Intraperitoneal hyperthermic chemotherapy using carboplatin: A phase I analysis in ovarian carcinoma

Gynecologic Oncology 106 (2007) 207 – 210 www.elsevier.com/locate/ygyno

Intraperitoneal hyperthermic chemotherapy using carboplatin: A phase I analysis in ovarian carcinoma Samuel S. Lentz a,⁎, Brigitte E. Miller a , Gregory L. Kucera b , Edward A. Levine c a

Section on Gynecologic Oncology, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA b Section on Hematology-Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA c Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA Received 29 July 2006 Available online 10 May 2007

Abstract Objective. Cyclic platinum-based intraperitoneal chemotherapy has proven to be effective after optimal surgical cytoreduction in ovarian carcinoma. Hyperthermia is directly cytotoxic and enhances chemotherapy tumoricidal effects. This study was designed to determine the maximum tolerated dose (MTD) of carboplatin used intraoperatively as intraperitoneal hyperthermic chemotherapy (IPHC), the effect on postoperative systemic chemotherapy administration, and the potential for repeat IPHC at second look surgery. Methods. Using the ThermoChem™ HT System, escalating doses of carboplatin (400, 600, 800, 1000, and 1200 mg/m2) were administered intraoperatively as IPHC with a perfusion time of 90 min. A subgroup of eight patients that received initial IPHC and subsequent systemic chemotherapy underwent second look reassessment surgery with IPHC. Results. The first 4 dose levels were well tolerated without dose-defining toxicity. The initial two patients treated at 1200 mg/m2 developed grade 4 myelosuppression thus defining the MTD at 1000 mg/m2. Newly diagnosed ovarian cancer patients receiving the initial IPHC at the MTD defined above completed standard systemic chemotherapy with six courses of systemic chemotherapy. Eight patients having initial IPHC and systemic chemotherapy subsequently had repeat IPHC performed at second look laparotomy without grade 3 or 4 toxicities. Four patients were found to have extensive adhesions at the time of second look reassessment surgery yet completed IPHC. Conclusions. The MTD for intraperitoneal carboplatin administered as IPHC was established at 1000 mg/m2. IPHC at the initial cytoreductive procedure did not preclude subsequent systemic chemotherapy. In addition, repetitive IPHC was feasible at second look reassessment surgery. © 2007 Elsevier Inc. All rights reserved. Keywords: Chemotherapy; Intraperitoneal therapy; Hyperthermia; Ovarian carcinoma

Introduction The majority of patients with ovarian carcinoma have advanced disease at the time of diagnosis which remains confined to the peritoneal cavity for extended periods of time and thus potentially amenable to intraperitoneal therapy. Two randomized trials in optimally cytoreduced ovarian cancer have been performed comparing chemotherapy combinations incorporating cyclic intraperitoneal (IP) cisplatin to systemic therapy alone. The initial study which did not include paclitaxel showed a significant survival advantage for the intraperitoneal treated ⁎ Corresponding author. Fax: +1 336 716 4334. E-mail address: [email protected] (S.S. Lentz). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.03.022

group. The second study showed a significant progression-free survival again in favor of the IP group [1,2]. Recently, Armstrong et al. reported the results of a phase III trial of intravenous paclitaxel plus cisplatin compared to intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel in optimally debulked ovarian cancer. Intraperitoneal therapy was found to improve survival [3]. In addition, carboplatin has also been evaluated as IP therapy with two phase II trials demonstrating a complete response rate of approximately 25% in patients with minimal residual disease after initial platinumbased therapy [4,5]. Intraoperative hyperthermic chemotherapy has been shown to be effective in the treatment of carcinomatosis associated with gastrointestinal malignancies [6,7]. The cytotoxic mechan-

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isms associated with supranormal temperatures are unclear. Temperatures in the range of 42–45 °C for 10–60 min can cause lethal cellular damage [8]. The selective cytotoxic effect of hyperthermia on ovarian carcinoma cell lines has been observed in which temperature between 42 and 45 °C for 2–4 h is lethal whereas the non-neoplastic parental cell types are not significantly affected [9,10]. Hyperthermia, in addition to having cytotoxic properties per se, also appears to enhance platinum sensitivity [11]. Ryu et al. used intraperitoneal hyperthermic chemotherapy (IPHC) with carboplatin and interferon alpha at second look surgery in a group of patients with ovarian carcinoma. Although the findings suggested IPHC to be a promising treatment modality, the intraperitoneal dosing was apparently selected based on systemic therapy dosage without phase I assessment and IPHC was not administered with the initial cytoreductive procedure [12]. The objectives of this study were to define the maximum tolerated dose (MTD) of carboplatin, recognizing a prior pilot phase I trial that had suggested an MTD of IP carboplatin given with hyperthermia at 800 mg/m2; however, the 1000 mg/m2 dose level was not evaluated [13]. Second, the effect IPHC had on the ability to subsequently administer standard platinumbased systemic chemotherapy was evaluated in this study. With the recognition that repetitive drug exposure is important in the first order kinetics of tumor cytotoxicity, a subgroup of patients was treated with IPHC using carboplatin at the initial cytoreductive surgery as well as at second look reassessment surgery. Methods and materials This phase I study performed at the Wake Forest University Baptist Medical Center recruited patients with presumed stage III ovarian carcinoma and was approved by the institutional review board. After informed consent, seventeen patients were enrolled to determine the maximum tolerated dose (MTD) of carboplatin administered intraoperatively as intraperitoneal hyperthermic chemotherapy. The group included both those scheduled for initial cytoreductive surgery as well as second look reassessment surgery. Six patients evaluated for the MTD at second look laparotomy only had previously received standard platinum-based systemic chemotherapy. Eleven newly diagnosed patients undergoing IPHC with initial cytoreductive surgery were also evaluated for tolerability of post-IPHC standard systemic chemotherapy with a taxane and platinum drug combination. Eight patients that received initial IPHC and subsequent systemic chemotherapy underwent second look laparotomy and repeat IPHC. The average patient age was 53 years with all patients having stage III disease. The majority of patients had poorly differentiated serous histology.

cooled intravenous fluids) when needed. Perfusion continued for 90 min with gentle abdominal agitation performed by the surgical team. Upon completion of the perfusion, the abdomen was irrigated with saline then re-explored removing the cannulas followed by formal abdominal closure.

Phase I carboplatin MTD calculation The MTD of carboplatin was determined according to a standard phase I analysis with the initial dose of 400 mg/m2 followed by incremental increases of 200 mg/m2. Body surface area rather than area under the curve (AUC) was used for dose calculation since therapy was confined to the peritoneal cavity and posttreatment washout was performed with limited dwell time. Therefore, the dependency of renal clearance for carboplatin elimination was significantly reduced. Cohorts of three patients were treated at each dose level without doselimiting toxicities (DLT) before escalation was permitted. Using the standard NCI toxicity scoring system, dose-limiting toxicities were defined as grade 4 neutropenia (<500 cells/mm3) or thrombocytopenia (<10,000 platelets/mm3) and any grade 3 or 4 non-hematologic toxicity excluding grade 3 nausea and vomiting or grade 3 fever occurring during the immediate treatment period. After IPHC treatment, complete blood counts were performed every other day for the first postoperative week then twice weekly until systemic therapy was initiated. If one occurrence of DLT was observed three additional patients were treated at that level without toxicities before dose escalation. The MTD was defined as the dose that was one level below the level in which two occurrences of DLT were observed.

Systemic chemotherapy and subsequent IPHC Patients who underwent IPHC as part of the initial cytoreductive surgery were subsequently scheduled to receive systemic chemotherapy with paclitaxel 175 mg/m2 and carboplatin AUC of 6 every 3–4 weeks for six courses. Appropriate dose modification criteria were established in the protocol for systemic therapy. Patients clinically without evidence of disease after systemic therapy were evaluated for second look reassessment surgery and repeat IPHC as outline above.

Results The MTD was based on myelosuppression observed in both groups with no significant IPHC-related non-hematologic toxicities noted. Myelosuppression was not seen at doses of 400, 600, or 800 mg/m2. Table 1 depicts the nadirs of white blood cell and platelet counts observed at the last two dose levels tested. At 1000 mg/m2, one episode of MTD defining myelosuppression was observed in the first cohort of three patients thus requiring evaluation of an additional cohort. Two patients subsequently received IPHC at 1200 mg/m2 with second look surgery only and were noted to have grade 4 toxicity thus defining the MTD at 1000 mg/m2. No sequelae

IPHC technique IPHC was administered after performing successful cytoreductive surgery which was defined as residual intraperitoneal lesions each less than 1 cm. Two 32 French inflow catheters and two 36 French outflow catheters were placed in the upper and lower abdominal quadrants respectively. The abdomen was closed using a running suture in the skin. After cannulation the ThermoChem HT peritoneal perfusion device was utilized as a closed circuit. The perfusion circuit was established using 2–3 l of isotonic saline as the perfusate with a flow rate of 600–800 ml/min. Once the inflow temperature reached 39 °C the carboplatin calculated according to the phase I protocol was added to the perfusate. Flow rates were adjusted to maintain stable temperatures with inflow temperatures not exceeding 43.5 °C and outflow temperatures not exceeding 43 °C. The patient's core temperature was not allowed to exceed 38.5 °C using passive (turning off usual warming devices) and active cooling methods (external ice packs and

Table 1 IPHC ovarian carcinoma phase I study maximum tolerated dose (MTD) Carboplatin 1000 mg/m2

Carboplatin 1200 mg/m2

Nadirs

Nadirs

WBC

ANC

PLT

WBC

ANC

PLT

5000 1600 5600 5400 1600 2500

3154 204 2884 4536 672 1200

46,000 9000 198,000 210,000 15,000 54,000

1600 1000

400 99

7000 10,000

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209

Table 2 IPHC-carboplatin: 1000 mg/m2 clinical characteristics Diagnosis

Procedure

Nadir counts (WBC/ANC/Platelets)

Systemic therapy

1. Stage 2. Stage 3. Stage 4. Stage 5. Stage 6. Stage

TAH/BSO, omentectomy, transverse colectomy, splenectomy a TAH/BSO, omentectomy, sigmoid resection a TAH/BSO, omentectomy a LSO omentectomy a Second look (microscopic disease) b Second look (macroscopic disease) b

5000/3154/46,000 1600/204/9000 1600/672/15000 2500/1200/54000 5600/2884/198000 5400/4536/210000

Paclitaxel/Carboplatin, ×6 courses Paclitaxel/Carboplatin, ×6 courses Paclitaxel/Carboplatin, ×6 courses Paclitaxel ×3, carboplatin ×6 Paclitaxel/Carboplatin, ×6 pre-IPHC Paclitaxel/Carboplatin, ×6 pre-IPHC

a b

IIIC ovarian carcinoma IIIC ovarian carcinoma IIIC ovarian carcinoma IIIC ovarian carcinoma III ovarian carcinoma III ovarian carcinoma

IPHC at time of initial cytoreductive surgery. Initial IPHC at time of second look surgery.

related to myelosuppression were observed. Table 2 further characterizes the treatment course of patients at the MTD. All patients receiving IPHC with initial cytoreductive surgery completed standard systemic chemotherapy with six courses of paclitaxel and carboplatin except for one patient with paclitaxelrelated neurotoxicity completing therapy with carboplatin alone. One patient during systemic chemotherapy had repetitive treatment delays and subsequently necessitated a dose reduction in paclitaxel and carboplatin secondary to grade 3 thrombocytopenia. Systemic chemotherapy was started on an average of 28 days (range 11–42 days) after initial surgical cytoreduction and IPHC with a mean of 34 days for the subgroup receiving IPHC at 1000 mg/m2. Second look surgery and repeat IPHC were performed within 8 weeks of completing systemic chemotherapy. There were no intraoperative complications or postoperative serious adverse events. Of note, three patients receiving IPHC with initial surgery had a bowel resection with anastomosis performed (one small bowel and two large bowel) as part of the initial cytoreductive procedure including two patients receiving IPHC at the MTD. No anastomotic-related complications were observed. One patient suffered serious postoperative morbidity including a pulmonary embolism and superficial wound

Table 3 IPHC initial surgery and second look laparotomy Diagnosis

IPHC carboplatin dosage

Complications

1. Stage IIIC ovarian carcinoma 2. Stage IIIC ovarian carcinoma 3. Stage IIIC ovarian carcinoma 4. Stage IIIC ovarian carcinoma 5. Stage IIIC ovarian carcinoma 6. Stage IIIC ovarian carcinoma 7. Stage IIIC ovarian carcinoma

#1: 400 mg/m2 #2: 400 mg/m2 #1: 400 mg/m2 #2: 400 mg/m2 #1: 600 mg/m2 #2: 600 mg/m2 #1: 600 mg/m2 #2: 600 mg/m2 #1: 800 mg/m2 #2: 800 mg/m2 #1: 800 mg/m2 #2; 800 mg/m2 #1: 1000 mg/m2

None None None None None None None None None None None None Pulmonary embolism, wound dehiscence None None None

8. Stage IIIC ovarian carcinoma

#2: 1000 mg/m2 #1: 1000 mg/m2 #2: 1000 mg/m2

dehiscence. However, this patient subsequently underwent systemic chemotherapy and a second look reassessment with repeat IPHC. Repeat IPHC was performed in eight patients at the time of second look reassessment surgery. This included two patients receiving both initial and repeat IPHC at the MTD of 1000 mg/ m2 (Table 3). No significant toxicities were observed. Review of the operative record in these eight patients revealed extensive adhesions in four although IPHC was completed. Discussion This phase I study established the MTD for carboplatin of 1000 mg/m2 when administered intraoperatively as intraperitoneal hyperthermic therapy at the initial cytoreductive procedure in patients with advanced ovarian carcinoma. It is conceivable that the MTD could have been higher if the 1200 mg/m2 cohort had received IPHC prior to rather than after systemic therapy. However, the established MTD of 1000 mg/m2 appears valid in light of prior phase I analysis noting significant toxicity at 1200 mg/m2 [13]. Furthermore, the group of patients undergoing IPHC at the initial cytoreductive procedure subsequently received standard systemic chemotherapy with significant delay and dose reduction required in only one patient. The mean time of 28 days until the initiation of systemic chemotherapy is not excessive in this study. A recent study indicates that the timing of systemic chemotherapy after initial surgery is not a significant variable regarding therapeutic response [14]. The present study also showed that in eight patients repeat IPHC at second look laparotomy was safe and without significant toxicities. However, long-term follow-up data after second look reassessment surgery and repeat IPHC is needed to evaluate non-hematologic toxicities such as bowel sequelae more thoroughly. The potential therapeutic effect of IPHC with carboplatin is yet to be determined; however, it may be related to enhanced platinum sensitivity or reversal of drug resistance. This may be related to the substantial pharmacologic advantage of intraperitoneal platinum drug concentrations overcoming a degree of drug resistance. Pharmacokinetic properties of carboplatin, similar to cisplatin, enhance its intraperitoneal administration including a peak peritoneal cavity/plasma concentration ratio of 18:1 [15]. In vitro data indicate that platinum resistance is relative, not absolute, thereby drug concentration increases may

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overcome resistance [16]. These effects appear to be related to intracellular drug accumulation, adduct formation, and adduct processing. Treatment of tumor cells simultaneously with hyperthermia and platinum leads to an increased number of platinum–DNA adducts and a more than additive cytotoxic effect [17]. Technical issues limit the expanded use of IPHC at present. Based on first-order log tumor kill associated with chemotherapeutics, repetitive drug exposure including IPHC could be potentially important. However, due to rapid adhesion formation after cytoreductive surgery, cyclic use of IPHC at present is prohibitive. Furthermore, design of intraperitoneal catheters which allow for adequate flow rates to maintain proper intraperitoneal temperature and remain in place over an extended period of time for repetitive use would be required. Also, other modalities for achieving hyperthermia have been described including radiofrequency and microwave techniques [18,19]. These may be useful methods for cyclic non-surgical administration of hyperthermia in conjunction with chemotherapy. Another challenge facing the future use of IPHC involves the paucity of phase I data for other drugs known to be effective against ovarian carcinoma. For example, paclitaxel has a significant intraperitoneal pharmacologic advantage where the drug concentration ratio of peritoneal cavity to plasma is in the range of 1000:1 [20]. Use of present cyclic IP pharmacokinetic data to establish drug dosage for IPHC is not appropriate since there are differences which would potentially impact systemic drug absorption and thus side effects. With IPHC, reduced intraperitoneal drug dwell time would likely decrease systemic absorption while peritoneal surface alterations associated with surgery and the use of hyperthermia would possibly increase drug absorption. IPHC is a potentially promising therapeutic modality for patients with carcinomatosis related to gastrointestinal malignancy [21,22]. Additional phase II evaluation would be needed to determine its potential use in patients with ovarian carcinoma. Acknowledgment Supported, in part, by a grant from Viacirq. References [1] Alberts DS, Lui PY, Hannigan EV, O'Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335(26):1950–5. [2] Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001;19(4):1001–7. [3] Armstrong DK, Bundy BN, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.

[4] Speyer JL, Beller U, Colombo N, Sorich J, Wernz JC, Hochster H, et al. Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy. J Clin Oncol 1990;8(8): 1335–41. [5] Pfeiffer P, Bennedaek O, Bertelsen K. Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. Gynecol Oncol 1990;36: 306–11. [6] Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol 2004;5(4):219–28. [7] Sugarbaker PH. A curative approach to peritoneal carcinomatosis from colorectal cancer. Semin Oncol 2005;32(6 Suppl 9):S68–73. [8] Oleson JR. Hyperthermia. In: Devita VT, Hellman S, Rosenburg SA, editors. Cancer, principles and practice of Oncology. Philadelphia: JB Lippincott Company; 1989. p. 2426–35. [9] Giovanella BC, Stehlin Jr JS, Morgan AC. Selective lethal effect of supranormal temperatures on human neoplastic cells. Cancer Res 1976; 36:3944–50. [10] Kimura E, Howell SB. Analysis of the cytotoxic interaction between cisplatin and hyperthermia in a human ovarian carcinoma cell line. Cancer Chemother Pharmacol 1993;32:419–24. [11] Los G, van Vugt MJ, Pinedo HM. Response of peritoneal solid tumuors after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer 1994;69:235–41. [12] Ryu KS, Kim JH, Ko HS, Kim JW, Ahn WS, Park YG, et al. Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer. Gynecol Oncol 2004;94(2):325–32. [13] Steller MA, Egorin MJ, Trimble EL, Bartlett DL, Zuhowski EG, Alexander HR, et al. A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer. Cancer Chemother Pharmacol 1999;43(2):106–14. [14] Gadducci A, Sartori E, Landoni F, Zola P, Maggino T, Maggioni A, et al. Relationship between time interval from primary surgery to the start of taxane- plus platinum-based chemotherapy and clinical outcome of patients with advanced epithelial ovarian cancer: results of a multicenter retrospective Italian study. J Clin Oncol 2005;23(4):751–8. [15] Elferink F, van der Vijgh WJ, Klein I, ten Bokkel Huinink WW, Dubbelman R, McVie JG. Pharmacokinetics of carboplatin after intraperitoneal administration. Cancer Chemother Pharmacol 1988;21(1): 57–60. [16] Behrens BC, Hamilton TC, Masuda H, Grotzinger KR, Whang-Peng J, Louie KG, et al. Characterization of a cis-diamminedichloroplatinum(II)resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res 1987;47(2):414–8. [17] Los G, van Vugt MJ, den Engelse L, Pinedo HM. Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA. Biochem Pharmacol 1993;46(7):1229–37. [18] Vasanthan A, Mitsumori M, Park JH, Zhi-Fan Z, Yu-Bin Z, Oliynychenko P, et al. Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency. Int J Radiat Oncol Biol Phys 2005; 61(1):145–53. [19] Wren J. Evaluation of three temperature measurement methods used during microwave thermotherapy of prostate enlargement. Int J Hypertherm 2004;20(3):300–16. [20] Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis Jr JL, et al. Phase I trial of intraperitoneal taxol: a Gynecologic Oncology Group study. J Clin Oncol 1992;10(9):1485–91. [21] Glehen O, Kwiatkowski F, Sugarbaker PH, Elias D, Levine EA, De Simone M, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol 2004;22(16):3284–92. [22] Shen P, Levine EA, Hall J, Case D, Russell G, Fleming R, et al. Factors predicting survival following intraperitoneal hyperthermic chemotherapy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis. Arch Surg 2003;138(1):26–33.