Research ArticleClinical Studies

First-Line Gemcitabine, Nab-Paclitaxel, and Oxaliplatin Chemotherapy With Itraconazole in Patients With Metastatic Pancreatic Cancer: A Single Institution Experience

MIYUKI SAWASAKI, HIROSHI TSUBAMOTO, AYAKO SUGIHARA, SHINICHI IKUTA, YOSHIYUKI SAKAI, YUKIO OSAKI and TAKASHI SONODA
Anticancer Research December 2022, 42 (12) 6063-6069; DOI: https://doi.org/10.21873/anticanres.16118

Abstract

Background/Aim: Combination chemotherapy with gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) was administered as first-line chemotherapy in patients with metastatic pancreatic cancer (mPC). The efficacy and toxicity of these treatments were retrospectively investigated. Patients and Methods: A total of 81 patients (mean age=64 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were enrolled in the study, and administered nab-paclitaxel (125 mg/m2), gemcitabine (1,000 mg/m2), and oxaliplatin (85 mg/m2) on day 1 and itraconazole (400 mg) on days −2 to +2, repeated every 2 weeks. Results: Metastatic sites observed in patients included the liver (n=55, 68%), peritoneum (n=23, 28%), distant lymph nodes (n=24, 30%), and lungs (n=18, 22%). Within 28 days after initiation of chemotherapy, 15 patients (19%) experienced common ≥3 grade hematological adverse events. The major reason for discontinuation of treatment among the responders was peripheral sensory neuropathy in 36 patients (44%). The overall response rate to treatment was 64% [95% confidence interval (CI)=54-75%]. The median progression-free survival and median overall survival were 8.3 months (95% CI=6.8-9.8 months) and 14.4 months (95% CI=11.4-17.3 months), respectively. Among the 52 responders, 24 (46%) underwent conversion surgery, which did not improve survival (p=0.279). Second-line treatment with irinotecan was required in 71 (88%) patients. Hepatic arterial chemotherapy and radiotherapy were administered to 33 (41%) and 27 (33%) patients, respectively. Conclusion: The GnPO-ITC regimen showed promising efficacy with manageable toxicities for controlling disease progression and improving overall survival.

Key Words:

According to the recent global cancer statistics (2022), pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide, with a five-year relative survival rate of 11% across all stages (1). More than 80% of patients have advanced unresectable or metastatic tumors at initial diagnosis. Currently, the standard first-line treatment for patients with metastatic pancreatic cancer (mPC) is a combination of oxaliplatin, irinotecan, fluorouracil, leucovorin (FOLFIRINOX), or gemcitabine plus nanoparticle-bound (nab)-paclitaxel (GnP). The median overall survival (mOS) for each regimen in randomized phase 3 trials has been shown to be 11.7 months or 8.7 months, respectively (2, 3). FOLFIRINOX treatment is effective but toxic. The development of novel therapeutic approaches is necessary to improve efficacy and reduce toxicity.

Previously, we conducted a clinical trial evaluating a regimen comprising docetaxel, gemcitabine, carboplatin, and itraconazole (ITC) between 2008 and 2013 in patients with chemotherapy-refractory mPC (4). Responders to chemotherapy underwent subsequent conversion surgery and showed favorable survival outcomes. The initial rationale for the addition of ITC to cytotoxic regimens was their capacity to reverse chemoresistance (5). Since then, many other anticancer mechanisms involving ITC have been observed in various types of cancers in both preclinical and clinical studies (6). The anticancer activity of ITC takes place through inhibition of intracellular signal transduction [specifically of the Akt/mechanistic target of rapamycin (mTOR), hedgehog, and Wnt/beta-catenin pathways], voltage-dependent anion-selective channel 1 in mitochondria, and lipid transportation. Based on the promising results among patients with mPC, who had refractory disease after chemotherapy, we conducted a single-arm phase 2 trial of a regimen comprising gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) in a first-line treatment setting for mPC. The dose and schedule were planned according to the treatment regimens of mPC from a previous report and a phase 2 trial for gastric cancer, which had started prior to the study (7). This trial was approved by the Institutional review board of the Meiwa Hospital, registered in the UMIN Clinical Trials Registry (UMIN000025398), opened in June 2016. However, due to a change in Japanese laws and regulations, the prospective trial was discontinued in March 2018 following the enforcement of the “Law on Clinical Research”. Based on the results of the analysis conducted at the time of discontinuation, the same treatment was subsequently administered to patients who wished to receive the treatment. This study retrospectively reviewed patients with mPC who were administered the GnPO-ITC regimen in the first-line setting between June 2016 and March 2020 (Ethics committee approval, No. 28-06).

Patients and Methods

Inclusion and exclusion criteria. A total of 81 patients with mPC were treated at the Meiwa Hospital, Nishinomiya, Japan. Metastases were defined in accordance with the Clinical Guidelines for Pancreatic Cancer of the Japan Pancreas Society (8) and TNM classification (9). The inclusion criteria outlined in the initial protocol were as follows: an Eastern Cooperative Oncology Group PS of 0 or 1; 20-80 years of age; mPC with at least one measurable lesion; adequate hematological, liver, and renal function (hemoglobin ≥9.0 g/dl, white blood cell count ≤10,000 cells/mm3, neutrophil count ≥2,000 cells/mm3, platelet count ≥100,000/mm3, total bilirubin ≤upper limit of normal, aspartate transaminase and alanine transaminase ≤100 IU/l, creatinine ≤1.2 mg/dl, and C-reactive protein ≤2.0 mg/dl). Patients were excluded if they had received prior chemotherapy or radiation therapy, grade 2 or higher peripheral sensory neuropathy, apparent pericardial effusion, poorly controlled diabetes, synchronous or metachronous double cancer, active infection, or other serious concomitant diseases. In addition to patients who participated in the prospective trial, all patients who received the GnPO-ITC regimen in daily practice provided written informed consent.

Treatment schedule. The GnPO-ITC regimen comprised nab-paclitaxel (125 mg/m2), gemcitabine (1,000 mg/m3), and oxaliplatin (85 mg/m3) on day 1 and itraconazole (400 mg/day) on days −2 to +2. This regimen was repeated every two weeks. Treatment was continued until disease progression, unacceptable toxicity, discontinuation as decided by the investigators, or patient refusal. Chemotherapy was withheld until recovery if patients developed the following criteria: neutrophil count <1,000/mm3, platelet count <75,000/mm3, total bilirubin >1.5 mg/dl, grade 3 or higher peripheral sensory neuropathy, grade 2 or higher diarrhea, and watery stools. When pre-defined toxic events occurred during the protocol, dose adjustment was performed. After a multimodal conference, patients who responded to chemotherapy underwent cytoreductive surgery.

Assessment of toxicity and efficacy. All toxicities experienced during the study were recorded and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor response was assessed using computed tomography (CT) or magnetic resonance imaging during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Response rate (RR) was defined as the proportion of patients who have a partial response (PR) or complete response (CR) to treatment. Progression-free survival (PFS) was defined as the time from GnPO-ITC regimen administration to disease progression or death, whichever came first. If a patient was alive without disease progression at the date of the last contact, the date was counted as censored. If a patient responded to chemotherapy and received cytoreductive surgery, the date of surgery was counted as censored. Overall survival (OS) was defined as the time from the administration of the GnPO-ITC regimen to death from any cause or censored at the date of the last follow-up for survivors. PFS and OS were estimated using the Kaplan–Meier method. Statistical analyses were performed using the R software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria).

Results

Between June 2016 and March 2020, 81 patients with mPC were administered GnPO-ITC in the first-line setting. The mean and median follow-up times were 18 and 14 months, respectively. The longest time to follow-up was 65 months for a patient who died of disease. The baseline characteristics of patients are summarized in Table I. The median number of treatment cycles was 9.3 (range=1-24). No treatment-related deaths were observed among the 81 patients, although one patient with an Eastern Cooperative Oncology Group (ECOG) PS of 0 died after 10 days owing to disseminated intravascular coagulation. Common adverse events are summarized in Table II. Common hematologic adverse events (AEs) grade ≥3 included leukopenia in 15 (19%) and 31 (39%) patients within 28 days of initiation and during the total treatment period of the GnPO-ITC regimen, respectively. Forty (49%) patients had grade 2 or higher peripheral sensory neuropathy, and 26 (32%) patients discontinued the treatment protocol (Table III). Regarding other non-hematological toxicities, grade 2 or more fatigue and appetite loss were observed in 18 (22%) and 10 (12%) patients, respectively.

View this table:
Table I.

Patient characteristics (n=81).

View this table:
Table II.

Adverse events of the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) regimen.

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Table III.

Reasons for discontinuation of the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) regimen (n=81).

The overall RR was 64.2% (95% CI=53.8-74.6%) (Table IV). The median PFS and OS were 8.3 months (95% CI=6.9-9.8 months) and 14.4 months (95% CI=11.4-17.3 months), respectively (Figure 1 and Figure 2). The survival rate at 24, 36, and 48 months were 22% (95% CI=13-31%), 10% (95% CI=3.3-18%), and 8% (95% CI=1.6-15%), respectively.

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Table IV.

Response to the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) regimen [response evaluation criteria for solid tumors (RECIST) v1.1, n=81].

Figure 1.
Figure 1.

Progression-free survival (PFS) of patients who were administered the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) regimen. The median PFS of chemo-naïve patients with metastatic pancreatic cancer was 8.3 months (M).

Figure 2.
Figure 2.

Overall survival (OS) of patients who were administered the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) regimen. The median OS between responders who underwent surgery and those who did not (w/o) was 21.1 and 15.8 months (M), respectively, and showed no statistical significance (log-rank test, p=0.279).

The median OS among responders with and without conversion surgery was 21 months (95% CI=17.8-24.4 months) and 15.8 months (95% CI=7.7-23.9 months), respectively. No statistically significant difference was observed between the two groups (log-rank test, p=0.279). Multivariate analysis using the Cox proportional hazards model did not show any effect of RT. The second-line regimen of systemic chemotherapy included irinotecan in 71 (88%) patients. Hepatic arterial chemotherapy and radiotherapy were administered to 33 (41%) and 27 (33%) patients, respectively (Table V).

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Table V.

Subsequent treatment after the gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPo-ITC) regimen (excluding conversion surgery or systemic chemotherapy).

Discussion

The described GnPO-ITC-based regimens for patients with mPC in the first-line setting showed a median PFS and OS of 8.3 months and 14.4 months, respectively. Compared to the current FOLFIRINOX regimen, the efficacy and toxicity were favorable, except for severe peripheral sensory neuropathy, which occurred in approximately 50% of patients on the GnPO-ITC regimen.

The survival advantage of this study might have been due to additional efforts of multimodal treatment, including conversion surgery. Neoadjuvant chemotherapy is recommended by the National Comprehensive Cancer Network for patients with borderline resectable and locally advanced pancreatic cancer (LAPC), preferably using FOFIRINOX and GnP regimens (10). A systematic review showed no significant difference in OS between patients with unresectable LAPC and those with metastatic disease after conversion surgery (11). However, the use of conversion surgery remains a matter of debate. In this study, no significant difference was observed in the OS of responders who received conversion surgery and those who did not; however, five patients had recurrence-free survival beyond 2 years after surgery. Considering the disadvantage of interrupting chemotherapy among responders, selecting group factors that could be associated with improved prognosis after conversion surgery is necessary. Resectability is a well-known prognostic factor that is generally assessed using CT and serum levels of CA19-9 (12). Furthermore, OS was associated with operative time, prognostic nutrition index, and neutrophil-to-lymphocyte ratio, among patients with liver-only synchronous metastases who underwent surgery following chemotherapy (13).

The interpretation of the efficacy of the GnPO-ITC regimen in this study is complicated in terms of its impact on favorable prognosis. First, the regimen contained a triplet of cytotoxic agents, such as gemcitabine, nab-paclitaxel, and oxaliplatin. In a phase 2 trial comparing GnP versus GnP followed by FOFRINOX, the latter increased the rate of conversion surgery and histopathological downstaging. However, the RR, median PFS, median OS, and resection rate of conversion surgery were similar (14). Second, ITC was added to the cocktail. In this study, combination chemotherapy with itraconazole was planned according to previous reports of refractory mPC (4). The results of previous clinical studies on repurposing ITC as an anticancer drug are summarized in Table VI.

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Table VI.

Summary of the clinical research of repurposing itraconazole as an anticancer drug for solid tumors.

In the era of precision medicine, molecular profiling and biomarker-driven targeted therapy have emerged as standard approaches. For patients with a germline BRCA mutation and mPC, the poly ADP-ribose polymerase (PARP) inhibitor olaparib was recommended as maintenance treatment after platinum therapy (15). Additionally, KRAS mutations occur in >90% of pancreatic cancers. Sotorasib was the first U.S. Food and Drug Administration (FDA)-approved KRAS inhibitor for patients with non-small cell lung cancer with a KRAS G12C mutation. KRAS inhibitors targeting G12C, as well as other common mutant alleles are now being developed for pancreatic cancer (16). The PI3K/AKT/mTOR and hedgehog signaling pathways play crucial roles in the progression and metastasis of cancers and are activated in pancreatic cancer. Clinical trials of drugs targeting these pathways are currently ongoing in pancreatic cancer (17, 18). In preclinical studies, ITC has shown an inhibitory effect on intracellular signal transduction, including Akt/mTOR and hedgehog signaling. In a phase 2 study of ITC among patients with basal cell carcinoma, the administration of ITC decreased the levels of hedgehog pathway activity in the obtained tissues (19). The precise mechanism underlying the anticancer activity of ITC in patients with cancer remains unknown. We have been conducting window of opportunity clinical trials of ITC treatment for solid tumors (jRCTs051190006), in which a case of vaginal melanoma has been reported (20).

A limitation of this study was its small sample size. The treatment was initially conducted according to the protocol in a phase 2 study; however, the current study was a retrospective study due to the interruption of the prospective study. As neither biopsy specimens nor peripheral blood were obtained in the current study, molecular biomarkers of responders or the action of ITC were not analyzed.

Conclusion

Combination chemotherapy with ITC for patients with mPC appeared favorable in a first-line setting in terms of efficacy and toxicity. The molecular biomarkers of treatment response should be further studied to implement ITC as an anticancer drug.

Footnotes

  • Authors’ Contributions

    MS and HT conceived and designed the study. All authors analyzed and interpreted the data and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no financial conflicts of interest with regard to the study.

  • Received October 20, 2022.
  • Revision received October 25, 2022.
  • Accepted November 8, 2022.

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