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Phase I study of intravenous oxaliplatin and intraperitoneal docetaxel in recurrent ovarian cancer
  1. Sarah E Taylor1,
  2. Jennifer S Petschauer2,3,
  3. Heidi Donovan4,
  4. Allison Schorzman2,3,
  5. Juan Razo2,3,
  6. William C Zamboni2,3,
  7. Robert P Edwards1 and
  8. Kristin K Zorn5
  1. 1 Division of Gynecologic Oncology, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania, USA
  2. 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
  3. 3 UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
  4. 4 School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  5. 5 University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  1. Correspondence to Sarah E Taylor, Division of Gynecologic Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; taylorse2{at}mail.magee.edu

Abstract

Introduction Intraperitoneal (IP) chemotherapy improves survival in ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective of this study was to define the maximum tolerated dose and dose-limiting toxicity of intravenous (IV) oxaliplatin and IP docetaxel in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives were response rate, time to progression, symptom interference with quality of life, and pharmacokinetics.

Methods Patients received a constant dose of oxaliplatin 75 mg/m2 IV on day 1 and docetaxel escalating from 50 mg/m2 IP on day 2 every 3 weeks using a 3 + 3 design. Treatment continued until disease progression, remission, or intolerable toxicity occurred. Plasma and IP samples were taken to determine drug concentrations. Patients completed the MD Anderson Symptom Inventory weekly.

Results Twelve patients were included. The median number of cycles was 4 (range 2–6) with a median time to progression of 4.5 months. Among eight patients with measurable disease, the best responses were partial response in two patients, stable disease in five, and progressive disease in one. A total of 14 grade 3–4 toxicities were noted, most commonly hematologic. Four patients, all dose level 3, had six dose-limiting toxicities: two with prolonged neutropenia, one with infection, one with hyponatremia, and two with abdominal pain. Dose level 3 was therefore considered intolerable. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. Symptom interference with life activities steadily decreased from cycle 1 to 5.

Conclusions Oxaliplatin 75 mg/m2 IV on day 1 and docetaxel 75 mg/m2 IP on day 2 was the maximum tolerated dose. Most patients had partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life.

  • intraperitoneal chemotherapy
  • ovarian cancer
  • phase I

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Highlights

  • We defined the maximum tolerated dose of intravenous oxaliplatin and intraperitoneal docetaxel in recurrent ovarian cancer.

  • Most patients had partial response (PR) or stable disease (SD), even in the heavily pre-treated population.

  • Patients had temporary decrements in quality of life.

Introduction

Ovarian cancer is the second most common gynecologic malignancy with an estimated 22 000 women in the USA being diagnosed with the disease each year. There are over 14 000 reported deaths from the disease, making it the leading cause of death from gynecologic cancers.1 Currently there are no effective screening strategies. Consequently, over 70% of cases are diagnosed at an advanced stage. Ovarian cancer is sensitive to frontline chemotherapy in approximately 75% of women. Unfortunately, relapses occur in an equal percentage, leading to an approximate 40% 5 year overall survival.2 Because of the high rate of initial response, research efforts are now focusing on transforming the initial chemosensitivity into a durable cure. The use of intraperitoneal (IP) chemotherapy is one area of investigation.

The Gynecologic Oncology Group (GOG) has documented an overall survival benefit for women with optimally debulked ovarian cancer treated in the frontline setting with a combination of intravenous (IV) and IP chemotherapy.3–6 Specifically, GOG 172 combined IP cisplatin and paclitaxel with IV paclitaxel and demonstrated a 65.6 month median survival with a relative risk of death of 0.71 when compared with the IV-only regimen.5 These results were tempered by the fact that toxicities were significantly increased in the IV/IP arm, with only 42% of patients completing the anticipated six cycles. Current efforts are focusing on evaluating regimens that continue the survival benefit of IV/IP treatment but limit the toxicity.

In our previously published phase I study examining a combination of IV docetaxel and IP oxaliplatin in patients with recurrent ovarian cancer, most patients had either a partial response or stable disease. This is particularly notable given the heavily pre-treated population. The median number of cycles received during that trial was six, demonstrating a regimen with clinical activity as well as tolerability. At the maximum tolerated dose level, patient-reported outcomes demonstrated temporary but acceptable increases in symptoms and symptom interference with life activities. Additionally, IP oxaliplatin provided a significant pharmacokinetic advantage for the treatment of IP tumors compared with historical IP cisplatin data.7 These data demonstrate a role for combination IV and IP chemotherapy in a population with recurrent ovarian cancer. Additionally, the use of docetaxel and oxaliplatin has potential advantages such as less nephrotoxicity than cisplatin, less neurotoxicity than cisplatin and paclitaxel, and a possible impact on platinum-resistant disease.7 8

This trial complements our previously reported phase I trial; the two trials ran in parallel with the goal of looking for a platinum and taxane IV/IP combination that could be more easily tolerated while maintaining dose intensity. As such, the primary objective of the trial was to determine the dose limiting toxicity and maximum tolerated dose of IV oxaliplatin and IP docetaxel in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. The secondary objectives of the trial were to determine the pharmacokinetics of docetaxel and oxaliplatin when administered in an IV/IP combination and to assess patient-reported symptoms and symptom interference with life activities on the regimen. Although unusual in a phase I trial, we felt that inclusion of quality of life data was critical to future development of the regimen if it was found to be active, since toxicity has undermined adoption of frontline cisplatin-containing IP regimens. For patients with measurable disease, response rate and time to progression were also determined.

Methods

Eligibility Criteria

Eligible patients had recurrent, histologically confirmed, platinum-sensitive or platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer, but must not have had platinum or taxane within the prior 6 months. Last chemotherapy must have been >4 weeks before enrollment. Subjects may not have had prior whole abdomen or pelvic radiation, >6 cycles of an alkylating agent or >450 mg/m2 of doxorubicin. They did not need to have measurable disease. The patients needed an ECOG (Eastern Cooperative Oncology Group) performance score ≤2, adequate bone marrow (absolute neutrophil count >≥1500/μL, hemoglobin ≥8 g/dL and platelet count >≥100 000/μL), adequate renal function (serum creatinine <≤1.5 mg/dL), and adequate hepatic function (serum total bilirubin <≤1.5 mg/dL, alkaline phosphatase, aspartate transaminase/alanine transaminase <3× upper limit of normal or <5× upper limit of normal if hepatic metastases).

Exclusion Criteria

Ineligible patients included those with known dense intra-abdominal adhesions, an active infection or with a fever ≥101.30 F (38.5° C) within 3 days of the first scheduled day of protocol treatment, active extra-abdominal metastases, history of prior malignancy within the past 5 years except for curatively treated skin basal cell carcinoma or cervical intra-epithelial neoplasia, known hypersensitivity to any of the components of docetaxel or oxaliplatin, peripheral neuropathy ≥grade 2, history of allogeneic transplant, and known HIV or hepatitis B or C. All eligible patients underwent informed consent before the initiation of treatment. Institutional review board approval was granted before the start of the trial.

Treatment Regimen

This is a non-randomized, open-label phase I trial. Patients received oxaliplatin at a constant dose of 75 mg/m2 IV on day 1 and docetaxel escalating from 50 mg/m2 IP on day 2 every 3 weeks using a 3+3 design. Cycles of treatment were repeated every 3 weeks until disease progression, intolerable toxicity, study completion or discontinuation, or interruption of treatment >3 weeks for any reason.

The 3+3 design to define the maximum tolerated dose was as follows: three patients were entered at each level, but if a dose-limiting toxicity occurred, that level was expanded to six patients. If two of the six patients experienced a dose-limiting toxicity, the previous dose level was considered the maximum tolerated dose. If two of six patients experienced a dose-limiting toxicity at dose level 1, a de-escalation level with a 20% dose reduction of both agents was to be tested (−1 dose level 40 mg/m2 each). Depending on the number of dose levels necessary to determine the maximum tolerated dose, the planned analysis was for approximately 10 to 20 patients to be enrolled in the study.

Dose reductions were made per the system showing the greatest degree of toxicity. Toxicities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 3.0. One dose reduction of the IP study drug was permitted; if additional reductions were required, the patient was taken off study treatment. Treatment delay was permitted for no more than 3 weeks to allow recovery from acute toxicity. A dose-limiting toxicity was defined as any of the following: absolute neutrophil count <500 mm3 for ≥7 days, absolute neutrophil count <500 mm3 of any duration with fever >100.4°F (38°C), platelet count <10 000/mL, any ≥grade 3 non-hematologic toxicity related to treatment, or inability to re-treat within 3 weeks.

Tumor assessment for all lesions was performed after every other cycle while patients were on protocol treatment and every 2 months for patients who discontinued treatment without documented progressive neoplastic disease. Responses were measured according to RECIST 1.0 criteria.

After the end of the study treatment, the patients were followed for at least 1 month. All patients who discontinued the trial secondary to an adverse event were followed until resolution, stabilization or return to a baseline condition. Patients who discontinued the trial without documented tumor progression were evaluated for the extent of disease at the time of trial discontinuation.

Pharmacokinetic Analytical Methods

Pharmacokinetic studies of oxaliplatin IV on day 1 and docetaxel IP on day 2 were performed on cycle 1 only. A full description of analytic methods can be found in the supplementary text.9–12

Supplemental material

Patient-Reported Symptoms and Symptom Interference with Life Activities

The MD Anderson Symptom Inventory, with additional symptoms specific to ovarian cancer, was used for weekly assessments of patients’ self-reported symptoms and symptom interference with life activities.13 14 The first section of the inventory contained a list of 26 symptoms common to ovarian cancer and/or treatment. Participants were asked to rate the severity of each symptom on a scale of 0 (did not have the symptom) to 10 (symptom as bad as I can imagine). The second section of the inventory asked the patients to identify on a 0–10 scale the extent to which their symptoms had interfered with six general areas of life activities. Two scores were tracked over time: symptom burden (sum of severity ratings for 26 symptoms; range 0–260) and symptom interference (mean score of six interference items). Type, severity and frequency of specific symptoms experienced were also described.

Results

Twelve patients were included. Mean age was 61.8 years (range 48–77). The majority (83%) were Caucasian. Median body mass index was 30.25 kg/m2 (range 23.4–35.5). Most (83%) had an ECOG performance status of 0 and the remainder had a performance status of 1 at the start of treatment. Eleven (92%) had ovarian cancer; the other one had primary peritoneal cancer. All had serous histology. There were nine patients with platinum-sensitive disease and three with platinum-resistant disease. The median number of prior lines of therapy was two (range 1–3). Four had ≥3 prior regimens. Three had secondary cytoreduction immediately before study therapy (Table 1). Four had prior IP therapy. For this subset of four, the median number of cycles was three (range 2–6). Best response to therapy in the setting of prior IP exposure included one partial response (PR), two stable disease (SD) and one that did not have measurable disease. Among the eight patients who did not have IP therapy as their primary adjuvant treatment, all received IV carboplatin and paclitaxel. Two of these eight also received bevacizumab as part of their primary adjuvant treatment. At the time of recurrence, patients were treated with platinum-based regimens with gemcitabine, pegylated doxorubicin, and bevacizumab. Patients were also given tamoxifen, ABT-888 or everolimus (with the latter two given on a trial protocol).

Table 1

Patientcharacteristics

Three patients were treated at dose levels 1 and 2 with no dose-limiting toxicities. Dose level 3 was expanded to six patients after two dose-limiting toxicities were encountered, with a total of six dose-limiting toxicities in the expanded cohort. Dose level 3 was therefore deemed intolerable. Median number of cycles was four (range 2–6) with a median duration of treatment of 109 days (range 49–173). The median cumulative dose of oxaliplatin was 530.5 mg (range 243–888). The median cumulative dose of docetaxel was 485 mg (range 300–1114). The averaged dose intensity of oxaliplatin received was 146.7 mg (range 120–150). The averaged dose intensity of docetaxel received was 138 mg (range 91–280).

A total of 14 grade 3–4 toxicities were noted, most commonly hematologic (Table 2). Four patients, all in dose level 3, had six dose-limiting toxicities: prolonged neutropenia (two), infection (one), hyponatremia (one), and abdominal pain (two). Treatment was delayed in three patients and dose was reduced in five. Two patients received bone marrow support with pegfilgastrim. Treatment ended due to disease progression (three), toxicity (three), remission (three), port complication (two), and non-compliance (one). Of the four patients without measurable disease at the start of treatment, two had secondary cytoreductive surgery before initiation of the trial—one with no gross residual disease, and the other with microscopic residual disease at the end of surgery. One of the other two patients had miliary disease that was biopsied at the time of laparoscopic assessment but had no measurable radiographic lesions. The last patient had radiographic evidence of disease noted as stranding and subcentimeter peritoneal lesions. The median time to progression for this group was 6.3 months (range 2.4–46.1 months). Among the eight patients with measurable disease, the best responses were two partial responses, five with stable disease, and one with progressive disease (Figure 1). Median time to progression for the entire cohort was 4.5 months (range 1.6–46.1 months). As dose level 3 was deemed intolerable, the maximum tolerated dose was dose level 2: day 1 oxaliplatin 75 mg/m2 IV, and day 2 docetaxel 75 mg/m2 IP.

Figure 1

Response of target lesions by patient.

Table 2

Toxicities

Pharmacokinetics

The mean plasma concentrations versus time profiles of total and ultrafiltrate platinum (UF Pt) after IV administration of oxaliplatin at 75 mg/m2 (n=12) are presented in Figure 2A. Mean plasma and IP fluid concentration versus time profiles of docetaxel after IP administration of docetaxel at 50 mg/m2 (n=2), 75 mg/m2 (n=3), and 100 mg/m2 (n=6) are presented in Figures 2 B-D, respectively. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. The pharmacokinetic parameters associated with IV administration of oxaliplatin at 75 mg/m2 are summarized in online supplementary table 1. The mean±SD total platinum area under the curve (AUC) and UF Pt AUC in plasma were 48.2±5.8 ug/mL•hour and 5.8±2.4 ug/mL•hour, respectively. The plasma pharmacokinetic disposition of IV oxaliplatin in combination with IP docetaxel was similar to IV oxaliplatin alone.

Supplemental material

Figure 2

(A) Plasma concentration versus time profiles of total and ultrafiltrate (UF) platinum after intravenous (IV) administration of oxaliplatin at 75 mg/m2 ×1 in combination with intraperitoneal (IP) docetaxel. Concentration versus time profiles of docetaxel in IP fluid and plasma after administration of docetaxel at (B) 50 mg/m2 IP ×1, (C) 75 mg/m2 IP ×1, and (D) 100 mg/m2 IP ×1 in combination with oxaliplatin.

The pharmacokinetic parameters associated with IP administration of docetaxel are summarized in online supplementary table 2. The mean total administered IP dose of docetaxel in the 50 mg/m2 group, 75 mg/m2 group, and 100 mg/m2 group was 95 mg, 137 mg, and 177 mg, respectively. The mean±SD ratio of docetaxel AUC in IP fluid to AUC in plasma after administration of docetaxel IP at 50, 75, and 100 mg/m2 were 179±42, 284±133, and 247±77, respectively.

Supplemental material

Patient-Reported Outcomes

Symptom burden and symptom interference peaked at the day 8 assessment for patients in all dose levels (Figure 3A and 3C). Mean symptom burden on day 1 of each treatment cycle in all three dose levels decreased over the first 2–3 cycles, but then began to increase over time (Figure 3B). Individual symptom burden trajectories over time (Figure 3C) demonstrate the high inter- and intra-individual variability in symptoms over time. Furthermore, patients experiencing dose-limiting toxicities did not experience more extreme levels of symptom burden than those who did not experience a dose-limiting toxicity. The six most severe symptoms reported during the week following treatment were fatigue (6.00±2.81), bowel problems (5.47±3.29), abdominal pain (5.41±3.10), lack of appetite (4.89±3.12), nausea (4.18±3.41), and peripheral neuropathies (4.01±2.95). Mean symptom interference with life activities on day 1 of each treatment cycle decreased over time between cycle 1 (2.65+2.11) and cycle 4 (1.02+0.99).

Figure 3

Symptom burden of participants: (A) during week of treatment cycle by dose level; (B) over time on treatment by dose level; (C) individual trajectories over time on treatment.

Discussion

The addition of IP chemotherapy to IV therapy has shown an overall survival benefit for women with optimally debulked ovarian cancer treated in the frontline.3–5 The limited data regarding the utility if IP chemotherapy in the setting of recurrent disease is mostly observational.15–20 However, the principles that are employed for its use in the upfront setting can be extrapolated into the recurrent setting. IP chemotherapy provides the ability to deliver high concentrations of a cytotoxic agent directly to the peritoneal space, which can provide additional benefit to patients with cancer types confined to the peritoneal cavity. This work adds to data to support both the safety and feasibility of IP chemotherapy for patients with recurrent disease.

Studies have shown enhanced tumor exposure and tolerability to other cytotoxic agents administered via the IP route.4 5 Successful IP delivery can be described utilizing the AUCIP/AUCPlasma and CmaxIP/CmaxPlasma ratios and is defined as the pharmacological advantage.20 IP paclitaxel has been recommended for patients with stage III optimally debulked ovarian cancer patients in combination with IV paclitaxel and IP cisplatin. This recommendation was based on single-agent pharmacologic data that showed a 1000-fold increase in paclitaxel drug concentration within the peritoneal cavity compared with IV levels. However, the dosing was limited by toxicity, namely abdominal pain.21–23 Our data indicate that at the lowest dose of IP docetaxel, the AUC pharmacological advantage approached a mean 179-fold increase in availability in the IP cavity compared with plasma. Mean AUC pharmacological advantage at doses of 75 mg/m2 was even greater at 284 but leveled off at doses of 100 mg/m2 with a 248-fold increase. While the 100 mg/m2 dose was deemed intolerable, these data suggest that there is no loss in pharmacologic advantage at the maximum tolerated dose of 75 mg/m2.

Moreover, it has been reported that IP drug penetration is limited to a few millimeters of tumor on the peritoneal surface layers and thus treatment was felt to be best for patients who have been optimally cyto-reduced and with tumors <1.0 cm in length. Our work demonstrates that even in patients who have measurable disease at the start of therapy, partial responses as well as stabilization of disease can be obtained even without 1000-fold level increases in IP concentration as seen with paclitaxel. These are meaningful outcomes for patients with recurrent disease who have received multiple lines of therapy.

In this study, oxaliplatin 75 mg/m2 IV on day 1 and docetaxel 75 mg/m2 IP on day 2 was deemed the maximum tolerated dose. Most patients had either partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life. In fact, despite high peak symptom burden at day 8 of each cycle, symptom burden and symptom interference with life activities before each treatment cycle decreased over time, suggesting an early palliative effect of the treatment. This is important information for both patients and providers to ensure that: (a) patients are provided with aggressive symptom management during the first week after treatment; and (b) treatment is not prematurely stopped in response to high but temporary spikes in symptom burden.

Five-year overall survival for ovarian cancer remains around 40%, in part because of the high rate of recurrence. Fortunately, most of those recurrences still have a high rate of response to platinum re-treatment. Given the tendency for ovarian cancer to recur intra-abdominally, there is a good reason to consider regional treatment with IP therapy. This combination has shown both response and tolerability even in heavily pre-treated patients. Therefore, additional investigation is warranted.

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