Phosphorus-32 microparticles for locally advanced pancreatic cancer: how and when?

KEYWORDS:

• Pancreas cancer
• selective internal radiation therapy
• phosphorus-32: microparticles
• positron emission computed tomography
• radionuclide therapy

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) stands as the sixth leading cause of global mortality and the fourth in Europe. The mortality rates exhibit an upward trajectory, marked by significant variations among different countries [1]. These differences may be attributed to a range of factors, including distinct genetic and cultural backgrounds, as well as unequal access to emerging therapeutic options. While surgery remains the sole curative option, approximately 30% of patients at diagnosis face inoperability due to locally advanced disease. Despite notable advances in recent years, the prognosis in locally advanced PDAC remains grim, with a median overall survival spanning 9–11 months [2]. While there is a broad consensus that patients with inoperable PDAC should undergo chemotherapy, the therapeutic approach in this clinical context remains suboptimal. Indeed, current chemotherapeutic regimens predominantly rely on data extrapolated from trials involving metastatic patients, including chemotherapy alone or chemotherapy followed by radiotherapy [3]. In this context, an unmet need for alternative therapeutic options is undeniable. Internal radiation therapy (IRT) is a well-established approach in nuclear medicine that involves the insertion of radioactive implants directly into cancerous tissue [4,5]. Along this trajectory, a recently introduced medical device utilizes silicon microparticles containing radioactive phosphorus (³²P), implanted via endoscopic ultrasound (EUS), for treating locally advanced PDAC [6]. Our objective is to provide a concise overview of the methodology (‘how’) and the most effective timing (‘when’) for the application of ³²P-microparticles within the therapeutic framework for locally advanced PDAC, through a comprehensive review of the existing scientific evidence (Table 1).

Table 1. First clinical applications of ³²P-particles in pancreas carcinoma.

Author	Year/Country	Study	n. of patients	Safety	Results	Comment
Bhutani et al. [11]	USA/2019	Open-label, Single-Arm Pilot Study	9	1 grade IV toxicity 23 grade III toxicity neutropenia, anemia, and thrombocytopenia	LDCR at week 16 was 88%, with PR or SD reported in 7/8 patients	The procedure for ^32P-microparticles’ implantation resulted feasible and relatively safe
Ross et al. [12]	UK/2022	Single-arm pilot study	50 (ITT) 42 (PP)	41 TEAEs in 16 (38.1%) patients were deemed possibly or probably related to ^32P-microparticles, with 167 (15.1%) classified as grade ≥ III	LDCR was 82% and 90.5% for the ITT and PP patients, with 10 downstaged becoming amenable for surgery	The integrated regimen with ^32P-microparticles and chemotherapy was relatively safe and led to surgical resection the 20% of treated patients
Nadu et al [14]	Australia/2022	Prospective, singe center	12	No significant peri-procedural complications	Reduction in tumor volume and metabolic activity in all cases, 5 of which underwent surgery	The integrated regimen combining ^32P-microparticles and chemotherapy is safe and results in an improved tumor resection rate

LDCR: local disease control rate; ITT: intention-to-treat population; PP: population treated with ³²P-microparticles; treatment-emergent adverse events.

2. Preclinical and preliminary clinical studies with ³²P-colloids/microspheres

One of the first attempts to employ ³²P for the treatment of PDAC in vitro and in vivo was carried out by Gao et al. [7]. The authors investigated the distribution and anticancer effects of ³²P-chromic phosphate colloid (³²p-CP) following intratumoral injection in Pc-3 human pancreatic carcinoma-bearing nude mice. Eighty-four mice were divided into 11 groups, receiving different doses of ³²p-CP. Results showed significant accumulation of ³²p-CP in tumors with long retention. Tumor-inhibiting rates, proliferating index, and microvascular density varied with dosage. No significant differences in white blood cells, platelets, or body weight were observed compared to controls. The study suggested that intratumoral injection of ³²p-CP might be a safe and effective therapy for pancreatic carcinoma in mice, thus paving the ground for the first-in-human explorations. The same group of research evaluated the efficacy of using ³²P colloids or microspheres, administered intra-arterially or through stromal injection, for treating refractory solid tumors. Sixty cases were treated, with administration guided by various imaging techniques. Results showed significant tumor growth inhibition post-injection, with a high average survival time of 35 months and a tumor inhibition rate of 93.4%. Histological examination revealed intratumoral necrosis and intense fibrosis. Overall, arterial administration or stromal injection of ³²P-microspheres or colloid demonstrated promising clinical effectiveness, with recommended safe dosage ranges identified for both [8]. The experiences conducted by Gao and colleagues, although promising, highlighted a certain heterogeneity in the modality of administration and the employed compound (i.e. ³²P-microspheres/colloids), emphasizing the need to develop a dedicated device that would standardize the implantation procedure and be compatible with clinical practice.

3. First clinical applications of dedicated device

A first report describing the use of a dedicated device based on ³²P-microparticles for the management of locally advanced PDAC was published by Bhutani and coworkers [9]. Their procedure was conducted as part of an ongoing clinical trial, specifically the OncoPaC-1 (NCT03076216). This involved the implantation of ³²P-microparticles either during the 4th or 5th week of the initial chemotherapy cycle. A predefined preparation protocol was followed to generate a suspension of ³²P-microparticles suitable for administering a tumor dose of 100 Gy. In accordance with the protocol, the microparticles were suspended in 8% of the tumor volume and delivered via EUS into the center of the PDAC using a 22-gauge needle during the 4th week of chemotherapy, as schematized in Figure 1. After completing the procedure, planar images and bremsstrahlung single-photon emission computed tomography (SPECT/CT) at 4 h and 7 days post implantation were carried out to visualize the biodistribution of microparticles and rule out extrapancreatic deposition. Subsequently, the chemotherapeutic regimen was resumed following implantation. Follow-up CT scans were performed every 8 weeks, revealing a notable 58% reduction in tumor volume by the 16th week post-therapy. Furthermore, the patient experienced complete resolution of abdominal pain, a significant decrease in the tumor-related biomarker (CA 19–9) compared to baseline, and the procedure exhibited no significant associated toxicity.

Figure 1. Schematic representation of EUS-guided administration of ³²P-microparticles (left side). In published studies, microparticles’ biodistribution has been assessed by bremsstrahlung SPECT/CT at 4 h and 7 days’ post implantation, while tumor response has been evaluated at 16 weeks by CT and 12 weeks by ¹⁸F-FDG PET/CT (right side). Figure created with BIorender.com.

Subsequently, the same research group published the detailed technical protocol of the OncoPaC-1 trial and reported the first clinical results [10,11]. In nine enrolled patients, the procedure was successfully conducted during the course of chemotherapy. Notably, the local disease control rate (LDCR) at week 16 was 88%, with partial response or stable disease observed in seven out of eigth patients. Additionally, the median change in tumor volume at week 16 showed a reduction of −9% (ranging from +61 to −80%). One grade IV adverse event (AE) and 23 grade III AEs (neutropenia, anemia, and thrombocytopenia) were reported as possibly or probably related to either chemotherapy or ³²P-microparticles. These promising results led to the approval of the Oncosil^TM device for the treatment of locally advanced PDAC by the Food and Drug Administration first, and subsequently by the corresponding European regulatory authority (https://www.oncosil.com accessed on the 20 December 2023).

More recently, the results of The PanCO study, an international, multicenter, single-arm, open-label pilot study, have been published [12]. The study was conducted in patients with locally advanced PDAC (target lesion diameter 2–6 cm), who were treated with ³²P-microparticles in combination with either FOLFIRINOX or gemcitabine/nab-paclitaxel chemotherapy. The primary objective of the study was to assess safety and tolerability, focusing on the frequency of treatment-emergent adverse events (TEAEs). The secondary objective involved determining the LDCR at 16 weeks, encompassing complete or partial responses, or stable disease in the target lesion. Evaluation was performed according to the Response Evaluation Criteria in Solid Tumors v.1 (RECIST.1). Additionally, changes in tumor metabolic parameters were assessed through positron emission computed tomography (PET/CT) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) at 12 weeks [13]. The intention-to-treat population (ITT), receiving chemotherapy, comprised 50 patients, with 42 also undergoing treatment with ³²P-microparticles (PP). A total of 1102 TEAEs were reported, with 167 (15.1%) classified as grade ≥ III. Notably, in the population subjected to ³²P-microparticles, 41 TEAEs in 16 (38.1%) patients were deemed possibly or probably related to ³²P-microparticles or the implantation procedure, with no grade five TEAEs. Among the reported AEs, the most prevalent grade ≥3 AEs were hematological (neutropenia and anemia) and fatigue, predominantly attributed to chemotherapy. Regarding the PP population, it is significant to note that 30.2% of TEAEs were observed before the implantation of ³²P microparticles, while 69.8% occurred afterward. It is noteworthy that the LDCR yielded results of 82% and 90.5% for the ITT and PP populations, respectively. In all cases, a reduction in PET-derived metabolic parameters was observed at the 12-week follow-up PET/CT scan, with six patients achieving a complete metabolic response. Most significantly, 10 cases (20%) underwent surgical resection.

Along this trajectory, a subsequent study conducted by Nadu and colleagues assessed clinical outcomes in 12 patients with PDAC, treated with ³²P-microparticles after completing two cycles of chemotherapy, followed by an additional six cycles of chemotherapy [14]. In all cases, the procedure was successfully completed, with no significant complications. Additionally, response evaluation assessed by ¹⁸F-FDG PET/CT showed a meaningful reduction in tumor volume in all cases, with minimal or absent tracer uptake in nine cases. Tumor downstaging led to surgical resection in five cases (42%), four of which showed microscopically negative surgical margins (R0).

4. Final considerations

From the analysis of the available literature on ³²P-microparticles in locally advanced PDAC, some considerations can be done. Returning to the 1st of the two questions posed in the title: ‘How should ³²P-microparticles be administered?,“ the delivery of microparticles guided by EUS was found to be feasible, with no significant peri-procedural complications reported. However, it is noteworthy that the PanCO trial documented one case of intravasation of ³²P-microparticles leading to shunting into the lungs [12]. This occurrence was attributed to intratumoral varices, prompting the study safety review committee to advice against enrolling the affected patient. Therefore, precise patient selection is imperative prior to enrolling individuals in ³²P-microparticles therapy. As for the 2nd question, namely ”When should ³²P-microparticles be administered?,’ it is evident that all the conducted studies employed the device during the course of chemotherapy, with a highly variable timing (between the 4th and 5th week, at the 16th week, or after two cycles), hence the most appropriate timing for applying this type of treatment remains to be established. In this regard, the association between the two approaches (³²P-microparticles and chemotherapy) was found to be relatively safe and, in some cases, led to successful surgical resection. Considering all the aforementioned factors, integrated regimens combining ³²P-microparticles and chemotherapy appear particularly promising in locally advanced PDAC, especially given the limited therapeutic options in this clinical setting. However, it should be emphasized that all the studies conducted thus far have involved small cohorts of patients. Additionally, further investigations are required to determine whether the combination of ³²P-microparticles with chemotherapy not only improves response rates but also yields a significant survival benefit. Therefore, well-designed clinical trials, preferably randomized and prospective, involving larger cohorts of patients through multicenter collaborations, are essential to better evaluate the potential and impact of this innovative device in the context of locally advanced PDAC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.