3/13/06. The clinical characteristics of the patients enrolled are listed in Table 2. Sixty-nine doses of the gemcitabine/cisplatin combination therapy, median of six per patient, were administered during radiation therapy. Although dose level 1 was well tolerated, at dose level 2 all three patients suffered acute dose-limiting non-hematologic toxicity with nausea and vomiting or diarrhea requiring intravenous hydration in all three patients (Table 3). Additionally, two patients had grade 3 neutropenia, one of which had neutropenic fever. One of these patients had grade 3 thrombocytopenia with radiation proctitis and cystitis. These toxicities occurred on cycle 2, 4 and 5 of therapy. In view of the potential for synergy with the cisplatin and gemcitabine combination, we elected to decrease the dose of cisplatin to 30 mg/m2 in an effort to dose escalate gemcitabine (Table 4). However, dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/ m2 and gemcitabine at a dose of 75 mg/m2 (dose level 3) in three of six patients who completed therapy after the third course (N = 2) and after the fifth course (N = 1). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 or 4 GI and GU toxicities have occurred in one of three patients at dose level 1 and two of six patients at dose level 3. Eleven of thirteen patients remained disease-free following treatment with a median disease-free survival of 20+ months (range 15+–38+ months) at the time of this analysis. Discussion A number of chemotherapeutic agents including paclitaxel, topotecan, vinorelbine and gemcitabine have demonstrated relatively modest activity as single agents in cervical cancer but are considerably more active in combination with cisplatin. Which of these platinum combinations is superior for patients with advanced and recurrent cervical cancer is the subject of a current randomized trial (GOG 204). Each of these agents could also be considered for combining with cisplatin and irradiation. In the current phase I study we attempted to determine the maximally tolerated dose of gemcitabine delivered weekly when followed by weekly cisplatin and pelvic radiation therapy. At the time of the

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original design of the trial, the only study that had used gemcitabine with pelvic radiation therapy was the study by Pattaranutaporn [25]. This was a trial of single agent gemcitabine administered at a dose of 300 mg/m2/week. Therefore, a seven level dose escalation schema was designed (Table 1). However, before the trial was opened, the results of Zarba et al., Umanzor et al., and Duanes-Gozales et al. all reported acceptable tolerance of cisplatin at 40 mg/m2 followed by gemcitabine at 125 mg/m2 weekly with 50 Gy of pelvic radiation therapy [26–28]. At that time we elected to repeat this phase I trial within the GOG to confirm the tolerability of these doses. However, at the second dose level, gemcitabine 100 mg/m2 followed by cisplatin 40 mg/m2 weekly, we encountered significant dose-limiting toxicities in all three patients. Since the dose of cisplatin in the weekly schedule was based on a prior empirically chosen cisplatin dose, we elected to lower the dose of cisplatin in an effort to maximize the dose of gemcitabine. The protocol was amended and reopened at a new dose level 3 with cisplatin decreased to a dose of 30 mg/m2/week and gemcitabine at a dose of 75 mg/m2. Despite this modification, excessive doselimiting toxicities occurred and the study was closed. Since the inception and conduct of this trial, a number of other authors have completed slightly different phase I trials or phase II trials of radiation therapy with cisplatin and gemcitabine. Zarba et al. performed a phase I and subsequent phase II trial [26]. None of the patients treated with cisplatin 40 mg/m2/week and gemcitabine 75–100 mg/m2 experienced dose-limiting toxicities. A less than 20% grade 3 or 4 toxicity rate was seen in the next 26 patients treated at cisplatin 40 mg/m2/week and gemcitabine 125 mg/m2. Umanzor et al. similarly reported very acceptable toxicity in a phase II trial in 23 patients with locally advanced cervical cancer [27]. Only 8.7% had grade 3 or 4 toxicities — a grade 3 neutropenia in one patient and a grade 3 diarrhea in another. In both studies, only 5 weeks of external radiation and concurrent chemotherapy were planned. Duenas-Gonzales et al. performed a randomized phase II trial comparing concurrent cisplatin 40 mg/m2/week versus cisplatin 40 mg/ m2/week and gemcitabine 125 mg/m2/week prior to adjuvant radical hysterectomy for patients with stage IB2 and IIB, squamous, adenosquamous and adenocarcinoma of the cervix [28]. A statistically higher complete pathologic or near complete pathologic (microscopic disease only) was seen in the hysterectomy specimens with the cisplatin/gemcitabine combination (77.5% vs 55%). Although a median of six courses were planned in both arms, six courses of chemotherapy were tolerable in 82% of the patients who received cisplatin but only 63% of the patients who received the combination. Treatment delays were also more common in the patients who received the combination regimen 63% vs 15% with cisplatin alone (p = 0.0001). A multinational randomized trial comparing these two regimens in locally advanced disease has been completed with an accrual of 500 patients. Gemcitabine inhibits nuclear excision repair that occurs after platinum adduct formation [29]. To maximize this effect,

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we administered gemcitabine before cisplatin to pre-block the action of the nuclear excision repair proteins. This sequence was also used by Swisher et al. who reported excessive doselimiting toxicity events with cisplatin at 40 mg/m2 with the addition of gemcitabine at both 100 mg/m2 and 50 mg/m2 [30]. The primary toxicities they reported were nonhematologic and consisted of dose-limiting fatigue, diarrhea and tinnitus. Both the Swisher study and our study standout as having greater toxicity than reported by Zarba et al., Umanzor et al., or Duenas-Gonzales who used an alternative administration schedule in which cisplatin was given followed by gemcitabine. Although not evaluated in the current study, the sequence of drug administration is one possible explanation for the increased toxicity seen with this combination. However, Kroep et al. reported in a four-arm sequence study that hematologic toxicity was greater when cisplatin preceded gemcitabine [31]. In view of the toxicity seen with the gemcitabine/cisplatin combination, we elected not to open the feasibility cohort awaiting the results of a completed large randomized trial comparing cisplatin/gemcitabine versus cisplatin alone during radiation therapy for locally advanced cervical cancer. Acknowledgments This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical and Data Center (CA37517). The following Gynecologic Oncology Group member institutions participated in this study: University of Iowa Hospitals and Clinics, The Cleveland Clinic Foundation and University of Oklahoma. References [1] Whitney CW, Sause W, Bundy BN, et al. A randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB–IVA carcinoma of the cervix with negative paraaortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–48. [2] Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based chemoradiation improves progression free and overall survival in advanced cervical cancer: results of a randomized Gynecologic Oncology Group study. N Engl J Med 1999;340:1144–53. [3] Keys HM, Bundy BM, Stehman FB, et al. A comparison of weekly cisplatin during radiation therapy versus irradiation alone each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. N Engl J Med 1999;340:1154–61. [4] Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high risk cervical cancer: a randomized Radiation Therapy Oncology Group clinical trial. N Engl J Med 1999;340:1137–43. [5] Peters III WA, Liu PY, Barrett RJ, et al. Cisplatin and 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive in highrisk early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: report of a phase III intergroup study. J Clin Oncol 2000;18:1606–13. [6] NCI Clinical Announcement, U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, February 1999.

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