Abstract
Objective
To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer.
Methods
In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The dose-limiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes.
Results
From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2, no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD.
Conclusion
Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.
Trial Registration
ClinicalTrials.gov Identifier: NCT05410483
Keywords: Cisplatin, Docetaxel, Hyperthermic Intraperitoneal Chemotherapy, Maximum Tolerated Dose, Ovarian Cancer
Synopsis
HIPEC with docetaxel and cisplatin is feasible and well tolerated after debulking surgery in patients with ovarian cancer. The maximum tolerated dose for docetaxel is 75 mg/m2 when it is combined with a fixed dose of cisplatin (75 mg/m2) in HIPEC.
INTRODUCTION
The standard treatment for patients with newly diagnosed advanced ovarian cancer is a combination of debulking surgery and platinum-based chemotherapy [1]. Unfortunately, even among patients who achieve complete clinical remission, 70% eventually relapse and die of the disease [2]. Peritoneal metastasis (PM) is the primary pattern of metastasis of ovarian carcinoma, which creates an ideal target for intraperitoneal chemotherapy (IPC). Three randomized controlled trials (RCTs) have shown a survival benefit from IPC when compared with intravenous chemotherapy, especially in patients with optimally debulked stage III ovarian cancer [3,4,5]. However, IPC is not widely used in comprehensive cancer centers because of increased risks of toxicity and catheter complications [6].
IPC can also be administered under hyperthermic conditions, which is termed hyperthermic intraperitoneal chemotherapy (HIPEC). HIPEC has several biological advantages. Hyperthermia has a direct cytotoxic effect, improves the penetration of chemotherapy into tumor tissues and is synergistic with commonly used chemotherapeutic agents, including cisplatin, paclitaxel and oxaliplatin [7]. In addition, hyperthermia induces the synthesis and secretion of heat shock proteins and activates cytotoxic T lymphocytes, dendritic cells, and natural killer cells, thereby triggering innate and adaptive immune responses [8]. Three prospective trials in ovarian cancer patients showed that the addition of cisplatin HIPEC to interval debulking surgery (IDS) results in superior progression-free survival (PFS) and overall survival (OS) [9,10,11]. A recent meta-analysis that included 519 patients confirmed these findings and concluded that the combination of HIPEC and IDS is a safe treatment option that significantly improved 5-year OS and disease-free survival [12]. The clinical benefits of HIPEC with cisplatin after primary debulking surgery (PDS) have also been reported in recent studies [13].
Taxanes, along with alkylating agents, play critical roles in the treatment of ovarian cancer. In a study conducted at the Cleveland Clinic, the addition of paclitaxel to cisplatin for HIPEC during IDS in women with advanced epithelial ovarian cancer was associated with improved oncologic outcomes compared to cisplatin alone [14]. Docetaxel is a semisynthetic compound in the taxane class. Even though docetaxel and paclitaxel share a tubulin binding site and have similar efficacy in the treatment of ovarian cancer, docetaxel has a longer intracellular half-life and less neurotoxicity than paclitaxel [15,16]. In addition, docetaxel is reported to act synergistically with cisplatin in ovarian cancer in vitro [15]. Based on these results, we hypothesized that docetaxel could be a reasonable alternative to paclitaxel for inclusion in cisplatin-based HIPEC for the treatment of advanced ovarian cancer. Here, we report the results of a phase I study that extended this HIPEC strategy by determining the maximum tolerated dose (MTD) of docetaxel in combination with a fixed dose of cisplatin in patients with newly diagnosed ovarian cancer.
MATERIALS AND METHODS
1. Study design
This was an investigator-initiated, open-label, multicenter phase I dose-finding study. The study was reviewed and approved by the Institutional Review Board of Sun Yat-sen Memorial Hospital and conducted in accordance with ethical principles of the Declaration of Helsinki. The trial was registered on Clinicaltrials.gov (NCT05410483). Written informed consent was obtained from all the patients before enrolment.
The primary objective of the present study was to identify the MTD for docetaxel when it was administered in HIPEC with a fixed dose of cisplatin (75 mg/m2). The secondary outcomes were the toxicity of HIPEC using this combination and patient-reported outcomes (PROs).
2. Patients
Patients were eligible if they were 18 to 70 years of age and had histologically confirmed newly diagnosed International Federation of Gynaecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (any grade or histologic subtype). The decision to recommend PDS versus neoadjuvant chemotherapy (NACT) followed by IDS was made based on the triage algorithm described by Straubhar et al. [17]. Additional inclusion criteria included an Eastern Cooperative Oncology Group performance status ≤2, a residual tumor smaller than 1 cm following debulking surgery and sufficient bone marrow, coagulation, renal function (blood creatinine: 58–96 μmol/L) and hepatic function. Patients with borderline tumors were not eligible, nor were patients who had received other investigational agents, had a history of allergic reactions to taxanes or compounds used in platinum doublet drugs, or a history of other malignant neoplasms or psychiatric/social barriers that would limit compliance with study requirements.
3. HIPEC treatment
After completion of all resections and anastomoses, four HIPEC tubes were placed: two in the bilateral subdiaphragmatic area for use as intake tubes and two in the pelvic cavity for use as exit tubes. The fascia and skin were then closed in a conventional manner. HIPEC was delivered at 43±0.10°C by a closed technique at a flow rate of 400–600 mL/min, with docetaxel and cisplatin (75 mg/m2) each dissolved in 3,000 mL of normal saline. The treatment procedure consisted of a 30-minute preheating period and a 60-minute perfusion period. At the end of the perfusion, three tubes were removed, and one tube was left in place for abdominal drainage. A high precision hyperthermic intraperitoneal perfusion treatment system (approved by the State Food Drug Administration of China, approval No. 2009-3260924) was used. The system has a precision of ±0.10°C for temperature control and ±5% for flow control. Intraabdominal temperature was checked in real time with temperature monitoring probes in the infusion and outflow catheters. Urine output was monitored continually and was maintained at a minimum of 1 ml/kg per hour during and for 6 hours after HIPEC. Sodium thiosulfate was administered to prevent nephrotoxicity, as described by van Driel et al. [9]. Additionally, all patients were required to receive intravenous hydration, which was started an hour prior to the commencement of HIPEC and continued for 24 hours following the completion of treatment. The decision to use bevacizumab and/or poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors was based on current guidelines [18].
4. Assessments
All patients underwent a baseline assessment within 7 days prior to HIPEC. Safety assessments, including toxicities, adverse events (AEs) and laboratory parameters, were performed on the day of HIPEC and on days 1, 3, 7, 14 and 21 after HIPEC. AEs were classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Clinical follow-up was performed every 3 weeks during chemotherapy to monitor the disease status. After completion of chemotherapy, follow-up visits were scheduled every three months until disease progression or death. PROs following HIPEC were assessed via the MD Anderson (modified for ovarian cancer) every three days for three weeks [19,20].
5. Statistical analysis
The time-to-event Bayesian optimal interval (TITE-BOIN) design was used to identify the MTD of escalating doses of docetaxel [21]. The MTD was explored with a dose-limiting toxicity (DLT) rate of 25% and 4 predefined doses (60 mg/m2, 65 mg/m2, 70 mg/m2 and 75 mg/m2), and the DLT assessment window was 21 days after HIPEC. The prespecified maximum sample size was 30 patients treated in cohorts of three. Fig. 1 shows the TITE-BOIN design and summarizes the study schema. The first patient cohort was enrolled and treated with hyperthermic docetaxel at a dose of 60 mg/m2. Based on the DLT rate at this dose level, the Data and Safety Monitoring Board (DSMB) made dose-escalation or de-escalation decisions according to the pregenerated decision table (Table S1) for treating the next patient cohort and then repeated this step until the prespecified maximum sample size was reached. When the trial was completed, MTD was selected using the statistical method of isotonic regression [21]. The DSMB recommended using grade 3 AEs to define DLT, which was defined as AEs that were associated with the combination of docetaxel and cisplatin within three weeks of HIPEC. Post-HIPEC complications that were attributable to surgery were not considered DLTs.
Fig. 1. Time-to-event Bayesian Optimal Interval Design. According to the time-to-event Bayesian optimal interval (TITE-BOIN) design, the decision to escalate or de-escalate the dose was made by a comparison of the observed DLT rate at the current dose with fixed prespecified dose escalation and de-escalation boundaries. We sought to determine the MTD for hyperthermic docetaxel with a target DLT rate of 25%, 4 prespecified doses (60 mg/m2, 65 mg/m2, 70 mg/m2 and 75 mg/m2) and 30 patients. The corresponding dose escalation and de-escalation boundaries were 0.197 and 0.298, respectively.
DLT, dose-limiting toxicity; MTD, maximum tolerated dose.
The TITE-BOIN Design Desktop Program, which was downloaded from the MD Anderson Software Download website (http://www.trialdesign.org), was used to generate the dose-escalation and de-escalation table and to select the MTD. Baseline patient characteristics, clinical laboratory evaluations and safety data were summarized using descriptive statistics. All statistical analyses were performed using Stata statistical software (version 15.0, Stata Corp LP, College Station, TX, USA).
RESULTS
Between August 2022 and November 2022, 30 patients with ovarian cancer consented and were enrolled from two centers. The enrolment process is depicted in Fig. S1. All 30 patients received HIPEC with docetaxel and cisplatin following debulking surgery and were included for DLT assessment. Patient characteristics are shown in Table 1. Overall, 16 of the 30 patients received NACT-IDS. Following HIPEC, all patients received a subsequent cycle of adjuvant chemotherapy within three to four weeks without dose delay or dose reduction. Of the eight patients with mucinous carcinoma, two received gastrointestinal-type chemotherapy, including oxaliplatin/capecitabine and oxaliplatin/5-fluorouracil. Twelve patients received bevacizumab, all of whom had FIGO stage IV disease and 10 of whom had massive ascites. Of the 5 patients with deleterious tumor BRCA mutations, 4 received olaparib, and 1 received a combination of olaparib and bevacizumab as the first-line maintenance therapy. Of the 25 patients without a BRCA mutation, 11 received maintenance treatment with bevacizumab, whereas the remaining 14 patients did not receive any form of maintenance therapy.
Table 1. Baseline characteristics.
| Variables | Values | ||
|---|---|---|---|
| Age (yr), median (range) | 56.5 (28–70) | ||
| BMI (kg/m2), median (range) | 21.0 (17.4–29.1) | ||
| Primary tumor location | |||
| Ovary | 25 (83.3) | ||
| Fallopian tube | 1 (3.3) | ||
| Peritoneum | 4 (13.3) | ||
| Histopathology | |||
| High-grade serous | 17 (56.7) | ||
| High-grade endometrioid | 1 (3.3) | ||
| Clear cell adenocarcinoma | 2 (6.7) | ||
| Carcinosarcoma | 2 (6.7) | ||
| Mucinous | 8 (26.7) | ||
| FIGO stage | |||
| Stage IIIC | 18 (60.0) | ||
| Stage IV | 12 (40.0) | ||
| Debulking surgery | |||
| PDS | 14 (46.7) | ||
| NACT/IDS | 16 (53.3) | ||
| Surgical procedures | |||
| Lymphadenectomy | 15 (50.0) | ||
| Small bowel resection | 1 (3.3) | ||
| Large bowel resection | 12 (40.0) | ||
| Hepatectomy | 1 (3.3) | ||
| Spleen resection | 1 (3.3) | ||
| Pancreas resection | 1 (3.3) | ||
| Diaphragmatic peritonectomy | 6 (20.0) | ||
| Surgical complexity score group | |||
| Low (score 1 to 3) | 15 (50.0) | ||
| Intermediate (score 4 to 7) | 12 (40.0) | ||
| High (score ≥8) | 3 (10.0) | ||
| Operation time (hr), median (range) | 4.5 (1.0–8.5) | ||
| Estimated blood loss (mL), median (range) | 175 (5–900) | ||
| Blood transfusion during surgery | |||
| Yes | 9 (30.0) | ||
| No | 21 (70.0) | ||
| Residual disease | |||
| 0 cm | 26 (86.7) | ||
| ≤1 cm | 4 (13.3) | ||
| ICU stay | |||
| Yes | 0 (0.0) | ||
| No | 30 (100.0) | ||
| Deleterious tumor BRCA mutation | |||
| Yes | 5 (16.7) | ||
| No | 17 (56.7) | ||
| Unknown | 8 (26.7) | ||
| Chemotherapy following debulking surgery | |||
| Three-week carboplatin/paclitaxel | 26 (86.7) | ||
| Carboplatin/liposomal doxorubicin | 1 (3.3) | ||
| Weekly carboplatin/paclitaxel | 1 (3.3) | ||
| Gastrointestinal-type chemotherapy | 2 (6.7) | ||
| Neoadjuvant chemotherapy* | |||
| Regimen | |||
| Three-week carboplatin/paclitaxel | 12 (75.0) | ||
| Weekly carboplatin/paclitaxel | 4 (25.0) | ||
| Neoadjuvant cycles | |||
| Two cycles | 2 (12.5) | ||
| Three cycles | 14 (87.5) | ||
| Frontline maintenance therapy | |||
| Bevacizumab | 11 (36.7) | ||
| Olaparib | 4 (13.3) | ||
| Bevacizumab + olaparib | 1 (3.3) | ||
| No | 14 (46.7) | ||
Values are presented as number (%) unless otherwise indicated.
BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; ICU, intensive care unit; IDS, interval debulking surgery; NACT, neoadjuvant chemotherapy; PDS, primary debulking surgery.
*16 patients received neoadjuvant chemotherapy.
No patients experienced AEs during HIPEC that required procedure termination. All patients experienced at least one AE within three weeks of HIPEC. The AEs are summarized in Table 2. The most common AEs were anaemia (63.3%), nausea and vomiting (26.7%), and neutropenia (20.0%). No deaths from the drug combination occurred. No neutropenic fever, kidney injury, neurotoxicity or anastomotic leakage were observed. The incidence of grade 3 or higher AEs was 13.3%. A grade 4 AE was noted in only one patient (3.3%). In the first cohort (docetaxel 60 mg/m2 and 75 mg/m2 cisplatin) and the second cohort (docetaxel 65 mg/m2 and 75 mg/m2 cisplatin), no DLT was observed. Of the 12 patients in the third cohort (docetaxel 70 mg/m2 and 75 mg/m2 cisplatin), one had DLT. Of the 12 patients in the fourth cohort (docetaxel 75 mg/m2 and 75 mg/m2 cisplatin), 3 patients experienced 3 DLTs: grade 3 anaemia (n=1), grade 3 hepatic impairment (n=1), and grade 4 thrombocytopenia (n=1). Based on these findings, the estimates of toxicity probabilities of the four doses were 0.02 (95% confidence interval [CI]=0.00–0.20), 0.02 (95% CI=0.00–0.20), 0.09 (95% CI=0.00–0.29) and 0.25 (95% CI=0.06–0.52). The isotonic estimate of the DLT rate was 25% when docetaxel was administered at a dose level of 75 mg/m2 with 75 mg/m2 cisplatin, which was closest to the target DLT rate. Therefore, 75 mg/m2 was selected as the MTD with a probability of 46% that the toxicity probability would be greater than the target DLT rate.
Table 2. Adverse events.
| Adverse events | NCI-CTCAE 5.0 | ||||
|---|---|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | ||
| 60 mg/m2 (n=3) | |||||
| Neutropenia | 0 | 1 | 0 | 0 | |
| Anemia | 0 | 3 | 0 | 0 | |
| Thrombocytopenia | 1 | 0 | 0 | 0 | |
| 65 mg/m2 (n=3) | |||||
| Nausea and vomiting | 1 | 0 | 0 | 0 | |
| Bloating | 1 | 0 | 0 | 0 | |
| Anemia | 0 | 2 | 0 | 0 | |
| 70 mg/m2 (n=12) | |||||
| Nausea and vomiting | 2 | 1 | 0 | 0 | |
| Inappetence | 2 | 0 | 0 | 0 | |
| Dizziness | 3 | 0 | 0 | 0 | |
| Fatigue | 4 | 0 | 0 | 0 | |
| Bloating | 1 | 0 | 0 | 0 | |
| Diarrhea | 2 | 0 | 0 | 0 | |
| Neutropenia | 0 | 2 | 0 | 0 | |
| Anemia | 3 | 3 | 1 | 0 | |
| Thrombocytopenia | 0 | 1 | 0 | 0 | |
| 75 mg/m2 (n=12) | |||||
| Nausea and vomiting | 4 | 0 | 0 | 0 | |
| Bloating | 2 | 0 | 0 | 0 | |
| Diarrhea | 3 | 0 | 0 | 0 | |
| Neutropenia | 0 | 3 | 0 | 0 | |
| Anemia | 3 | 3 | 1 | 0 | |
| Thrombocytopenia | 1 | 0 | 0 | 1 | |
| Hepatic function impairment | 0 | 0 | 1 | 0 | |
| Hypokalemia | 0 | 2 | 0 | 0 | |
| Hyponatremia | 0 | 2 | 0 | 0 | |
Fig. 2 shows the PROs. For the patients in all four dose levels, symptom burdens peaked on day 9. Pain (5.30±0.53), distress (5.30±0.53), nausea (4.80±0.99), vomiting (4.73±0.94), and lack of appetite (4.57±0.68) were the five most severe symptom burdens. The main symptom interferences were work (6.37±0.49) and enjoyment of life (5.90±0.61). Symptom burden was observed to increase with dose escalation, with participants at dose levels 3 and 4 experiencing comparable symptom burdens. Symptom interferences, on the other hand, did not change significantly with increasing dose.
Fig. 2. Patient-reported outcomes. (A) Symptom burden. (B) Symptom interference over time.
ID, identification.
DISCUSSION
Eliminating PM is one of the greatest challenges in the management of ovarian cancer. Historically, PM has been treated with aggressive peritoneal therapies that combine cytoreductive surgery with HIPEC [22]. Although the prognostic role of maximal debulking surgery for women with ovarian cancer has been well established, level 1 evidence supporting the complementary value of HIPEC to debulking surgery in ovarian cancer was not available until 2018. In the landmark OVHIPEC trial (NCT00426257), van Driel et al. [9] reported that the addition of cisplatin HIPEC to IDS increased recurrence-free survival by 3.5 months and OS by 11.8 months. These findings provide support for the inclusion of cisplatin HIPEC in the National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines, and greatly enhance the utility of HIPEC for ovarian cancer in the United States [1,23]. Lim et al. [11] recently published a second RCT (NCT01091636) investigating the role of HIPEC in the treatment of ovarian cancer, which provided additional evidence of the survival benefit of cisplatin HIPEC in the IDS setting. Consistent with these trials, KGOG 3042 (NCT03448354), which was present at the recent 2022 International Gynaecologic Cancer Society (IGCS) annual meeting, demonstrated superior survival outcomes with the combination of IDS and HIPEC when compared to IDS alone [10]. Although the role of HIPEC in the PDS setting remains undefined, results from retrospective studies and recent meta-analysis suggest that the addition of HIPEC is associated with a better prognosis [13,24,25]. To explore a novel HIPEC regimen in a broader population, patients receiving both PDS and IDS were enrolled in this trial.
In current NCCN ovarian cancer guidelines, cisplatin monotherapy is recommended for HIPEC [1]. However, previous studies have shown that two drugs are more effective than one. In a retrospective study, 249 patients with peritoneal mesothelioma received cytoreductive surgery followed by HIPEC [26]. The authors reported better OS and PFS in those included in the dual-drug HIPEC arm than in those included in the single-drug HIPEC arm. In a recent prospective cohort study, Chambers et al. [14] reported 54 women with stage III or stage IV ovarian cancer treated at Cleveland Clinic. All patients received IDS followed by HIPEC with single-agent cisplatin or the combination of cisplatin and paclitaxel administered at the primary surgeon’s discretion. The authors reported a PFS of 22.2 months in the paclitaxel-cisplatin group compared to 10.9 months in the cisplatin-alone group (hazard ratio=0.38; 95% CI=0.18–0.81; p=0.009). In women with ovarian cancer, docetaxel has been confirmed to have a similar efficacy profile to paclitaxel but causes significantly less severe symptoms of neurotoxicity [16]. Furthermore, docetaxel is susceptible to moderate heat enhancement and may act synergistically with cisplatin [15]. These results suggest that docetaxel may be a reasonable adjunct to cisplatin-based HIPEC. To date, only Wu and colleagues have studied the combination of docetaxel and a platinum derivative (lobaplatin) in HIPEC [27,28]. The authors reported that HIPEC with lobaplatin 50 mg/m2 and docetaxel 60 mg/m2 had acceptable toxicity and could improve survival. In a review, Sugarbaker and Van der Speeten [29] suggested docetaxel 30 mg/m2 plus cisplatin 50–75 mg/m2 as a potential HIPEC doublet for patients with PM from ovarian cancer; however, they did not provide safety or efficacy data. Van der Kaaij’s study [30] was the only study to explore the MTD for intraperitoneal docetaxel. The MTD for normothermic docetaxel was 50 mg/m2 when combined with 460 mg/m2 oxaliplatin in HIPEC.
To our knowledge, this is the first phase I clinical trial to date to evaluate the combination docetaxel-cisplatin HIPEC. Although the majority of the included patients underwent aggressive surgical procedures in debulking surgery, as indicated by the surgical complexity scores of intermediate in 40% and high in 10%, the AEs in our cohort were expected based on the known profiles of each of the individual agents, and no new safety signals were observed; therefore, we believe that docetaxel-cisplatin combination HIPEC following debulking surgery could be feasible and well tolerated. Anaemia was the most frequent AE, with an incidence of 63.3%, which is in line with the toxic profile of docetaxel [15]. In addition, AEs ≥grade 3 were observed in 13.3% of our cohort, which was comparable to the incidence in patients receiving cisplatin monotherapy [9,11], suggesting that adding docetaxel to cisplatin HIPEC may not significantly increase toxicity. The analysis of the PROs showed temporary but acceptable increases in the prevalence and interference of symptoms with life activities in patients receiving hyperthermic docetaxel at a dose of 75 mg/m2; these findings reinforced the traditional method of reporting DLTs and provided further reassurance for reliability of this dose level as MTD.
Notably, the cisplatin dose (75 mg/m2) used in the present study is lower than the NCCN-recommended dose (100 mg/m2) [1,9]. The main concern with the use of cisplatin in HIPEC is renal toxicity, which is characterized by notable ethnic differences [31,32]. We previously identified 85 mg/m2 as the MTD for cisplatin in Asian women who do not receive bevacizumab after HIPEC [33]. As an approved agent for the first-line treatment of advanced ovarian cancer, bevacizumab is also nephrotoxic [34]. Gouy et al. [35] reported that the dose of hyperthermic cisplatin should not exceed 80 mg/m2 if bevacizumab is administered after HIPEC. Considering the safety concerns and efficacy data from RCTs, we selected a cisplatin dose of 75 mg/m2 for this study. This measure, together with the use of sodium thiosulfate, may contribute to the low incidence of kidney injury observed in our cohort.
Limitations of this study include its design and a relatively small sample size, which limited our ability to draw reliable conclusions about the efficacy of the docetaxel-cisplatin combination in HIPEC. Second, since no consensus was reached on the standardization of HIPEC, our results should be interpreted in the context of variability in HIPEC implementation across centers [8]. Third, systemic levels of docetaxel during and after HIPEC could not be determined due to the lack of funding to perform pharmacokinetic analysis. Future research is needed to answer this question.
In conclusion, we identified the MTD for docetaxel when administered in combination with cisplatin for HIPEC. The addition of docetaxel did not appear to notably increase the risk of AEs associated with HIPEC. Further studies are warranted to assess the effectiveness of this doublet in patients with ovarian cancer.
ACKNOWLEDGEMENTS
We are deeply grateful to the patients and their families for participating in this study and clini-cians who referred cases.
Footnotes
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: Y.Y.F., L.Z.Q., L.J.
- Data curation: Y.Z.Y., W.M.F., L.H., W.L.J., L.J.
- Formal analysis: Y.Z.Y., W.M.F., Y.Y.F.
- Funding acquisition: L.J.
- Investigation: Y.Z.Y., L.H.
- Methodology: Y.Y.F., L.Z.Q., L.J.
- Project administration: Y.Z.Y., W.M.F., L.J.
- Resources: W.M.F., W.L.J., L.J.
- Supervision: L.J.
- Validation: L.J.
- Writing - original draft: Y.Z.Y., W.M.F.
- Writing - review & editing: L.Z.Q., L.J.
SUPPLEMENTARY MATERIALS
Dose escalation and de-escalation rule for the TITE-BOIN design with a target DLT rate of 0.25 and a cohort size of 3
Enrolling process. Patients were treated in cohort sizes of 3, and the number to the right of the “→” indicates the time when DLT occurred.
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Associated Data
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Supplementary Materials
Dose escalation and de-escalation rule for the TITE-BOIN design with a target DLT rate of 0.25 and a cohort size of 3
Enrolling process. Patients were treated in cohort sizes of 3, and the number to the right of the “→” indicates the time when DLT occurred.