Next Article in Journal
Development of a Gene and Nucleic Acid Delivery System for Skeletal Muscle Administration via Limb Perfusion Using Nanobubbles and Ultrasound
Previous Article in Journal
Magnetic Nanoparticles for Therapy and Diagnosis in Nanomedicine
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 15
Issue 6
10.3390/pharmaceutics15061664
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review

by
Akira Saito
1,
Joji Kitayama
1,2,
Ryozo Nagai
3 and
Kenichi Aizawa
2,4,*
1
Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
2
Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi, Tochigi 329-0498, Japan
3
Department of Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
4
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
*
Author to whom correspondence should be addressed.
Pharmaceutics 2023, 15(6), 1664; https://doi.org/10.3390/pharmaceutics15061664
Submission received: 12 May 2023 / Revised: 2 June 2023 / Accepted: 4 June 2023 / Published: 6 June 2023
(This article belongs to the Special Issue Targeted Drug Delivery for Diagnostic and Therapeutic Applications)
Browse Figure
Review Reports Versions Notes

Abstract

:
Despite remarkable recent progress in developing anti-cancer agents, outcomes of patients with solid tumors remain unsatisfactory. In general, anti-cancer drugs are systemically administered through peripheral veins and delivered throughout the body. The major problem with systemic chemotherapy is insufficient uptake of intravenous (IV) drugs by targeted tumor tissue. Although dose escalation and treatment intensification have been attempted in order to increase regional concentrations of anti-tumor drugs, these approaches have produced only marginal benefits in terms of patient outcomes, while often damaging healthy organs. To overcome this problem, local administration of anti-cancer agents can yield markedly higher drug concentrations in tumor tissue with less systemic toxicity. This strategy is most commonly used for liver and brain tumors, as well as pleural or peritoneal malignancies. Although the concept is theoretically reasonable, survival benefits are still limited. This review summarizes clinical results and problems and discusses future directions of regional cancer therapy with local administration of chemotherapeutants.

1. Introduction

In recent years, prognoses of patients with metastatic cancer have improved due to advances in chemotherapeutic drugs and emergence of new molecular targets [1,2]. However, outcomes of cancer patients, especially those with solid tumors, still remain unsatisfactory. Anticancer agents are usually administered though peripheral veins, since most anti-cancer agents are easily absorbed in blood and rapidly carried throughout the body. Despite being the most common route of drug administration, systemic chemotherapy, especially with dose-escalation strategies, often has limited anti-cancer effects because of hematologic and non-hematologic toxicities [3,4]. Indeed, distribution of systemically administered drugs depends largely on the blood supply of each organ. As a result, healthy organs may be subjected to high drug doses while insufficient doses are delivered to target lesions, producing high systemic toxicity with minimal anti-tumor efficacy. In such cases, it is necessary to develop drug transporters, e.g., nanoparticles [5,6], that can reach the target more efficiently or to develop more efficient drug delivery methods in order to enhance therapeutic effectiveness.
An alternative approach is regional administration of anti-cancer drugs. Because the route of administration directly affects drug bioavailability, which determines both onset and duration of pharmacological effects in targeted organs, various types of local-regional chemotherapy have been attempted [7,8,9,10]. Among them, intra-arterial (IA), intrathecal (ITh), intrapleural (I-Pl), intraperitoneal (I-Pr) and intratumoral (IT) routes have been reported as useful treatment strategies for specific tumors (Figure 1). This review provides a comprehensive overview of clinical results and challenges of current anti-cancer therapies using various routes of administration, and discusses the future of local cancer therapy.

2. Intra-Arterial Route (IA)

This regional approach is suitable for cancers in organs with abundant arterial blood supply. Currently, IA administration of anticancer drugs is performed for hepatocellular carcinomas (HCC), metastatic liver tumors, brain tumors, and head and neck cancers.

2.1. HCC

A wide range of therapeutic options is available for HCC. Outcomes for patients undergoing liver resections are generally unfavorable, as a result of the high postoperative recurrence rate [11]. Chemotherapy is one of the most important treatment modalities for advanced HCC. However, the efficacy of chemotherapy is still unsatisfactory, resulting in poor prognoses [12,13,14,15,16,17]. As progression of HCC is largely dependent on blood flow from the hepatic artery, transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are often used in clinical practice, and these greatly improve therapeutic effects.
TACE is one of the standard treatment modalities. In the international guideline-approved Barcelona Clinic Liver Cancer (BCLC) staging system, TACE is considered the standard of care for intermediate-stage HCC, including unresectable, multinodular HCC without extrahepatic metastases [18,19]. TACE consists of an intra-arterial injection of anti-cancer drugs emulsified in Lipiodol, an oily and radiopaque agent, followed by an additional intra-arterial injection of an embolic agent, such as a gelatin sponge. By this method, Lipiodol allows the anti-cancer drug to reach the tumor directly, causing embolization of tumor microcirculation, enhancing antitumor efficacy. Moreover, Lipiodol that remains in the tumor can be detected by image inspections even after treatment, making it possible to determine therapeutic efficacy.
Drug-eluting beads (DEBs), non-resorbable, embolic microspheres, can release drugs. By using DEB, sustained tumor effects of cytotoxic agents with tumor embolic effects were maintained, and their efficacy has recently been evaluated [20,21,22,23]. Irie et al. reported development of a technique called balloon-occluded TACE (B-TACE) [24]. B-TACE is defined as infusion of a chemotherapeutic emulsion containing Lipiodol, followed by infusion of a gelatin particle sponge with occlusion of the feeding artery using a microballoon catheter [25]. Occlusion of the feeding artery containing Lipiodol at the target nodule, results in higher accumulation of the chemotherapeutic emulsion. In recent years, several reports have shown that the therapeutic effect of B-TACE is superior to that of conventional TACE [26,27,28]. In the future, it may offer a safe and effective alternative to the current standard catheter TACE [29].
HAIC is employed to treat patients who are deemed unsuitable candidates for surgical resection, local ablative therapy, or TACE, that is, patients who have extrahepatic metastasis, show evidence of vascular invasion, or are refractory to TACE [12,13,14,15,16,17]. HAIC permits chemotherapeutic agents to be delivered directly into feeding arteries of liver tumors while maintaining high local drug concentrations using an implantable port system. Therefore, compared with systemic chemotherapy, it is possible to enhance anti-tumor effects and to minimize systemic toxicity [30]. Several reports have suggested that HAIC improves overall survival (OS) and progression-free survival (PFS) in patients with advanced HCC, suggesting that HAIC is more effective than conventional systemic chemotherapy [31,32,33,34,35]. In the future, the efficacy of HAIC combined with systemic chemotherapy or molecularly targeted drugs will be investigated [36,37], and if a survival benefit is demonstrated, HAIC will be recognized as a standard treatment for patients with advanced HCC [38].

2.2. Metastatic Liver Tumors

Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and mortality [39]. Liver metastatic disease invariably results from metastasis in colorectal cancer patients due to the fact that venous drainage from the colon and rectum allows metastases to migrate to the liver via the portal vein. Because of its high prevalence, liver-directed therapies have been developed, and hepatic arterial infusion (HAI) is now used for metastatic liver tumors as well.
In patients with unresectable metastases to the liver, HAI combined with systemic chemotherapy, increases the likelihood of resection to provide patients with a chance for cure, compared with systemic therapy alone. It shows increased reaction and conversion [40]. In patients who receive HAI in an adjuvant setting after liver surgery, HAI therapy given with systemic chemotherapy can increase disease-free survival [41].

2.3. Brain Tumors

First-pass metabolism of intravenously (IV)-delivered drugs and the blood-brain barrier (BBB) make it difficult to achieve therapeutically effective concentrations of anti-neoplastic agents against brain tumors. These are the biggest obstacles to treating brain tumors [42]. IA chemotherapy is a form of regional delivery to brain tumors, designed to enhance intra-tumoral concentrations of drugs, in comparison with the intravenous route. IA delivery directly to the cerebral vasculature, obviates first-pass metabolism and associated systemic adverse effects of IV chemotherapy. Recently, clinical studies have shown therapeutic efficacy of IA chemotherapy for low- and high-grade gliomas and cerebral lymphomas. Additionally, carboplatin and methotrexate can reduce toxicity [43,44], but no Phase III trials have been conducted with carboplatin or methotrexate. Further clinical studies are needed to establish IA chemotherapy in treatment of primary brain tumors.

2.4. Head and Neck Cancers

Advanced head and neck cancers typically involve multiple organs, such as the larynx, pharynx, tongue, and maxilla, and treatment strategies, including partial or complete resection have been considered. However, while these are curative treatments for cancer, they still pose major problems as they inevitably lead to substantial functional impairment and disfigurement [45]. The desired treatment for head and neck tumors is eradication of the tumor while preserving function and appearance. Therefore, in order to improve the survival rate of patients with advanced head and neck cancer without sacrificing function, multidisciplinary treatment including, not only surgery, but also radiotherapy and systemic chemotherapy is needed. Blood is supplied to head and neck tumors mainly from branches of the external carotid artery, and IA chemotherapy, which is specialized for local chemotherapy, is a suitable treatment for localized malignant neoplasms of head and neck cancer. Recently, significant advances in vascular radiology techniques and development of new devices, such as fluoroscopy units and angiographic catheters, have enabled repetitive hyperselective IA chemotherapy. IA infusion of high-dose cisplatin with systemic neutralization and intravenous sodium thiosulfate for advanced head and neck cancer has become a therapeutic modality with low systemic toxicity and high tumor response [46]. In addition, Heianna et al. suggested that selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin may achieve both good local control and survival in bulky, node-fixed head and neck cancer of unknown primary origin (HNCUP) [47] (Table 1).

3. Intrathecal Route (ITh)

The incidence of metastatic brain tumors from various cancers ranges from 9% to 30% [48,49,50,51,52]. Melanoma, breast cancer, and lung cancer are the main carcinomas that cause brain metastasis [48], and metastatic brain tumors generally have poor prognosis [51]. Conventional systemic anti-cancer treatments, including chemotherapy and targeted therapies, are largely ineffective against metastatic brain tumors. This is because there are three barrier systems (arachnoid, blood-cerebrospinal fluid (BCSFB), and blood-brain barrier (BBB)) that physically and functionally separate extracellular fluids from the central nervous system (CNS). Therefore, anti-cancer drugs fail to reach metastatic brain tumors at effective concentrations [48,50,53,54,55]. For most antineoplastic agents, total cerebrospinal fluid (CSF) exposure following administration of a systemic dose is less than 10% of systemic exposure. Furthermore, since there is a BBB after that, most anticancer drugs do not reach the brain [56]. Therefore, ITh administration was developed with the hope of effectively delivering anticancer drugs to brain tumors. ITh delivery injects substances directly into CSF-containing spaces in the CNS. Anti-cancer drugs can be delivered to the subarachnoid space by three ITh methods (lumbar injection, cerebellar medullary cistern injection, or injection into the ventricular system) [57]. ITh administration allows transport of anti-cancer drugs between the BBB and BCSFB, enhancing drug concentrations in the much smaller volume of CSF (compared to plasma). This allows drug doses to be reduced while maintaining drug concentrations in the CNS and minimizing systemic toxicity [57,58]. ITh drug delivery involves injection into the lateral ventricles via a subcutaneous reservoir called an Ommaya reservoir and a ventricular catheter [59]. The Ommaya reservoir is a subcutaneous device, with a catheter inserted into one of the lateral ventricles of the brain, providing direct access to ventricular CSF [60]. “CNS prophylaxis” with repeated cycles of ITh methotrexate (MTX) has replaced CNS prophylactic irradiation in children with low-risk acute lymphoblastic leukemia, drastically reducing the incidence of CNS relapse from 50% to 23% [61].
Donovan et al. suggest that repeat administration of CAR-T-cells, perhaps through an Ommaya reservoir, could increase therapeutic efficacy, compared to either IV administration, or single dose intraventricular administration via the lateral ventricle (LV). Delivery of CART-cell therapy directly into the CSF likely increases the exposure of CAR-T-cells to cancer cells and may decrease systemic toxicity. From the above, Donovan et al. suggested that locoregional delivery of CAR-T-cells directly into the CSF may reduce risk of systemic toxicities associated with CAR-T-cells, in comparison to the more commonly used intravenous approach [62].
In addition, ITh was investigated not only for brain tumors, but also for leptomeningeal metastases (LM). Rhun et al. reported a clinically meaningful gain in LM-related PFS when breast cancer patients with newly diagnosed LM received intrathecal liposomal cytarabine chemotherapy together with systemic treatment, compared with systemic treatment alone [63].
Finally, we present another administration route for brain tumors, convection-enhanced delivery (CED), which is slightly different from the intrathecal route. CED is a new drug administration method that uses a pressure-driven catheter to locally inject drugs into intercellular spaces of the brain under continuous positive pressure to achieve high concentration and wide drug distribution [64]. Specifically, this catheter is stereotactically placed into the tumor tissue via a burr hole under magnetic resonance imaging (MRI) guidance. The catheter is then connected to an extracranial infusion pump to distribute the infusate to the tumor by convective transport. Thus, therapeutic agents can penetrate tissue by several centimeters from the catheter tip in a pseudo-spherical distribution, in contrast to only a few millimeters with diffusion-dependent injection modalities [65]. Considering that the vast majority of brain tumor recurrences occur within 2 cm of the tumor border, the area of drug penetration after dosing completely permeates this tissue [66,67,68,69]. Currently, many clinical trials have been conducted with this administration method, and favorable results have been reported (Table 2).

4. Intrapleural Route (I-Pl)

Clinical situations in which drugs are administered into the pleural cavity by the I-Pl route, include intrapleural fibrinolytic therapy for empyema [71], pleurodesis for recurrent pneumothorax and recurrent pleural effusion [72], and I-Pl administration of anticancer drugs for malignant pleural effusion (MPE).
MPE is the most serious complication of non-small cell lung cancer (NSCLC). MPE occurs in approximately 15% of patients with NSCLC and 50% of these patients eventually develop MPE [73,74]. MPE results in symptoms such as chest discomfort, shortness of breath, palpitations, pain, and an inability to lie down, which significantly reduces patient quality of life [75,76,77]. MPEs have poor prognoses, with a median survival time of 3 to 12 months [78]. Traditional treatments for MPE include systemic chemotherapy, targeted therapy, immunotherapy, and locoregional therapy [79]. Among them, locoregional therapy for MPE is the local perfusion of talc, chemotherapeutic agents, biologic agents, and antiangiogenic agents into the pleural space to achieve adhesions in the pleural cavity [80,81,82]. Intracavity infusion of drugs after removal of pleural effusion is a standard treatment for symptomatic MPE. Drugs administered intrapleurally have been used as cytotoxics, biological response modifiers, and sclerosing agents. However, efficacies and toxicities are unsatisfactory [83].
In recent years, however, I-Pl administration of various anticancer drugs has been investigated for MPE of lung cancer, with hopeful results. Song et al. compared efficacy of I-Pl infusion of Bevacizumab (BEV) and pemetrexed with BEV and cisplatin in MPE caused by NSCLC. The objective response rate (ORR) and disease control rate (DCR) of patients treated with I-Pl infusion of BEV combined with pemetrexed was superior to that of those treated with BEV and cisplatin. The BEV and pemetrexed group also showed statistical improvement in PFS compared with the group treated with BEV and cisplatin [84].
Nie et al. compared efficiency and toxicities of I-Pl and IV infusion of bevacizumab for MPE mediated from non-squamous NSCLC in order to reveal the relationship between serum VEGF levels and outcomes of pleural effusion in NSCLC. The result was that I-Pl infusion of bevacizumab had a higher objective response rate (ORR), longer duration of response (DOR) and less toxicity than IV infusion [85]. Recently, extracellular vesicles labeled as tumor microparticles (TMPs) released by tumor cells are used as natural carriers to deliver chemotherapeutic drugs or oncolytic viruses to tumor cells [86,87]. In particular, I-Pl injection of TMP packaging methotrexate (TMPs-MTX) has proven safe and effective in maintaining anti-tumor effects and in reversing drug resistance [86,88,89,90] (Table 3).

5. Intraperitoneal Route (I-Pr)

Metastasis to the peritoneum is a severe complication of abdominal cancers that causes debilitating symptoms and clinical deterioration with poor prognosis. The peritoneum covers the abdominopelvic organs and the physiologic peritoneum-plasma barrier limits uptake of effective concentrations of chemotherapeutics after systemic administration. After intraperitoneal administration, however, the peritoneum-plasma barrier also hinders drug loss to the systemic circulation, facilitating prolonged exposure and higher drug concentrations at the peritoneal surface than in plasma. Therefore, if anti-cancer agents used for IP chemotherapy can be prevented from exiting the peritoneal cavity rapidly, they can achieve greater tumor penetration [91]. Thus, the peritoneum-plasma barrier can be used to enhance locoregional therapeutic efficacy with limited systemic toxicity. The theoretical rationale for I-Pr chemotherapy was first described in 1978 by Dedrick et al., who showed that IP administration results in higher drug concentrations and longer half-lives in the peritoneal cavity, compared with systemic administration [92]. In the past, treatment of peritoneal metastases consisted of systemic chemotherapy or palliative surgery, which were not effective treatments [93].

5.1. Heated Intraperitoneal Chemotherapy (HIPEC)

Historically, I-Pr chemotherapy has been performed under hyperthermic conditions (heated intraperitoneal chemotherapy; HIPEC in a single intraoperative procedure that delivers anti-cancer drugs in a heated solution directly to the abdominal cavity after cytoreductive surgery (CRS) [94]. Moderate hyperthermia (41–43 °C) sensitizes tumor cells to DNA-damaging agents, such as platinum compounds and alkylating agents [95,96,97]. Heat also increases tumor cell membrane permeability leading to higher intracellular drug concentrations, and increased penetration of chemotherapeutants at the peritoneal surface [98,99,100]. The procedure to deliver anticancer drugs in a heated solution directly into the peritoneal cavity was first employed by Spratt et al. for treatment of peritoneal pseudomyxoma [101]. Later, Sugarbaker et al. successfully introduced HIPEC in combination with cytoreduction surgery (CRS), because peritoneal metastases (PM) were considered to be lesions confined to the peritoneal cavity [102]. CRS performed in combination with HIPEC is preferentially performed via open rather than laparoscopic surgery. Also, complete cytoreductive surgery requires comprehensive surgical exploration and periodic omentectomy. Peritoneal and organ resection are performed depending on the extent and location of the lesion [103]. Currently, HIPEC combined with CRS is performed mainly for pseudomyxoma, mesothelioma, ovarian, and colorectal cancers, resulting in improved outcomes of patients with peritoneal PM from colorectal [104,105] or ovarian [106,107] cancer, or mesothelioma [108]. Although evidence for efficacy of HIPEC is relatively limited because of its infrequent use in western countries, effective chemotherapeutic regimens and therapeutic effects are being investigated for gastric [109,110] and pancreatic [111] cancer. However, it is likely that HIPEC will offer fewer benefits for patients with PM of gastric or pancreas cancer because of the high-grade metastatic cancer cells. In fact, a recent review suggests that aggressive treatment for gastric cancer should be applied only in cases with a low Peritoneal Carcinoma Index (PCI < 6) [112]. Representative clinical results on HIPEC are summarized in Table 4.
On the other hand, HIPEC with CRS is often associated with serious complications that require intensive management. Gagniere et al. suggested that HIPEC for elderly patients, especially those over 70 years of age, may be associated with more grade 3 or higher complications and deaths; thus, such cases require special attention [113]. The extent to which effectiveness and adverse events of HIPEC are affected by patient selection, choice of intraperitoneal chemotherapeutic drugs, doses, and durations, temperature, and HIPEC regimens, remain largely unknown. Therefore, at present, CRS + HIPEC is performed only on selected patients in specialized facilities, and there are few data from clinical trials comparing it to other treatment methods [114]. It is necessary to perform large-scale, randomized, control trials to optimize and determine the clinical usefulness of HIPEC.
Predictive markers for potential benefit and harm associated with CRS + HIPEC are clinically important for appropriate patient selection. Concomitant lymph node metastasis, liver metastasis, signet ring cell tumor biology, and poor tumor differentiation are poor prognostic factors [115]. Translational research to identify novel molecular and biological markers is a future challenge in this field.
Efficacy of HIPEC in combination with perioperative systemic chemotherapy is being studied in colorectal cancer. The CAIRO6 [116] study is a randomized trial to determine the role of perioperative systemic therapy in addition to CRS + HIPEC for patients with colorectal peritoneal metastases. However, the effect of HIPEC with perioperative systemic chemotherapy remains undetermined. Further investigation is necessary to assess the exact role of CRS + HIPEC combined with perioperative chemotherapy, as it may offer additional clinical benefits.

5.2. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

PIPAC, a method to deliver anti-cancer drugs in aerosolized form created with a nebulizer system, has been proposed as an alternative to HIPEC to improve drug distribution and tissue uptake, as well as enhanced tolerance by patients [117,118]. Using aerosols allows uniform redistribution of substances within an enclosed space. Creating an artificial pressure gradient can offset the tumor interstitial fluid pressure, which is an obstacle to cancer therapy [119,120]. In addition, increasing intraperitoneal pressure particularly enhances uptake of drugs into tumors, resulting in a higher local disposition [117,121,122,123]. Another property leading to superior local disposition is the high drug concentration in the aerosol. Although administered at only 1/10 of the total dose, anticancer drug concentration in the aerosol can be three times higher than that in intraperitoneal fluids typically used in HIPEC, without compromising tolerability [122,124]. Moreover, preclinical studies showed that PIPAC results in good distribution and penetration into tumor nodules in the abdominal cavity [125,126]. Based on these results, PIPAC has been broadly adopted during the past decade, mainly in Europe. Recent reviews suggest that PIPAC is safe and feasible, and offers hope for patients with various types of peritoneal malignancies, although prospective controlled trials are necessary in the future [127,128].

5.3. I-Pr Repeated Administration of Taxanes

Another disadvantage of HIPEC is that single-dose administration results in insufficient anticancer agent exposure to peritoneal metastases. Therefore, repeated IP injections are required to obtain a sufficient therapeutic effect on PM. Recently, repeated IP infusion of anti-cancer drugs has become possible using implantable port systems [129,130]. Taxanes such as paclitaxel (PTX) or docetaxel (DOC) are broad-spectrum anticancer drugs that are clinically effective against various types of cancer. Taxanes are theoretically ideal drugs for I-Pr chemotherapy because they stay in the peritoneal space for a long time due to their hydrophobic properties [131], which enables direct penetration into peritoneal disseminated tumors [91,132,133]. However, the depth of infiltration after one-time IP administration of a taxane is limited [134]. In a previous study, we showed that the distance of PTX infiltration was only 100–200 μm beneath the surface of the tumor [133]. Therefore, it is necessary to repeat IP administration to improve antitumor effects to the PM. Fortunately, even if PTX is repeatedly administered intraperitoneally, it rarely causes adhesion of organs in the peritoneal cavity because of its antiproliferative effect, and distribution of i.p. PTX across the intra-abdominal space is not hampered by drug-induced peritonitis [135]. An implantable intraperitoneal access port system is useful for repeated administration of PTX. Once the port is implanted subcutaneously, anti-cancer drugs can be minimally invasive and repeatedly injected into the abdominal cavity without additional invasive surgery. Repeated IP chemotherapy using the port is safe and feasible with proper management and resolution of port complications [136]. In addition, ascites or lavages can be repeatedly collected from the port during each chemotherapeutic cycle, which can provide useful information to assess therapeutic effects.
Recent phase II studies have suggested that I-Pr administration of PTX at a normal temperature, i.e., without heating, is effective for PM from gastric [137,138,139] or pancreatic [140,141] cancer. A randomized, multicenter, phase Ⅲ trial (PHOENIX-GC Trial) [142] was performed to compare I-Pr and IV PTX + S-1 (IP) with the Japanese standard regimen of S-1 + cisplatin (SP) in patients with GC with peritoneal metastasis. Unfortunately, this trial failed to show statistical superiority of IP-PTX + systemic chemotherapy, possibly due to a randomization bias and protocol violations in many patients. However, subsequent exploratory sensitivity analyses (follow-up analysis of 3-year overall survival rate and comparison of treatment responses based on change in ascites among PPS, excluding patients with post-protocol treatment violations) strongly suggest clinical benefits of the IP regimen (Table 5).
Malignant ascites are often present in patients with peritoneal dissemination, seriously affecting the therapeutic efficacy of I-Pr chemotherapy. Reinfusion of autologous ascitic fluids, which contain large amounts of protein and nutrients after filtration and concentration using a special membrane system, is called cell-free and concentrated ascites reinfusion therapy (CART). This has been used with significant clinical benefits for cachexic patients with malignant ascites [143,144], and is especially effective for palliation for patients with symptomatic ascites. In addition, CART often improves performance status of patients who can receive repeated I-Pr administration of PTX, which results in improved survival [145]. CART is now recommended as a treatment option for patients with malignant ascites in Japan [146].
Table
Table 5. Studies that employed intraperitoneal drug administration (normothemic I-Pr).
Table 5. Studies that employed intraperitoneal drug administration (normothemic I-Pr).
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Peritoneal metastasis (PM)Gastric cancerPaclitaxe [131,133,136,142]Ⅲ
UMIN000005930
Gastric cancerDocetaxel [132]-
Gastric cancerCatumaxomab [147,148]Ⅱ/Ⅲ
NCT0083664
Pancreatic cancerPaclitaxel [134,135,140,141]Ⅰ/Ⅱ
UMIN000018878
Ovarian cancerCatumaxomab [147,148]Ⅱ/Ⅲ
NCT0083664
Ovarian cancerBevacizumab [149,150]Ⅱ
ANZGOG 11–01
Colorectal cancerBevacizumab [149]-
Breast cancerBevacizumab [149]-
Uterine cancerBevacizumab [149]-

5.4. Other Novel Drugs

Recently, novel molecular targeting drugs have been used clinically via IPr routes without heat (Table 5). Catumaxomab is a trifunctional monoclonal antibody with two antigen-binding sites, EpCAM and CD3, and a functional Fc domain that activates a complex antitumor immune reaction through various effector functions, such as antibody-dependent cellular cytotoxicity, phagocytosis, and T cell-mediated cytotoxicity [147]. Heiss et al. performed a randomized phase II/III trial, and reported that IP injection of catumaxomab improved puncture-free survival and exhibited better survival in patients with malignant ascites caused by various malignancies, including gastric cancer [148]. According to their results, catumaxomab, has been licensed for clinical use in the European Union since 2009 for malignant effusion, and promising results have been reported for patients with gastric cancer with PM from gastric cancer [151,152]. Another drug, bevacizumab, a humanized variant of an anti-VEGF antibody, could be useful against malignant ascites [149], since vascular endothelial growth factor A (VEGF-A) is a key mediator of angiogenesis. Sjoquist et al. have shown that IP infusion of bevacizumab is effective for patients with chemotherapy-resistant ovarian cancer with symptomatic ascites [150]. In addition, development of an engineered, exosome-based, peritoneal-localized hydrogel was recently reported to domesticate peritoneal macrophages. Exosomes were fabricated from genetically engineered M1-type macrophages with overexpressed Siglec-10 (SM1Aexo), which were further chemically decorated with sodium alginate oxide (OSA) to form a gelator (O-SM1Aexo). In addition to this, a hydrogel loaded with an efferocytosis inhibitor (MRX-2843) is co-administered intraperitoneally. Administered SM1Axo polarizes M2-type macrophages in the peritoneum to M1-type macrophages, and overexpressed Siglec-10 competitively blocks CD24 on macrophages and amplifies TAM phagocytosis. Furthermore, MRX-2843 enabled enhanced accumulation of dying tumor cells, ensuring adequate release of tumor-derived cGAMP and DAMPs to induce a strong STING-mediated secretion of type I interferon in TAMs and to improve immunogenicity. These factors exert an antitumor effect. In vivo experiments showed that intraperitoneal administration of this engineered exosome-based peritoneal-localized hydrogel is useful against peritoneal dissemination of ovarian cancer [153]. The efficacy of repeated I-Pr chemotherapy is highly dependent on uniform distribution of the drug throughout the abdomen and deep penetration of the drug into the peritoneal tumor. In the future, development of drug modifications and improved delivery methods to enhance drug infiltration into peritoneal tumors may further improve the prognosis of patients with peritoneal dissemination.

6. Intratumor Route (IT)

Intratumorally administered drugs diffuse into the injected area and reach the targeted tumor in high concentrations. Next, the drug slowly moves from tissues into the systemic circulation over time and leads to early access to tumor-draining lymph nodes, which are important for anti-tumor immune responses [154]. In addition, IT may provide access to tertiary lymphoid structures that occur in the tumor microenvironment as a result of immune responses to tumor antigens [155,156]. Compared to conventional systemic chemotherapy, advantages of this method of administration not only include high intratumor and tumor tissue drug concentrations and early delivery to tumor-associated lymph nodes, but also reduced systemic toxicity [157]. Intratumoral administration began in the 19th century with local injections of Streptococcus pyogenes and Corey toxin for treatment of soft-tissue sarcomas [158], and has been used for intravesical injections of Bacillus Calmette–Guerin (BCG), which is still used today as a treatment for superficial bladder cancer [159,160]. Recent studies have clarified the importance of an anti-tumor immune response mediated by IFNγ-producing T cells and natural killer (NK) cells, as well as by macrophages activated as a result of BCG injection [161]. Therefore, intratumoral immunotherapy is currently being intensively studied. Intratumoral immune therapies inject immunostimulatory products directly into a tumor lesion to locally stimulate an antitumor immune response and to generate a systemic immune response against the tumor by immune cells and antibodies in the blood and lymph [162]. At present, clinical trials of intratumoral administration of many immunostimulatory products and combination therapy with other drugs are being conducted for various carcinomas, and favorable results have been reported, mainly for malignant melanoma (Table 6). However, while the dose of systemic chemotherapy is calculated based on a patient’s body weight and body surface area, a method for calculating doses for intratumoral administration has not yet been determined. Since it is necessary to consider the extent of the lesion, the size of the tumor, and effects of concomitant therapy, methods for calculating doses for intratumoral administration and determining the appropriate regimen are future issues [163] (Table 6).
Supplemental Table S1 shows the drugs described so far and their mechanisms of action [173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193].

7. Emerging Preclinical Strategies for Intrathoracic Administration Route via Lymphatics

Efficiency of anticancer drug delivery by IV administration to lymph nodes is poor compared to blood-rich organs such as liver and lung. Recently, we examined retrograde administration of PTX from lymphatic vessels as a novel route of administration for extensive lymph node metastases (ELM) in the abdomen. The thoracic duct, the body’s central lymphatic vessel, originates in the cisterna chyli in the retroperitoneum, ascends between the esophagus and the descending aorta in the mediastinum, and flows into the left venous angle in humans [194,195]. Therefore, retrograde administration via the thoracic duct may deliver high doses of anticancer agents to metastatic lymph nodes in the retroperitoneum with low systemic toxicity. Based on this hypothesis, we used a swine model to catheterize the thoracic ducts of pig necks and to infuse PTX via catheters. Then, we compared pharmacokinetics of PTX administered intrathoracically to those of intravenous infusion [196]. The concentration of PTX in serum, liver, and spleen was significantly lower following thoracic duct (IT) infusion than after intravenous (IV) administration, 1–8 h after drug infusion. However, PTX levels in abdominal lymph nodes were maintained at relatively high levels up to 24 h after IT infusion compared to after IV infusion. Therefore, IT delivery of PTX into the thoracic duct may yield clinical benefits for patients with ELM in abdominal malignancies.

8. Conclusions and Future Directions

This review presents a comprehensive overview of current perspectives on routes of drug administration for cancer. Recently, various types of drugs, such as antibody preparations and nanomicellar modifications, have been developed to enhance selective targeting to solid tumors. However, the route of drug administration is another critical determinant that can regulate pharmacokinetics and toxicity, impacting the clinical efficacy of anti-cancer drugs [197]. A recent report shows that anti-PD-L1 antibody can be delivered more efficiently by an intraperitoneal route compared with the EPR effect of systemic infusion [198]. Future studies need to examine pharmacodynamics of newly developed anti-cancer agents after administration by different routes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharmaceutics15061664/s1, Table S1. Mechanisms of action of the drugs cited in this review.

Author Contributions

Conceptualization, A.S. and K.A.; methodology, A.S., K.A. and J.K.; validation, K.A. and J.K.; investigation, A.S., K.A., J.K. and R.N.; data curation, A.S., K.A., J.K. and R.N.; writing—original draft preparation, A.S., K.A. and J.K.; writing—review and editing, A.S., K.A. and J.K.; visualization, A.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Galmarini, D.; Galmarini, C.M.; Galmarini, F.C. Cancer chemotherapy: A critical analysis of its 60 years of history. Crit. Rev. Oncol. Hematol. 2012, 84, 181–199. [Google Scholar] [CrossRef] [PubMed]
  2. Tafesse, T.B.; Bule, M.H.; Khan, F.; Abdollahi, M.; Amini, M. Developing Novel Anticancer Drugs for Targeted Populations: An Update. Curr. Pharm. Des. 2021, 27, 250–262. [Google Scholar] [CrossRef]
  3. Brain, E.; Levy, C.; Serin, D.; Roché, H.; Spielmann, M.; Delva, R.; Veyret, C.; Mauriac, L.; Rios, M.; Martin, A.L.; et al. High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer. Br. J. Cancer 2011, 105, 1480–1486. [Google Scholar] [CrossRef]
  4. Ait-Oudhia, S.; Mager, D.E. Array of translational systems pharmacodynamic models of anti-cancer drugs. J. Pharmacokinet. Pharmacodyn. 2016, 43, 549–565. [Google Scholar] [CrossRef] [PubMed]
  5. Overchuk, M.; Harmatys, K.M.; Sindhwani, S.; Rajora, M.A.; Koebel, A.; Charron, D.M.; Syed, A.M.; Chen, J.; Pomper, M.G.; Wilson, B.C.; et al. Subtherapeutic Photodynamic Treatment Facilitates Tumor Nanomedicine Delivery and Overcomes Desmoplasia. Nano Lett. 2021, 21, 344–352. [Google Scholar] [CrossRef]
  6. Lin, Z.P.; Nguyen, L.N.M.; Ouyang, B.; MacMillan, P.; Ngai, J.; Kingston, B.R.; Mladjenovic, S.M.; Chan, W.C.W. Macrophages Actively Transport Nanoparticles in Tumors After Extravasation. ACS Nano 2022, 16, 6080–6092. [Google Scholar] [CrossRef] [PubMed]
  7. Krementz, E.T.; Creech, O., Jr.; Ryan, R.F.; Reemtsma, K. An appraisal of cancer chemotherapy by regional perfusion. Ann. Surg. 1962, 156, 417–428. [Google Scholar] [CrossRef]
  8. Chen, H.S.; Gross, J.F. Intra-arterial infusion of anticancer drugs: Theoretic aspects of drug delivery and review of responses. Cancer Treat. Rep. 1980, 64, 31–40. [Google Scholar]
  9. Alexander, R.L.; Greene, B.T.; Torti, S.V.; Kucera, G.L. A novel phospholipid gemcitabine conjugate is able to bypass three drug-resistance mechanisms. Cancer Chemother. Pharmacol. 2005, 56, 15–21. [Google Scholar] [CrossRef]
  10. Grootenboers, M.J.; Heeren, J.; van Putte, B.P.; Hendriks, J.M.; van Boven, W.J.; Van Schil, P.E.; Schramel, F.M. Isolated lung perfusion for pulmonary metastases, a review and work in progress. Perfusion 2006, 21, 267–276. [Google Scholar] [CrossRef]
  11. Llovet, J.M.; Bruix, J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008, 48, 1312–1327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Ikeda, M.; Mitsunaga, S.; Ohno, I.; Hashimoto, Y.; Takahashi, H.; Watanabe, K.; Umemoto, K.; Okusaka, T. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future. Diseases 2015, 3, 360–381. [Google Scholar] [CrossRef] [Green Version]
  13. Kudo, M.; Trevisani, F.; Abou-Alfa, G.K.; Rimassa, L. Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment. Liver Cancer 2016, 6, 16–26. [Google Scholar] [CrossRef] [PubMed]
  14. Kudo, M.; Matsui, O.; Izumi, N.; Iijima, H.; Kadoya, M.; Imai, Y.; Okusaka, T.; Miyayama, S.; Tsuchiya, K.; Ueshima, K.; et al. JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan. Liver Cancer 2014, 3, 458–468. [Google Scholar] [CrossRef]
  15. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J. Hepatol. 2012, 56, 908–943. [CrossRef] [Green Version]
  16. Bruix, J.; Sherman, M. Management of hepatocellular carcinoma: An update. Hepatology 2011, 53, 1020–1022. [Google Scholar] [CrossRef] [Green Version]
  17. Chow, P.K.; Choo, S.P.; Ng, D.C.; Lo, R.H.; Wang, M.L.; Toh, H.C.; Tai, D.W.; Goh, B.K.; Wong, J.S.; Tay, K.H.; et al. National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma. Liver Cancer 2016, 5, 97–106. [Google Scholar] [CrossRef] [PubMed]
  18. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol. 2018, 69, 182–236. [Google Scholar] [CrossRef] [Green Version]
  19. Heimbach, J.K.; Kulik, L.M.; Finn, R.S.; Sirlin, C.B.; Abecassis, M.M.; Roberts, L.R.; Zhu, A.X.; Murad, M.H.; Marrero, J.A. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018, 67, 358–380. [Google Scholar] [CrossRef] [Green Version]
  20. Burrel, M.; Reig, M.; Forner, A.; Barrufet, M.; de Lope, C.R.; Tremosini, S.; Ayuso, C.; Llovet, J.M.; Real, M.I.; Bruix, J. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J. Hepatol. 2012, 56, 1330–1335. [Google Scholar] [CrossRef]
  21. Spreafico, C.; Cascella, T.; Facciorusso, A.; Sposito, C.; Rodolfo, L.; Morosi, C.; Civelli, E.M.; Vaiani, M.; Bhoori, S.; Pellegrinelli, A.; et al. Transarterial chemoembolization for hepatocellular carcinoma with a new generation of beads: Clinical-radiological outcomes and safety profile. Cardiovasc. Interv. Radiol. 2015, 38, 129–134. [Google Scholar] [CrossRef] [PubMed]
  22. Deipolyi, A.R.; Oklu, R.; Al-Ansari, S.; Zhu, A.X.; Goyal, L.; Ganguli, S. Safety and efficacy of 70-150 μm and 100-300 μm drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J. Vasc. Interv. Radiol. 2015, 26, 516–522. [Google Scholar] [CrossRef] [PubMed]
  23. Richter, G.; Radeleff, B.; Stroszczynski, C.; Pereira, P.; Helmberger, T.; Barakat, M.; Huppert, P. Safety and Feasibility of Chemoembolization with Doxorubicin-Loaded Small Calibrated Microspheres in Patients with Hepatocellular Carcinoma: Results of the MIRACLE I Prospective Multicenter Study. Cardiovasc. Interv. Radiol. 2018, 41, 587–593. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Irie, T.; Kuramochi, M.; Takahashi, N. Dense accumulation of lipiodol emulsion in hepatocellular carcinoma nodule during selective balloon-occluded transarterial chemoembolization: Measurement of balloon-occluded arterial stump pressure. Cardiovasc. Interv. Radiol. 2013, 36, 706–713. [Google Scholar] [CrossRef]
  25. Hatanaka, T.; Arai, H.; Kakizaki, S. Balloon-occluded transcatheter arterial chemoembolization for hepatocellular carcinoma. World J. Hepatol. 2018, 10, 485–495. [Google Scholar] [CrossRef]
  26. Arai, H.; Abe, T.; Takayama, H.; Toyoda, M.; Ueno, T.; Kakizaki, S.; Sato, K. Safety and efficacy of balloon-occluded transcatheter arterial chemoembolization using miriplatin for hepatocellular carcinoma. Hepatol. Res. 2015, 45, 663–666. [Google Scholar] [CrossRef]
  27. Irie, T.; Kuramochi, M.; Kamoshida, T.; Takahashi, N. Selective balloon-occluded transarterial chemoembolization for patients with one or two hepatocellular carcinoma nodules: Retrospective comparison with conventional super-selective TACE. Hepatol. Res. 2016, 46, 209–214. [Google Scholar] [CrossRef]
  28. Ogawa, M.; Takayasu, K.; Hirayama, M.; Miura, T.; Shiozawa, K.; Abe, M.; Matsumoto, N.; Nakagawara, H.; Ohshiro, S.; Yamamoto, T.; et al. Efficacy of a microballoon catheter in transarterial chemoembolization of hepatocellular carcinoma using miriplatin, a lipophilic anticancer drug: Short-term results. Hepatol. Res. 2016, 46, E60–E69. [Google Scholar] [CrossRef] [Green Version]
  29. Chang, Y.; Jeong, S.W.; Young Jang, J.; Jae Kim, Y. Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2020, 21, 8165. [Google Scholar] [CrossRef]
  30. Song, M.J. Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World J. Gastroenterol. 2015, 21, 3843–3849. [Google Scholar] [CrossRef]
  31. Li, S.; Xu, J.; Zhang, H.; Hong, J.; Si, Y.; Yang, T.; He, Y.; Ng, D.M.; Zheng, D. The Role of Hepatic Arterial Infusion Chemotherapy in the Treatment of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Chemotherapy 2021, 66, 124–133. [Google Scholar] [CrossRef] [PubMed]
  32. Jang, B.K.; Chung, W.J.; Park, K.S.; Cho, K.B.; Hwang, J.S.; Ahn, S.H.; Kim, Y.H.; Choi, J.S.; Kwon, J.H. The efficacy of hepatic arterial infusion therapy for advanced hepatocellular carcinoma according to extrahepatic collateral feeding vessels. Korean J. Hepatol. 2005, 11, 359–370. [Google Scholar] [PubMed]
  33. Ando, E.; Tanaka, M.; Yamashita, F.; Kuromatsu, R.; Yutani, S.; Fukumori, K.; Sumie, S.; Yano, Y.; Okuda, K.; Sata, M. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: Analysis of 48 cases. Cancer 2002, 95, 588–595. [Google Scholar] [CrossRef] [PubMed]
  34. Kim, H.Y.; Kim, J.D.; Bae, S.H.; Park, J.Y.; Han, K.H.; Woo, H.Y.; Choi, J.Y.; Yoon, S.K.; Jang, B.K.; Hwang, J.S.; et al. A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembolization using doxorubicin for intractable, advanced hepatocellular carcinoma. Korean J. Hepatol. 2010, 16, 355–361. [Google Scholar] [CrossRef]
  35. Eun, J.R.; Lee, H.J.; Moon, H.J.; Kim, T.N.; Kim, J.W.; Chang, J.C. Hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil and cisplatin with or without interferon-alpha for the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombosis. Scand. J. Gastroenterol. 2009, 44, 1477–1486. [Google Scholar] [CrossRef] [PubMed]
  36. Abou-Alfa, G.K.; Johnson, P.; Knox, J.J.; Capanu, M.; Davidenko, I.; Lacava, J.; Leung, T.; Gansukh, B.; Saltz, L.B. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: A randomized trial. JAMA 2010, 304, 2154–2160. [Google Scholar] [CrossRef] [Green Version]
  37. Ikeda, M.; Okusaka, T.; Mitsunaga, S.; Ueno, H.; Tamai, T.; Suzuki, T.; Hayato, S.; Kadowaki, T.; Okita, K.; Kumada, H. Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma. Clin. Cancer Res. 2016, 22, 1385–1394. [Google Scholar] [CrossRef] [Green Version]
  38. Ikeda, M.; Morizane, C.; Ueno, M.; Okusaka, T.; Ishii, H.; Furuse, J. Chemotherapy for hepatocellular carcinoma: Current status and future perspectives. Jpn. J. Clin. Oncol. 2018, 48, 103–114. [Google Scholar] [CrossRef] [Green Version]
  39. Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015, 65, 87–108. [Google Scholar] [CrossRef] [Green Version]
  40. DʼAngelica, M.I.; Correa-Gallego, C.; Paty, P.B.; Cercek, A.; Gewirtz, A.N.; Chou, J.F.; Capanu, M.; Kingham, T.P.; Fong, Y.; DeMatteo, R.P.; et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: Conversion to resection and long-term outcomes. Ann. Surg. 2015, 261, 353–360. [Google Scholar] [CrossRef] [Green Version]
  41. Goéré, D.; Pignon, J.P.; Gelli, M.; Elias, D.; Benhaim, L.; Deschamps, F.; Caramella, C.; Boige, V.; Ducreux, M.; de Baere, T.; et al. Postoperative hepatic arterial chemotherapy in high-risk patients as adjuvant treatment after resection of colorectal liver metastases—A randomized phase II/III trial—PACHA-01 (NCT02494973). BMC Cancer 2018, 18, 787. [Google Scholar] [CrossRef] [PubMed]
  42. Karmur, B.S.; Philteos, J.; Abbasian, A.; Zacharia, B.E.; Lipsman, N.; Levin, V.; Grossman, S.; Mansouri, A. Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome. Front. Oncol. 2020, 10, 563840. [Google Scholar] [CrossRef] [PubMed]
  43. Newton, H.B.; Slivka, M.A.; Stevens, C.L.; Bourekas, E.C.; Christoforidis, G.A.; Baujan, M.A.; Chakeres, D.W. Intra-arterial carboplatin and intravenous etoposide for the treatment of recurrent and progressive non-GBM gliomas. J. Neurooncol. 2002, 56, 79–86. [Google Scholar] [CrossRef]
  44. Doolittle, N.D.; Miner, M.E.; Hall, W.A.; Siegal, T.; Jerome, E.; Osztie, E.; McAllister, L.D.; Bubalo, J.S.; Kraemer, D.F.; Fortin, D.; et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000, 88, 637–647. [Google Scholar] [CrossRef]
  45. Robbins, K.T.; Fontanesi, J.; Wong, F.S.; Vicario, D.; Seagren, S.; Kumar, P.; Weisman, R.; Pellitteri, P.; Thomas, J.R.; Flick, P.; et al. A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx. Arch. Otolaryngol. Head Neck Surg. 1996, 122, 853–857. [Google Scholar] [CrossRef]
  46. Robbins, K.T.; Storniolo, A.M.; Kerber, C.; Vicario, D.; Seagren, S.; Shea, M.; Hanchett, C.; Los, G.; Howell, S.B. Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer. J. Clin. Oncol. 1994, 12, 2113–2120. [Google Scholar] [CrossRef] [PubMed]
  47. Heianna, J.; Makino, W.; Hirakawa, H.; Agena, S.; Tomita, H.; Ariga, T.; Ishikawa, K.; Takehara, S.; Maemoto, H.; Murayama, S. Therapeutic efficacy of selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin for fixed bulky nodal disease in head and neck cancer of unknown primary. Eur. Arch. Otorhinolaryngol. 2022, 279, 3105–3113. [Google Scholar] [CrossRef] [PubMed]
  48. Nayak, L.; Lee, E.Q.; Wen, P.Y. Epidemiology of brain metastases. Curr. Oncol. Rep. 2012, 14, 48–54. [Google Scholar] [CrossRef]
  49. Suh, J.H.; Kotecha, R.; Chao, S.T.; Ahluwalia, M.S.; Sahgal, A.; Chang, E.L. Current approaches to the management of brain metastases. Nat. Rev. Clin. Oncol. 2020, 17, 279–299. [Google Scholar] [CrossRef]
  50. Scoccianti, S.; Ricardi, U. Treatment of brain metastases: Review of phase III randomized controlled trials. Radiother. Oncol. 2012, 102, 168–179. [Google Scholar] [CrossRef] [Green Version]
  51. Tsukada, Y.; Fouad, A.; Pickren, J.W.; Lane, W.W. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983, 52, 2349–2354. [Google Scholar] [CrossRef] [PubMed]
  52. Sampson, J.H.; Carter, J.H., Jr.; Friedman, A.H.; Seigler, H.F. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J. Neurosurg. 1998, 88, 11–20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Lowery, F.J.; Yu, D. Brain metastasis: Unique challenges and open opportunities. Biochim. Biophys. Acta Rev. Cancer 2017, 1867, 49–57. [Google Scholar] [CrossRef] [Green Version]
  54. Caroli, M.; Di Cristofori, A.; Lucarella, F.; Raneri, F.A.; Portaluri, F.; Gaini, S.M. Surgical brain metastases: Management and outcome related to prognostic indexes: A critical review of a ten-year series. ISRN Surg. 2011, 2011, 207103. [Google Scholar] [CrossRef] [PubMed]
  55. Angeli, E.; Nguyen, T.T.; Janin, A.; Bousquet, G. How to Make Anticancer Drugs Cross the Blood-Brain Barrier to Treat Brain Metastases. Int. J. Mol. Sci. 2019, 21, 22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Kerr, J.Z.; Berg, S.; Blaney, S.M. Intrathecal chemotherapy. Crit. Rev. Oncol. Hematol. 2001, 37, 227–236. [Google Scholar] [CrossRef]
  57. Pardridge, W.M. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS 2011, 8, 7. [Google Scholar] [CrossRef] [Green Version]
  58. Papisov, M.I.; Belov, V.V.; Gannon, K.S. Physiology of the intrathecal bolus: The leptomeningeal route for macromolecule and particle delivery to CNS. Mol. Pharm. 2013, 10, 1522–1532. [Google Scholar] [CrossRef] [Green Version]
  59. Olmos-Jiménez, R.; Espuny-Miró, A.; Cárceles Rodríguez, C.; Díaz-Carrasco, M.S. Practical aspects of the use of intrathecal chemotherapy. Farm. Hosp. 2017, 41, 105–129. [Google Scholar] [CrossRef]
  60. Ommaya, A.K. Implantable devices for chronic access and drug delivery to the central nervous system. Cancer Drug. Deliv. 1984, 1, 169–179. [Google Scholar] [CrossRef]
  61. Evans, A.E.; Gilbert, E.S.; Zandstra, R. The increasing incidence of central nervous system leukemia in children. (Children’s Cancer Study Group A). Cancer 1970, 26, 404–409. [Google Scholar] [CrossRef] [PubMed]
  62. Donovan, L.K.; Delaidelli, A.; Joseph, S.K.; Bielamowicz, K.; Fousek, K.; Holgado, B.L.; Manno, A.; Srikanthan, D.; Gad, A.Z.; Van Ommeren, R.; et al. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Nat. Med. 2020, 26, 720–731. [Google Scholar] [CrossRef] [PubMed]
  63. Le Rhun, E.; Wallet, J.; Mailliez, A.; Le Deley, M.C.; Rodrigues, I.; Boulanger, T.; Lorgis, V.; Barrière, J.; Robin, Y.M.; Weller, M.; et al. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro Oncol. 2020, 22, 524–538. [Google Scholar] [CrossRef]
  64. Bobo, R.H.; Laske, D.W.; Akbasak, A.; Morrison, P.F.; Dedrick, R.L.; Oldfield, E.H. Convection-enhanced delivery of macromolecules in the brain. Proc. Natl. Acad. Sci. USA 1994, 91, 2076–2080. [Google Scholar] [CrossRef] [Green Version]
  65. Mehta, A.M.; Sonabend, A.M.; Bruce, J.N. Convection-Enhanced Delivery. Neurotherapeutics 2017, 14, 358–371. [Google Scholar] [CrossRef] [Green Version]
  66. Konishi, Y.; Muragaki, Y.; Iseki, H.; Mitsuhashi, N.; Okada, Y. Patterns of intracranial glioblastoma recurrence after aggressive surgical resection and adjuvant management: Retrospective analysis of 43 cases. Neurol. Med. Chir. 2012, 52, 577–586. [Google Scholar] [CrossRef] [Green Version]
  67. Oppitz, U.; Maessen, D.; Zunterer, H.; Richter, S.; Flentje, M. 3D-recurrence-patterns of glioblastomas after CT-planned postoperative irradiation. Radiother. Oncol. 1999, 53, 53–57. [Google Scholar] [CrossRef]
  68. Bashir, R.; Hochberg, F.; Oot, R. Regrowth patterns of glioblastoma multiforme related to planning of interstitial brachytherapy radiation fields. Neurosurgery 1988, 23, 27–30. [Google Scholar] [CrossRef] [PubMed]
  69. Hochberg, F.H.; Pruitt, A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980, 30, 907–911. [Google Scholar] [CrossRef]
  70. Nwagwu, C.D.; Immidisetti, A.V.; Jiang, M.Y.; Adeagbo, O.; Adamson, D.C.; Carbonell, A.M. Convection Enhanced Delivery in the Setting of High-Grade Gliomas. Pharmaceutics 2021, 13, 561. [Google Scholar] [CrossRef]
  71. Saxena, K.; Maturu, V.N. A Comparative Study of the Safety and Efficacy of Intrapleural Fibrinolysis With Streptokinase and Urokinase in the Management of Loculated Pleural Effusions. Cureus 2022, 14, e26271. [Google Scholar] [CrossRef] [PubMed]
  72. Mierzejewski, M.; Korczynski, P.; Krenke, R.; Janssen, J.P. Chemical pleurodesis—A review of mechanisms involved in pleural space obliteration. Respir. Res. 2019, 20, 247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Antunes, G.; Neville, E.; Duffy, J.; Ali, N. BTS guidelines for the management of malignant pleural effusions. Thorax 2003, 58 (Suppl. S2), ii29–ii38. [Google Scholar] [CrossRef] [PubMed]
  74. Thomas, R.; Jenkins, S.; Eastwood, P.R.; Lee, Y.C.; Singh, B. Physiology of breathlessness associated with pleural effusions. Curr. Opin. Pulm. Med. 2015, 21, 338–345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Clive, A.O.; Kahan, B.C.; Hooper, C.E.; Bhatnagar, R.; Morley, A.J.; Zahan-Evans, N.; Bintcliffe, O.J.; Boshuizen, R.C.; Fysh, E.T.; Tobin, C.L.; et al. Predicting survival in malignant pleural effusion: Development and validation of the LENT prognostic score. Thorax 2014, 69, 1098–1104. [Google Scholar] [CrossRef] [Green Version]
  76. Zachary, I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am. J. Physiol. Cell. Physiol. 2001, 280, C1375–C1386. [Google Scholar] [CrossRef] [Green Version]
  77. Chen, Y.; Mathy, N.W.; Lu, H. The role of VEGF in the diagnosis and treatment of malignant pleural effusion in patients with non-small cell lung cancer (Review). Mol. Med. Rep. 2018, 17, 8019–8030. [Google Scholar] [CrossRef] [Green Version]
  78. Popper, H.H. Progression and metastasis of lung cancer. Cancer Metastasis Rev. 2016, 35, 75–91. [Google Scholar] [CrossRef] [Green Version]
  79. Kitamura, K.; Kubota, K.; Ando, M.; Takahashi, S.; Nishijima, N.; Sugano, T.; Toyokawa, M.; Miwa, K.; Kosaihira, S.; Noro, R.; et al. Bevacizumab plus chemotherapy for advanced non-squamous non-small-cell lung cancer with malignant pleural effusion. Cancer Chemother. Pharmacol. 2013, 71, 457–461. [Google Scholar] [CrossRef]
  80. Sandler, A. Bevacizumab in non small cell lung cancer. Clin. Cancer Res. 2007, 13, s4613–s4616. [Google Scholar] [CrossRef] [Green Version]
  81. Bradshaw, M.; Mansfield, A.; Peikert, T. The role of vascular endothelial growth factor in the pathogenesis, diagnosis and treatment of malignant pleural effusion. Curr. Oncol. Rep. 2013, 15, 207–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef] [PubMed]
  83. Ayantunde, A.A.; Parsons, S.L. Pattern and prognostic factors in patients with malignant ascites: A retrospective study. Ann. Oncol. 2007, 18, 945–949. [Google Scholar] [CrossRef] [PubMed]
  84. Song, X.; Chen, D.; Guo, J.; Kong, L.; Wang, H.; Wang, Z. Better efficacy of intrapleural infusion of bevacizumab with pemetrexed for malignant pleural effusion mediated from nonsquamous non-small cell lung cancer. Onco Targets Ther. 2018, 11, 8421–8426. [Google Scholar] [CrossRef] [Green Version]
  85. Nie, K.; Zhang, Z.; You, Y.; Zhuang, X.; Zhang, C.; Ji, Y. A randomized clinical study to compare intrapleural infusion with intravenous infusion of bevacizumab in the management of malignant pleural effusion in patients with non-small-cell lung cancer. Thorac. Cancer 2020, 11, 8–14. [Google Scholar] [CrossRef] [Green Version]
  86. Tang, K.; Zhang, Y.; Zhang, H.; Xu, P.; Liu, J.; Ma, J.; Lv, M.; Li, D.; Katirai, F.; Shen, G.X.; et al. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat. Commun. 2012, 3, 1282. [Google Scholar] [CrossRef] [Green Version]
  87. Ran, L.; Tan, X.; Li, Y.; Zhang, H.; Ma, R.; Ji, T.; Dong, W.; Tong, T.; Liu, Y.; Chen, D.; et al. Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy. Biomaterials 2016, 89, 56–66. [Google Scholar] [CrossRef]
  88. Ma, J.; Zhang, Y.; Tang, K.; Zhang, H.; Yin, X.; Li, Y.; Xu, P.; Sun, Y.; Ma, R.; Ji, T.; et al. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res. 2016, 26, 713–727. [Google Scholar] [CrossRef] [Green Version]
  89. Guo, M.; Wu, F.; Hu, G.; Chen, L.; Xu, J.; Xu, P.; Wang, X.; Li, Y.; Liu, S.; Zhang, S.; et al. Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion. Sci. Transl. Med. 2019, 11, eaat5690. [Google Scholar] [CrossRef]
  90. Dong, X.; Huang, Y.; Yi, T.; Hu, C.; Gao, Q.; Chen, Y.; Zhang, J.; Chen, J.; Liu, L.; Meng, R.; et al. Intrapleural infusion of tumor cell-derived microparticles packaging methotrexate or saline combined with pemetrexed-cisplatin chemotherapy for the treatment of malignant pleural effusion in advanced non-squamous non-small cell lung cancer: A double-blind, randomized, placebo-controlled study. Front. Immunol. 2022, 13, 1002938. [Google Scholar] [CrossRef]
  91. Markman, M. Intraperitoneal antineoplastic drug delivery: Rationale and results. Lancet Oncol. 2003, 4, 277–283. [Google Scholar] [CrossRef] [PubMed]
  92. Dedrick, R.L.; Myers, C.E.; Bungay, P.M.; DeVita, V.T., Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat. Rep. 1978, 62, 1–11. [Google Scholar] [PubMed]
  93. Sadeghi, B.; Arvieux, C.; Glehen, O.; Beaujard, A.C.; Rivoire, M.; Baulieux, J.; Fontaumard, E.; Brachet, A.; Caillot, J.L.; Faure, J.L.; et al. Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer 2000, 88, 358–363. [Google Scholar] [CrossRef]
  94. Sugarbaker, P.H.; Mora, J.T.; Carmignani, P.; Stuart, O.A.; Yoo, D. Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist 2005, 10, 112–122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. van de Vaart, P.J.; van der Vange, N.; Zoetmulder, F.A.; van Goethem, A.R.; van Tellingen, O.; ten Bokkel Huinink, W.W.; Beijnen, J.H.; Bartelink, H.; Begg, A.C. Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: Pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur. J. Cancer 1998, 34, 148–154. [Google Scholar] [CrossRef]
  96. Oei, A.L.; Vriend, L.E.; Crezee, J.; Franken, N.A.; Krawczyk, P.M. Effects of hyperthermia on DNA repair pathways: One treatment to inhibit them all. Radiat. Oncol. 2015, 10, 165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Krawczyk, P.M.; Eppink, B.; Essers, J.; Stap, J.; Rodermond, H.; Odijk, H.; Zelensky, A.; van Bree, C.; Stalpers, L.J.; Buist, M.R.; et al. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc. Natl. Acad. Sci. USA 2011, 108, 9851–9856. [Google Scholar] [CrossRef] [Green Version]
  98. Hildebrandt, B.; Wust, P.; Ahlers, O.; Dieing, A.; Sreenivasa, G.; Kerner, T.; Felix, R.; Riess, H. The cellular and molecular basis of hyperthermia. Crit. Rev. Oncol. Hematol. 2002, 43, 33–56. [Google Scholar] [CrossRef] [PubMed]
  99. Multhoff, G.; Mizzen, L.; Winchester, C.C.; Milner, C.M.; Wenk, S.; Eissner, G.; Kampinga, H.H.; Laumbacher, B.; Johnson, J. Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp. Hematol. 1999, 27, 1627–1636. [Google Scholar] [CrossRef]
  100. Los, G.; Smals, O.A.; van Vugt, M.J.; van der Vlist, M.; den Engelse, L.; McVie, J.G.; Pinedo, H.M. A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity. Cancer Res. 1992, 52, 1252–1258. [Google Scholar]
  101. Spratt, J.S.; Adcock, R.A.; Muskovin, M.; Sherrill, W.; McKeown, J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980, 40, 256–260. [Google Scholar] [PubMed]
  102. Sugarbaker, P.H. Peritonectomy procedures. Ann. Surg. 1995, 221, 29–42. [Google Scholar] [CrossRef] [PubMed]
  103. Arquillière, J.; Glehen, O.; Passot, G. Cytoreductive surgery in peritoneal carcinomatosis. J. Visc. Surg. 2021, 158, 258–264. [Google Scholar] [CrossRef] [PubMed]
  104. Ba, M.; Chen, C.; Long, H.; Gong, Y.; Wu, Y.; Lin, K.; Tu, Y.; Zhang, B.; Wu, W. Cytoreductive surgery and HIPEC for ma-lignant ascites from colorectal cancer—A randomized study. Medicine 2020, 99, e21546. [Google Scholar] [CrossRef] [PubMed]
  105. Pereira, F.; Serrano, A.; Manzanedo, I.; Pérez-Viejo, E.; González-Moreno, S.; González-Bayón, L.; Arjona-Sánchez, A.; Torres, J.; Ramos, I.; Barrios, M.E.; et al. GECOP-MMC: Phase IV randomized clinical trial to evaluate the efficacy of hyper-thermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases. BMC Cancer 2022, 22, 536. [Google Scholar] [CrossRef]
  106. van Driel, W.J.; Koole, S.N.; Sikorska, K.; Schagen van Leeuwen, J.H.; Schreuder, H.W.R.; Hermans, R.H.M.; de Hingh, I.; van der Velden, J.; Arts, H.J.; Massuger, L.; et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N. Engl. J. Med. 2018, 378, 230–240. [Google Scholar] [CrossRef]
  107. Souadka, A.; Essangri, H.; Majbar, M.A.; Benkabbou, A.; Boutayeb, S.; You, B.; Glehen, O.; Mohsine, R.; Bakrin, N. Hyper-thermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in Ovarian Cancer: An Umbrella Review of Meta-Analyses. Front. Oncol. 2022, 12, 809773. [Google Scholar] [CrossRef]
  108. Sugarbaker, P.H.; Chang, D. Cytoreductive Surgery Plus HIPEC With and Without NIPEC for Malignant Peritoneal Mesothelioma: A Propensity-Matched Analysis. Ann. Surg. Oncol. 2021, 28, 7109–7117. [Google Scholar] [CrossRef]
  109. Yonemura, Y.; Iahibashi, H.; Sako, S.; Mizumoto, A.; Takao, N.; Ichinose, M.; Motoi, S.; Liu, Y.; Wakama, S.; Kamada, Y.; et al. Advances with pharmacotherapy for peritoneal metastasis. Expert. Opin. Pharmacother. 2020, 21, 2057–2066. [Google Scholar] [CrossRef]
  110. Gronau, F.; Feldbruegge, L.; Oberwittler, F.; Gonzalez-Moreno, S.; Villeneuve, L.; Eveno, C.; Glehen, O.; Kusamura, S.; Rau, B. HIPEC in Peritoneal Metastasis of Gastric Origin: A Systematic Review of Regimens and Techniques. J. Clin. Med. 2022, 11, 1456. [Google Scholar] [CrossRef]
  111. Frassini, S.; Calabretto, F.; Granieri, S.; Fugazzola, P.; Viganò, J.; Fazzini, N.; Ansaloni, L.; Cobianchi, L. Intraperitoneal chemotherapy in the management of pancreatic adenocarcinoma: A systematic review and meta-analysis. Eur. J. Surg. Oncol. 2022, 48, 1911–1921. [Google Scholar] [CrossRef] [PubMed]
  112. Coccolini, F.; Catena, F.; Glehen, O.; Yonemura, Y.; Sugarbaker, P.H.; Piso, P.; Ceresoli, M.; Montori, G.; Ansaloni, L. Effect of intraperitoneal chemotherapy and peritoneal lavage in positive peritoneal cytology in gastric cancer. Systematic review and meta-analysis. Eur. J. Surg. Oncol. 2016, 42, 1261–1267. [Google Scholar] [CrossRef] [PubMed]
  113. Gagnière, J.; Veziant, J.; Pereira, B.; Pezet, D.; Le Roy, B.; Slim, K. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Elderly: Is It Reasonable? A Meta-Analysis. Ann. Surg. Oncol. 2018, 25, 709–719. [Google Scholar] [CrossRef] [PubMed]
  114. Pameijer, C.R. HIPEC Trials and the US: A Review and Call to Action. Ann. Surg. Oncol. 2022, 29, 866–872. [Google Scholar] [CrossRef]
  115. Kwakman, R.; Schrama, A.M.; van Olmen, J.P.; Otten, R.H.; de Lange-de Klerk, E.S.; de Cuba, E.M.; Kazemier, G.; Te Velde, E.A. Clinicopathological Parameters in Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Metastases: A Meta-analysis. Ann. Surg. 2016, 263, 1102–1111. [Google Scholar] [CrossRef]
  116. Rovers, K.P.; Bakkers, C.; Simkens, G.; Burger, J.W.A.; Nienhuijs, S.W.; Creemers, G.M.; Thijs, A.M.J.; Brandt-Kerkhof, A.R.M.; Madsen, E.V.E.; Ayez, N.; et al. Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: Protocol of a multicentre, open-label, parallel-group, phase II–III, randomised, superiority study (CAIRO6). BMC Cancer 2019, 19, 390. [Google Scholar] [CrossRef] [Green Version]
  117. Solaß, W.; Hetzel, A.; Nadiradze, G.; Sagynaliev, E.; Reymond, M.A. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg. Endosc. 2012, 26, 1849–1855. [Google Scholar] [CrossRef]
  118. Solass, W.; Kerb, R.; Mürdter, T.; Giger-Pabst, U.; Strumberg, D.; Tempfer, C.; Zieren, J.; Schwab, M.; Reymond, M.A. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: First evidence for efficacy. Ann. Surg. Oncol. 2014, 21, 553–559. [Google Scholar] [CrossRef]
  119. Reymond, M.A.; Hu, B.; Garcia, A.; Reck, T.; Köckerling, F.; Hess, J.; Morel, P. Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator. Surg. Endosc. 2000, 14, 51–55. [Google Scholar] [CrossRef] [Green Version]
  120. Heldin, C.H.; Rubin, K.; Pietras, K.; Ostman, A. High interstitial fluid pressure—An obstacle in cancer therapy. Nat. Rev. Cancer 2004, 4, 806–813. [Google Scholar] [CrossRef]
  121. Solass, W.; Herbette, A.; Schwarz, T.; Hetzel, A.; Sun, J.S.; Dutreix, M.; Reymond, M.A. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: Proof of concept. Surg. Endosc. 2012, 26, 847–852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Jacquet, P.; Stuart, O.A.; Chang, D.; Sugarbaker, P.H. Effects of intra-abdominal pressure on pharmacokinetics and tissue distribution of doxorubicin after intraperitoneal administration. Anticancer Drugs 1996, 7, 596–603. [Google Scholar] [CrossRef] [PubMed]
  123. Esquis, P.; Consolo, D.; Magnin, G.; Pointaire, P.; Moretto, P.; Ynsa, M.D.; Beltramo, J.L.; Drogoul, C.; Simonet, M.; Benoit, L.; et al. High intra-abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis. Ann. Surg. 2006, 244, 106–112. [Google Scholar] [CrossRef] [PubMed]
  124. Ozols, R.F.; Young, R.C.; Speyer, J.L.; Sugarbaker, P.H.; Greene, R.; Jenkins, J.; Myers, C.E. Phase I and pharmacological studies of adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Res. 1982, 42, 4265–4269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Grass, F.; Vuagniaux, A.; Teixeira-Farinha, H.; Lehmann, K.; Demartines, N.; Hübner, M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br. J. Surg. 2017, 104, 669–678. [Google Scholar] [CrossRef]
  126. Khosrawipour, V.; Khosrawipour, T.; Kern, A.J.; Osma, A.; Kabakci, B.; Diaz-Carballo, D.; Förster, E.; Zieren, J.; Fakhrian, K. Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model. J. Cancer Res. Clin. Oncol. 2016, 142, 2275–2280. [Google Scholar] [CrossRef]
  127. Alyami, M.; Hübner, M.; Grass, F.; Bakrin, N.; Villeneuve, L.; Laplace, N.; Passot, G.; Glehen, O.; Kepenekian, V. Pressur-ised intraperitoneal aerosol chemotherapy: Rationale, evidence, and potential indications. Lancet Oncol. 2019, 20, e368–e377. [Google Scholar] [CrossRef]
  128. Baggaley, A.E.; Lafaurie, G.; Tate, S.J.; Boshier, P.R.; Case, A.; Prosser, S.; Torkington, J.; Jones, S.E.F.; Gwynne, S.H.; Peters, C.J. Pressurized intraperitoneal aerosol chemotherapy (PIPAC): Updated systematic review using the IDEAL framework. Br. J. Surg. 2022, 110, 10–18. [Google Scholar] [CrossRef]
  129. Pfeifle, C.E.; Howell, S.B.; Markman, M.; Lucas, W.E. Totally implantable system for peritoneal access. J. Clin. Oncol. 1984, 2, 1277–1280. [Google Scholar] [CrossRef]
  130. Kimura, K.; Koide, A.; Suga, S.; Shimoyama, T.; Okamoto, E.; Utsunomiya, J.; Okawa, T.; Taguchi, T.; Wakui, A. Clinical experience of a subcutaneously implantable drug delivery catheter (PORT-A-CATH). Gan To Kagaku Ryoho 1987, 14, 1150–1155. [Google Scholar]
  131. Eiseman, J.L.; Eddington, N.D.; Leslie, J.; MacAuley, C.; Sentz, D.L.; Zuhowski, M.; Kujawa, J.M.; Young, D.; Egorin, M.J. Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemother. Pharmacol. 1994, 34, 465–471. [Google Scholar] [CrossRef] [PubMed]
  132. Soma, D.; Kitayama, J.; Konno, T.; Ishihara, K.; Yamada, J.; Kamei, T.; Ishigami, H.; Kaisaki, S.; Nagawa, H. Intraperitoneal administration of paclitaxel solubilized with poly(2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer. Cancer Sci. 2009, 100, 1979–1985. [Google Scholar] [CrossRef] [PubMed]
  133. Kamei, T.; Kitayama, J.; Yamaguchi, H.; Soma, D.; Emoto, S.; Konno, T.; Ishihara, K.; Ishigami, H.; Kaisaki, S.; Nagawa, H. Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) in peritoneal metastatic nodules. Cancer Sci. 2011, 102, 200–205. [Google Scholar] [CrossRef] [PubMed]
  134. Kyle, A.H.; Huxham, L.A.; Yeoman, D.M.; Minchinton, A.I. Limited tissue penetration of taxanes: A mechanism for resistance in solid tumors. Clin. Cancer Res. 2007, 13, 2804–2810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Yamaguchi, H.; Kitayama, J.; Ishigami, H.; Kazama, S.; Nozawa, H.; Kawai, K.; Hata, K.; Kiyomatsu, T.; Tanaka, T.; Tanaka, J.; et al. Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes. World J. Gastrointest. Oncol. 2015, 7, 285–291. [Google Scholar] [CrossRef] [PubMed]
  136. Emoto, S.; Ishigami, H.; Hidemura, A.; Yamaguchi, H.; Yamashita, H.; Kitayama, J.; Watanabe, T. Complications and management of an implanted intraperitoneal access port system for intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Jpn. J. Clin. Oncol. 2012, 42, 1013–1019. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Yamaguchi, H.; Kitayama, J.; Ishigami, H.; Emoto, S.; Yamashita, H.; Watanabe, T. A phase 2 trial of intravenous and intraperitoneal paclitaxel combined with S-1 for treatment of gastric cancer with macroscopic peritoneal metastasis. Cancer 2013, 119, 3354–3358. [Google Scholar] [CrossRef] [PubMed]
  138. Fushida, S.; Kinoshita, J.; Kaji, M.; Hirono, Y.; Goda, F.; Yagi, Y.; Oyama, K.; Sudo, Y.; Watanabe, Y.; Fujimura, T. Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis. Cancer Chemother. Pharmacol. 2013, 71, 1265–1272. [Google Scholar] [CrossRef] [Green Version]
  139. Saito, S.; Yamaguchi, H.; Ohzawa, H.; Miyato, H.; Kanamaru, R.; Kurashina, K.; Hosoya, Y.; Lefor, A.K.; Sata, N.; Kitayama, J. Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Oxaliplatin as Induction Therapy for Patients with Advanced Gastric Cancer with Peritoneal Metastases. Ann. Surg. Oncol. 2021, 28, 3863–3870. [Google Scholar] [CrossRef]
  140. Satoi, S.; Fujii, T.; Yanagimoto, H.; Motoi, F.; Kurata, M.; Takahara, N.; Yamada, S.; Yamamoto, T.; Mizuma, M.; Honda, G.; et al. Multicenter Phase II Study of Intravenous and Intraperitoneal Paclitaxel with S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis. Ann. Surg. 2017, 265, 397–401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Yamada, S.; Fujii, T.; Yamamoto, T.; Takami, H.; Yoshioka, I.; Yamaki, S.; Sonohara, F.; Shibuya, K.; Motoi, F.; Hirano, S.; et al. Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. Br. J. Surg. 2020, 107, 1811–1817. [Google Scholar] [CrossRef] [PubMed]
  142. Ishigami, H.; Fujiwara, Y.; Fukushima, R.; Nashimoto, A.; Yabusaki, H.; Imano, M.; Imamoto, H.; Kodera, Y.; Uenosono, Y.; Amagai, K.; et al. Phase III Trial Comparing Intraperitoneal and Intravenous Paclitaxel Plus S-1 Versus Cisplatin Plus S-1 in Patients with Gastric Cancer with Peritoneal Metastasis: PHOENIX-GC Trial. J. Clin. Oncol. 2018, 36, 1922–1929. [Google Scholar] [CrossRef] [PubMed]
  143. Matsusaki, K.; Ohta, K.; Yoshizawa, A.; Gyoda, Y. Novel cell-free and concentrated ascites reinfusion therapy (KM-CART) for refractory ascites associated with cancerous peritonitis: Its effect and future perspectives. Int. J. Clin. Oncol. 2011, 16, 395–400. [Google Scholar] [CrossRef]
  144. Ito, T.; Hanafusa, N.; Iwase, S.; Noiri, E.; Nangaku, M.; Nakagawa, K.; Miyagawa, K. Effects of cell-free and concentrated ascites reinfusion therapy (CART) on symptom relief of malignancy-related ascites. Int. J. Clin. Oncol. 2015, 20, 623–628. [Google Scholar] [CrossRef]
  145. Yamaguchi, H.; Kitayama, J.; Emoto, S.; Ishigami, H.; Ito, T.; Hanafusa, N.; Watanabe, T. Cell-free and concentrated ascites reinfusion therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal paclitaxel with oral S-1. Eur. J. Surg. Oncol. 2015, 41, 875–880. [Google Scholar] [CrossRef]
  146. Matsusaki, K.; Aridome, K.; Emoto, S.; Kajiyama, H.; Takagaki, N.; Takahashi, T.; Tsubamoto, H.; Nagao, S.; Watanabe, A.; Shimada, H.; et al. Clinical practice guideline for the treatment of malignant ascites: Section summary in Clinical Practice Guideline for peritoneal dissemination (2021). Int. J. Clin. Oncol. 2022, 27, 1–6. [Google Scholar] [CrossRef] [PubMed]
  147. Bokemeyer, C. Catumaxomab–trifunctional anti-EpCAM antibody used to treat malignant ascites. Expert. Opin. Biol. Ther. 2010, 10, 1259–1269. [Google Scholar] [CrossRef]
  148. Heiss, M.M.; Murawa, P.; Koralewski, P.; Kutarska, E.; Kolesnik, O.O.; Ivanchenko, V.V.; Dudnichenko, A.S.; Aleknaviciene, B.; Razbadauskas, A.; Gore, M.; et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int. J. Cancer 2010, 127, 2209–2221. [Google Scholar] [CrossRef] [Green Version]
  149. Kobold, S.; Hegewisch-Becker, S.; Oechsle, K.; Jordan, K.; Bokemeyer, C.; Atanackovic, D. Intraperitoneal VEGF inhibition using bevacizumab: A potential approach for the symptomatic treatment of malignant ascites? Oncologist 2009, 14, 1242–1251. [Google Scholar] [CrossRef]
  150. Sjoquist, K.M.; Espinoza, D.; Mileshkin, L.; Ananda, S.; Shannon, C.; Yip, S.; Goh, J.; Bowtell, D.; Harrison, M.; Friedlander, M.L. REZOLVE (ANZGOG-1101): A phase 2 trial of intraperitoneal bevacizumab to treat symptomatic ascites in patients with chemotherapy-resistant, epithelial ovarian cancer. Gynecol. Oncol. 2021, 161, 374–381. [Google Scholar] [CrossRef]
  151. Goéré, D.; Gras-Chaput, N.; Aupérin, A.; Flament, C.; Mariette, C.; Glehen, O.; Zitvogel, L.; Elias, D. Treatment of gastric peritoneal carcinomatosis by combining complete surgical resection of lesions and intraperitoneal immunotherapy using catumaxomab. BMC Cancer 2014, 14, 148. [Google Scholar] [CrossRef] [Green Version]
  152. Knödler, M.; Körfer, J.; Kunzmann, V.; Trojan, J.; Daum, S.; Schenk, M.; Kullmann, F.; Schroll, S.; Behringer, D.; Stahl, M.; et al. Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. Br. J. Cancer 2018, 119, 296–302. [Google Scholar] [CrossRef] [PubMed]
  153. Li, Q.; Song, Q.; Zhao, Z.; Lin, Y.; Cheng, Y.; Karin, N.; Luan, Y. Genetically Engineered Artificial Exosome-Constructed Hydrogel for Ovarian Cancer Therapy. ACS Nano 2023. [Google Scholar] [CrossRef] [PubMed]
  154. Chandrasekaran, S.; King, M.R. Microenvironment of tumor-draining lymph nodes: Opportunities for liposome-based targeted therapy. Int. J. Mol. Sci. 2014, 15, 20209–20239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Petitprez, F.; de Reyniès, A.; Keung, E.Z.; Chen, T.W.; Sun, C.M.; Calderaro, J.; Jeng, Y.M.; Hsiao, L.P.; Lacroix, L.; Bougoüin, A.; et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 2020, 577, 556–560. [Google Scholar] [CrossRef]
  156. Helmink, B.A.; Reddy, S.M.; Gao, J.; Zhang, S.; Basar, R.; Thakur, R.; Yizhak, K.; Sade-Feldman, M.; Blando, J.; Han, G.; et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020, 577, 549–555. [Google Scholar] [CrossRef]
  157. Melero, I.; Castanon, E.; Alvarez, M.; Champiat, S.; Marabelle, A. Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat. Rev. Clin. Oncol. 2021, 18, 558–576. [Google Scholar] [CrossRef]
  158. Nauts, H.C.; Swift, W.E.; Coley, B.L. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res. 1946, 6, 205–216. [Google Scholar]
  159. Morales, A.; Eidinger, D.; Bruce, A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 2002, 167, 891–893; discussion 893–895. [Google Scholar] [CrossRef]
  160. Mori, K.; Lamm, D.L.; Crawford, E.D. A trial of bacillus Calmette-Guérin versus adriamycin in superficial bladder cancer: A South-West Oncology Group Study. Urol. Int. 1986, 41, 254–259. [Google Scholar] [CrossRef]
  161. van Puffelen, J.H.; Keating, S.T.; Oosterwijk, E.; van der Heijden, A.G.; Netea, M.G.; Joosten, L.A.B.; Vermeulen, S.H. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat. Rev. Urol. 2020, 17, 513–525. [Google Scholar] [CrossRef]
  162. Champiat, S.; Tselikas, L.; Farhane, S.; Raoult, T.; Texier, M.; Lanoy, E.; Massard, C.; Robert, C.; Ammari, S.; De Baère, T.; et al. Intratumoral Immunotherapy: From Trial Design to Clinical Practice. Clin. Cancer Res. 2021, 27, 665–679. [Google Scholar] [CrossRef]
  163. Huppert, L.A.; Daud, A.I. Intratumoral therapies and in-situ vaccination for melanoma. Hum. Vaccin. Immunother. 2022, 18, 1890512. [Google Scholar] [CrossRef]
  164. Thompson, J.F.; Agarwala, S.S.; Smithers, B.M.; Ross, M.I.; Scoggins, C.R.; Coventry, B.J.; Neuhaus, S.J.; Minor, D.R.; Singer, J.M.; Wachter, E.A. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Ann. Surg. Oncol. 2015, 22, 2135–2142. [Google Scholar] [CrossRef] [Green Version]
  165. Ribas, A.; Medina, T.; Kummar, S.; Amin, A.; Kalbasi, A.; Drabick, J.J.; Barve, M.; Daniels, G.A.; Wong, D.J.; Schmidt, E.V.; et al. SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. Cancer Discov. 2018, 8, 1250–1257. [Google Scholar] [CrossRef] [Green Version]
  166. Babiker, H.; Borazanci, E.; Subbiah, V.; Agarwala, S.; Algazi, A.; Schachter, J.; Lotem, M.; Maurice-Dror, C.; Hendler, D.; Rahimian, S.; et al. Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101). Clin. Cancer Res. 2022, 28, 5079–5087. [Google Scholar] [CrossRef]
  167. Andtbacka, R.H.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef]
  168. Hersey, P.; Gallagher, S. Intralesional immunotherapy for melanoma. J. Surg. Oncol. 2014, 109, 320–326. [Google Scholar] [CrossRef]
  169. Namikawa, K.; Yamazaki, N. Targeted Therapy and Immunotherapy for Melanoma in Japan. Curr. Treat. Options Oncol. 2019, 20, 7. [Google Scholar] [CrossRef] [Green Version]
  170. Breitbach, C.J.; Moon, A.; Burke, J.; Hwang, T.H.; Kirn, D.H. A Phase 2, Open-Label, Randomized Study of Pexa-Vec (JX-594) Administered by Intratumoral Injection in Patients with Unresectable Primary Hepatocellular Carcinoma. Methods Mol. Biol. 2015, 1317, 343–357. [Google Scholar] [CrossRef]
  171. Desjardins, A.; Gromeier, M.; Herndon, J.E., 2nd; Beaubier, N.; Bolognesi, D.P.; Friedman, A.H.; Friedman, H.S.; McSherry, F.; Muscat, A.M.; Nair, S.; et al. Recurrent Glioblastoma Treated with Recombinant Poliovirus. N. Engl. J. Med. 2018, 379, 150–161. [Google Scholar] [CrossRef]
  172. Lang, F.F.; Conrad, C.; Gomez-Manzano, C.; Yung, W.K.A.; Sawaya, R.; Weinberg, J.S.; Prabhu, S.S.; Rao, G.; Fuller, G.N.; Aldape, K.D.; et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J. Clin. Oncol. 2018, 36, 1419–1427. [Google Scholar] [CrossRef] [PubMed]
  173. Ghosh, S. Cisplatin: The first metal based anticancer drug. Bioorg. Chem. 2019, 88, 102925. [Google Scholar] [CrossRef] [PubMed]
  174. Gyöngyösi, M.; Lukovic, D.; Zlabinger, K.; Spannbauer, A.; Gugerell, A.; Pavo, N.; Traxler, D.; Pils, D.; Maurer, G.; Jakab, A.; et al. Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance. Cardiovasc Res. 2020, 116, 970–982. [Google Scholar] [CrossRef]
  175. Hanada, M.; Baba, A.; Tsutsumishita, Y.; Noguchi, T.; Yamaoka, T.; Chiba, N.; Nishikaku, F. Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis. Cancer Chemother. Pharmacol. 2009, 64, 473–483. [Google Scholar] [CrossRef] [Green Version]
  176. Wigmore, P.M.; Mustafa, S.; El-Beltagy, M.; Lyons, L.; Umka, J.; Bennett, G. Effects of 5-FU. Adv. Exp. Med. Biol. 2010, 678, 157–164. [Google Scholar] [CrossRef]
  177. Tomasz, M.; Palom, Y. The mitomycin bioreductive antitumor agents: Cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol. Ther. 1997, 76, 73–87. [Google Scholar] [CrossRef]
  178. Riddell, I.A. Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions. Met. Ions Life Sci. 2018, 18. [Google Scholar] [CrossRef]
  179. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573–584. [Google Scholar] [CrossRef]
  180. Laqué-Rupérez, E.; Ruiz-Gómez, M.J.; de la Peña, L.; Gil, L.; Martínez-Morillo, M. Methotrexate cytotoxicity on MCF-7 breast cancer cells is not altered by exposure to 25 Hz, 1.5 mT magnetic field and iron (III) chloride hexahydrate. Bioelectrochemistry 2003, 60, 81–86. [Google Scholar] [CrossRef]
  181. Ojima, I.; Lichtenthal, B.; Lee, S.; Wang, C.; Wang, X. Taxane anticancer agents: A patent perspective. Expert Opin. Ther. Pat. 2016, 26, 1–20. [Google Scholar] [CrossRef] [Green Version]
  182. Ota, K. Nedaplatin. Gan To Kagaku Ryoho 1996, 23, 379–387. [Google Scholar] [PubMed]
  183. Fernández-Ramos, A.A.; Marchetti-Laurent, C.; Poindessous, V.; Antonio, S.; Laurent-Puig, P.; Bortoli, S.; Loriot, M.A.; Pallet, N. 6-mercaptopurine promotes energetic failure in proliferating T cells. Oncotarget 2017, 8, 43048–43060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Thomas, D.A.; Sarris, A.H.; Cortes, J.; Faderl, S.; O’Brien, S.; Giles, F.J.; Garcia-Manero, G.; Rodriguez, M.A.; Cabanillas, F.; Kantarjian, H. Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer 2006, 106, 120–127. [Google Scholar] [CrossRef]
  185. Bordin, D.L.; Lima, M.; Lenz, G.; Saffi, J.; Meira, L.B.; Mésange, P.; Soares, D.G.; Larsen, A.K.; Escargueil, A.E.; Henriques, J.A.P. DNA alkylation damage and autophagy induction. Mutat. Res. 2013, 753, 91–99. [Google Scholar] [CrossRef]
  186. Sterner, R.C.; Sterner, R.M. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J. 2021, 11, 69. [Google Scholar] [CrossRef] [PubMed]
  187. Wang, L.M.; White, J.C.; Capizzi, R.L. The effect of ara-C-induced inhibition of DNA synthesis on its cellular pharmacology. Cancer Chemother. Pharmacol. 1990, 25, 418–424. [Google Scholar] [CrossRef]
  188. You, F.; Gao, C. Topoisomerase Inhibitors and Targeted Delivery in Cancer Therapy. Curr. Top. Med. Chem. 2019, 19, 713–729. [Google Scholar] [CrossRef]
  189. Vogelbaum, M.A.; Sampson, J.H.; Kunwar, S.; Chang, S.M.; Shaffrey, M.; Asher, A.L.; Lang, F.F.; Croteau, D.; Parker, K.; Grahn, A.Y.; et al. Convection-enhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: Phase 1 study of final safety results. Neurosurgery 2007, 61, 1031–1037; discussion 1037–1038. [Google Scholar] [CrossRef]
  190. Hdeib, A.; Sloan, A. Targeted radioimmunotherapy: The role of ¹³¹I-chTNT-1/B mAb (Cotara) for treatment of high-grade gliomas. Future Oncol. 2012, 8, 659–669. [Google Scholar] [CrossRef]
  191. Garcia, J.; Hurwitz, H.I.; Sandler, A.B.; Miles, D.; Coleman, R.L.; Deurloo, R.; Chinot, O.L. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat. Rev. 2020, 86, 102017. [Google Scholar] [CrossRef] [PubMed]
  192. Pandit, B.; Royzen, M. Recent Development of Prodrugs of Gemcitabine. Genes 2022, 13, 466. [Google Scholar] [CrossRef] [PubMed]
  193. Zawit, M.; Swami, U.; Awada, H.; Arnouk, J.; Milhem, M.; Zakharia, Y. Current status of intralesional agents in treatment of malignant melanoma. Ann. Transl. Med. 2021, 9, 1038. [Google Scholar] [CrossRef]
  194. Champion, S.; Cheung, V.L.S.; Wiseman, D. Isolated thoracic duct injury from blunt force trauma. J. Radiol. Case Rep. 2020, 14, 18–29. [Google Scholar] [CrossRef] [PubMed]
  195. Ilahi, M.; St Lucia, K.; Ilahi, T.B. Anatomy, Thorax, Thoracic Duct. In StatPearls; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2022. [Google Scholar]
  196. Saito, A.; Kimura, N.; Kaneda, Y.; Ohzawa, H.; Miyato, H.; Yamaguchi, H.; Lefor, A.K.; Nagai, R.; Sata, N.; Kitayama, J.; et al. Novel Drug Delivery Method Targeting Para-Aortic Lymph Nodes by Retrograde Infusion of Paclitaxel into Pigs’ Thoracic Duct. Cancers 2022, 14, 3753. [Google Scholar] [CrossRef]
  197. Al Shoyaib, A.; Archie, S.R.; Karamyan, V.T. Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm. Res. 2019, 37, 12. [Google Scholar] [CrossRef]
  198. Yamamoto, M.; Kurino, T.; Matsuda, R.; Jones, H.S.; Nakamura, Y.; Kanamori, T.; Tsuji, A.B.; Sugyo, A.; Tsuda, R.; Matsumoto, Y.; et al. Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect. J. Control. Release 2022, 352, 328–337. [Google Scholar] [CrossRef]
Pharmaceutics 15 01664 g001 550
Figure 1. Schematic diagram of special anticancer drug administration route.
Figure 1. Schematic diagram of special anticancer drug administration route.
Pharmaceutics 15 01664 g001
Table
Table 1. Studies that administered chemotherapeutics by an intra-arterial route.
Table 1. Studies that administered chemotherapeutics by an intra-arterial route.
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Liver tumorHepatocellular carcinomaCisplatin (TACE [18],
HAIC [30,31,32,33,34,35])		-
Doxorubicin (TACE [18], TACE-DEB [18], B-TACE [25])-
Miriplatin (TACE [18],
B-TACE [25,26,28], HAIC [32])		-
Epirubicin (TACE [18], B-TACE [25], HAIC [31,32])-
5-FU (HAIC [30,31,32,33,34,35])-
Mitomycin (HAIC [30,31,32])-
Oxaliplatin (HAIC [31])-
Metastatic liver tumorColorectal cancerFloxuridine [40]Ⅱ
NCT00492999
Oxaliplatin [41]Ⅱ/Ⅲ
NCT02494973
Brain tumorNon-GBM gliomasCarboplatin [43]-
Primary central nervous system lymphoma (PCNSL)
Primitive neuroectodermal tumor (PNET)
Germ cell tumor		Methotrexate [44]Ⅱ
NCT00596154
Carboplatin [44]-
Head and neck cancerHead and neck cancerCisplatin [46]-
Docetaxel [47]-
Nedaplatin [47]-
Table
Table 2. Studies that employed intrathecal drug administration and CED.
Table 2. Studies that employed intrathecal drug administration and CED.
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Brain tumorCentral nervous system (CNS) leukemiaMethotrexate [61]-
6-mercaptopurine [60]-
Vincristine [61]-
Cyclophosphamide [61]-
Metastatic medulloblastoma
Ependymoma		CAR T cells [62]-
Leptomeningeal
metastasis		Breast cancerLiposomal cytarabine [63]Ⅲ
NCT01645839
Brain tumor
(CED)		Recurrent malignant gliomaPaclitaxel [70]-
Topotecan [70]Ⅰ
NCT03154996
Tf-CRM107 [70]Ⅲ
NCT00076986
TP-38 [70]Ⅰ/Ⅱ
NCT00074334
IL13-PE38QQR [70]Ⅲ
NCT00076986
Reovirus [70]Ⅰ
NCT02444546
Recurrence glioblastoma (rGBM)Paclitaxel [70]-
IL13-PE38QQR [70]Ⅲ
NCT00076986
LIPO-HSV-1-tk [70]-
CpG-28 [70]Ⅱ
NCT05506969
Recurrent malignant brain tumorsTf-CRM107 [70]-
TP-38 [70]Ⅰ/Ⅱ
NCT00074334
Recurrent high-grade glioma (HGG)Topotecan [70]Ⅰ
NCT03154996
Liposomal irinotecan [70]Ⅰ
NCT02022644
AP-12009 [70]Ⅲ
NCT00761280
Newly diagnosed malignant gliomaIL13-PE38QQR [70]Ⅲ
NCT00076986
Malignant glioma131I-chTNT-1/B MAb
(Cotara) [70]		Ⅰ/Ⅱ
NCT00509301
Table
Table 3. Studies that employed intrapleural drug administration.
Table 3. Studies that employed intrapleural drug administration.
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Malignant pleural
effusion (MPE)		Nonsquamous non-small cell lung cancer
(NS-NSCLC)		Bevacizumab [84]-
NSCLCBevacizumab [85]-
Lung cancerTumor microparticles
packaging methotrexate
(TMPs-MTX) [89]		-
NSCLCTMPs-MTX [90]-
Table
Table 4. Studies that employed intraperitoneal drug administration (heated intraperitoneal chemotherapy (HIPEC)).
Table 4. Studies that employed intraperitoneal drug administration (heated intraperitoneal chemotherapy (HIPEC)).
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Peritoneal metastasis
(PM)		Colorectal cancerOxaliplatin [104]-
Colon cancerMitomycin-C [105]Ⅳ
NCT05250648
Ovarian cancerCarboplatin [106]Ⅲ
NCT00426257
Ovarian cancerPaclitaxel [106]Ⅲ
NCT00426257
Gastric cancerDocetaxel [110]Ⅲ
NCT03023436
Gastric cancerMitomycin C [110]Ⅲ
NCT02158988
Gastric cancerCisplatin [110]Ⅲ
NCT02158988
Gastric cancerOxaliplatin [110]Ⅲ
NCT03348150
Pancreatic cancerGemcitabine [111]-
Primary and recurrent cancerOvarian cancerCisplatin [107]Ⅲ
NCT00426257
Primary cancerMalignant peritoneal mesotheliomaDoxorubicin [108]-
Malignant peritoneal mesotheliomaCisplatin [108]-
Table
Table 6. Studies that employed intratumor drug administration (IT).
Table 6. Studies that employed intratumor drug administration (IT).
IndicationsType of CancerAnti-Cancer DrugStudy Phase
Solid tumorMelanomaPV-10 [164]Ⅱ
NCT00521053
SD-101 [165]Ⅰ/Ⅱ
NCT02521870
Tilsotolimod [166]Ⅰ/Ⅱ
NCT02644967
Talimogene laherparepvec (T-VEC) [167]Ⅲ
NCT00769704
CAVATAK [168]Ⅱ
NCT01227551
HF10 [169]Ⅱ
NCT02272855
Primary Hepatocellular CarcinomaPexa-Vec [170]Ⅱ
NCT01171651
Glioma grade IVPVSRIPO [171]Ⅰ
NCT01491893
Malignant gliomaDNX-2401 [172]Ⅰ
NCT00805376
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Saito, A.; Kitayama, J.; Nagai, R.; Aizawa, K. Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review. Pharmaceutics 2023, 15, 1664. https://doi.org/10.3390/pharmaceutics15061664

AMA Style

Saito A, Kitayama J, Nagai R, Aizawa K. Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review. Pharmaceutics. 2023; 15(6):1664. https://doi.org/10.3390/pharmaceutics15061664

Chicago/Turabian Style

Saito, Akira, Joji Kitayama, Ryozo Nagai, and Kenichi Aizawa. 2023. "Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review" Pharmaceutics 15, no. 6: 1664. https://doi.org/10.3390/pharmaceutics15061664

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop