Figure 3. (A) Analysis of drug products and medical devices approved during the 2010s classified by the type of therapy. (B) Analysis of drug products and medical devices approved during the 2010s classified by the type of formulation.

5. Successes, Failures, and Lessons Learned

Over the past few decades, a wide range of innovative formulation strategies and pioneering technologies have reached the market (Figure 4) and entered into clinical trials as a result of the extensive efforts made in preclinical and clinical stages.

Concerning peptide-based therapy, the main aim pursued with novel formulation strategies has been to overcome the short elimination half-life of peptides. In this regard, the introduction into the market of the first microspheres and implants using biodegradable polymers in the 1990s for prolonged peptide release has enabled the administration of some peptides for cancer treatment that were not clinically available (namely, goserelin) and a reduction in the frequency of administrations, improving thereby patient compliance, of some other peptides that were previously available in daily injectable formulations (such as buserelin, triptorelin, leuprolide, and octreotide). The subsequent authorization of Vantas^® and Viadur^® in the 2000s, which extended peptide release over a year, further reduced the frequency of administration in comparison with the previous 3–4-months’ implants [168]. Unfortunately, Viadur^® was discontinued due to diminished market demand and growing manufacturing costs. However, during the 2010s the innovation in microspheres and implant-based formulation technologies for peptide delivery has been abruptly reduced. It could be due to a change in tendency as 75% of all nonmarketed formulations that have entered phase III clinical trials for peptide-based therapy are polymer conjugates. However, these data should be handled cautiously, given that these phase III trials had a negative outcome, or their results are still pending.

Hormone-dependent cancers have been favored to the greatest extent by prolonged-release systems of peptide-based therapies because these cancers require continuous administration over long periods. In fact, 75% of all formulations authorized for peptide-based therapy are designed to treat hormone-dependent cancers, of which prostate cancer is the most treated [169]. This can be seen as a major limitation of peptide-based therapy, as these formulations are restricted to hormone-dependent cancers. This trend, however, is reversed in phase III clinical trials, as 50% of the nonmarketed formulations for peptide-based therapy are being tested for the treatment of pancreatic cancer, suggesting that the interest in using peptide-based formulations to treat other cancers is increasing. Nevertheless, the translational potential of peptide-based therapy for other types of cancers remains to be fully demonstrated, as phase III trials with peptide-based therapy for pancreatic cancer failed to meet their primary outcomes.

Concerning chemotherapeutics, the main aim pursued with novel formulation strategies has been to improve their nonspecific distribution. In this regard, various carrier-based formulations incorporating chemotherapeutics have received marketing authorization in order to reduce their toxicity and improve their therapeutic index. Ever since Doxil^® was authorized in the 1990s as the first liposome formulation entrapping doxorubicin, liposomes have been trending upward in the market [170]. Many of them have introduced innovations such as Vyxeos^® with the incorporation of two chemotherapeutics within the same formulation. In this regard, Vyxeos^® may well set the foundation for future approvals exploring alternative drug combinations. In addition to their high biocompatibility, one reason why liposomes have been in the limelight over the past three decades may be the good results obtained by reducing the side effects of chemotherapy in the clinic. The reduction in the neurotoxicity using vincristine and the reduction in the cardiotoxicity of doxorubicin after encapsulation within liposomes are two representative examples [46,89,171] Other nanomedicines apart from liposomes have received marketing authorization for chemotherapy. This is the case of Abraxane^® in the 2000s, the first nanoparticle-based formulation using albumin as a carrier and, more recently, the first micelle-based formulation entrapping paclitaxel in 2018 under the tradename Apealea^®. Alternatively, during the 2000s and 2010s, microspheres containing chemotherapeutics were authorized for chemoembolization following local administration. Further improvements in these microspheres resulted in the first commercially available microsphere that combines chemotherapy with imaging function (DC Bead LUMI). Despite current research efforts, the combination of imaging and therapeutic functions remains to be achieved with nanomedicines at the clinical level.

However, the improvement of the therapeutic index of chemotherapy agents with these formulations is more related to an increase in the safety profile of the formulation than to an increase in therapeutic efficacy, which remains a challenge for the decades to come. Although the use of nanocarriers exploiting passive targeting through the EPR effect was thought to substantially improve the nonspecific distribution of chemotherapeutics, tumor accumulation remains a major hurdle as the extent of the EPR effect varies widely among patients and tumor type [170,172]. In fact, despite the wide range of preclinical studies on the pegylation strategy, only a few authorized formulations are actually stealth liposomes. Hence, it is worth noting that there currently seems to be a dilemma about whether or not the use of PEG is worthwhile [173]. The polymer chains that prevent the recognition of opsonins and subsequent phagocytosis by the RES may also prevent liposomes from being internalized by target cells and the PEG layer may even contribute to developing palmar–plantar erythrodysesthesia [174]. Later, researchers started to focus on the functionalization of the carrier with targeting moieties to exploit active targeting as an alternative to passive targeting. Nevertheless, the reality is that none of the formulations authorized during the past three decades are based on this strategy. Despite the wide range of preclinical studies on active targeting during the 2010s, its immediate clinical translation remains uncertain, as the phase III trial with the first antibody-targeted liposomal formulation (MM-302) was prematurely terminated. It seems that the high variability in receptor expression between tumors is directly related to the failure of active targeting [98,175]. Alternatively, microspheres for chemoembolization increase the selectivity of the chemotherapeutics following intra-arterial administration, but at the cost of causing discomfort to the patient, as this type of administration is a complex local invasive procedure that requires trained professionals to perform it.

Moreover, some other difficulties encountered with clinical translation are related to manufacturing issues. Platforms that require complex and/or laborious synthesis procedures generally have a limited potential for clinical translation, as they can be difficult to scale up. For example, of the 16 technologically modified formulations entrapping chemotherapeutics that have reached the market, DaunoXome^® and DepoCyt^® have been discontinued due to manufacturing issues.

Of all the cancers treated with chemotherapeutic agents, the most common indication is hepatocellular carcinoma (37.5%), which accounts for >80% of primary liver cancers worldwide [176], followed by breast cancer (19%), mostly as second-line and hematological malignancies (19%). Of the nonmarketed formulations for the delivery of chemotherapeutics that are currently being evaluated in clinical trials, breast cancer represents the most frequent indication (50%), followed by adenocarcinoma of the pancreas (37.5%). However, as it also occurred with peptide-based therapy, future trends should be analyzed with caution, given that six of these phase III trials with chemotherapeutic formulations had a negative outcome

Analogously to chemotherapeutics, concerning radiotherapeutics, the main aim pursued with novel formulation strategies has been to improve their nonspecific distribution in order to deliver the maximum amount of radiation to the tumor with minor radiation-induced damage. Microspheres containing radiotherapeutics have been authorized for radioembolization. Based on the encouraging results obtained with selective local procedures such as TACE and the lack of efficient targeting strategies observed following systemic administration, all microspheres for radiotherapy approved in the past three decades are given following intra-arterial administration. Further improvements in these microspheres resulted in the first commercially available microsphere that combines radiotherapy with imaging function (QuiremSpheres^®). Alternatively, in 2019 a new class of radiation-enhancing nanoparticles formulated in crystalline HfO2 were authorized in Europe, being the first generation of radio enhancers intratumorally administered available for the treatment of solid tumors. The most common indication for formulations encapsulating radiotherapeutics is hepatocellular carcinoma (75%) followed by sarcoma (25%). As long as targeting efficiency following systemic administration is not enhanced, this type of therapy will only be suitable for accessible cancer types in which local administration is enabled. No phase III clinical trial with nonmarketed formulations of radiotherapeutics has been active in the last five years.

Figure 1, Figure 2 and Figure 3 reflect how the formulations for cancer treatment have evolved depending on the type of therapy and the type of technology used. According to Figure 1a, Figure 2a and Figure 3a, the formulations for peptide-based therapy have gone from representing 55% of the total number of new formulations approved during the 1990s to account for only 17% of the formulations approved in the 2010s. A clear parallel can be drawn between this decrease and the increase in the number of novel formulations for the delivery of chemotherapeutics, which has risen from 36% of the formulations approved during the 1990s to 58% of all formulations approved during the 2010s. The percentage of radiotherapeutics has slowly increased as well. Figure 5a shows the evolution of the approved formulations for the three types of cancer therapy to be compared. Between 2010 and 2015 the number of approved formulations for chemotherapy surpassed the number of peptide-based formulations that received authorization. Apart from the types of therapy, it is important to mention how the types of authorized formulations have evolved over time. As shown in Figure 5b, concerning the type of formulation used, both microcarriers and nanocarriers lead the marketed formulations (36.5%), whereas solid implants and polymer conjugates are lagging behind (21% and 6%, respectively). Figure 1b, Figure 2b and Figure 3b illustrate how liposomes and microspheres have been in the limelight over the past three decades while implants have been trending downwards since the 2000s.

Regarding the new formulation technologies that are expected to be approved in the future, active targeting, stimuli-responsive systems, and multifunctional systems are setting trends at the preclinical level. However, only MM-302, an actively targeted liposomal formulation, and ThermoDox^®, a thermosensitive liposomal formulation, have reached phase III clinical trials. Hence, clinical translation of these sophisticated systems is not expected to occur in the short term. Most of the formulations that have reached phase III clinical trials are liposomes for chemotherapeutics and polymer conjugates for peptides. As a novelty, Stimuvax^®, a vaccine for non-small-cell lung cancer, has completed a phase III clinical trial.

Regulatory agencies play an important role in the approval of novel formulations. Even though some of the products reviewed herein are not approved either in Europe or in the United States, 42.4% of all formulations are approved by both regulatory agencies (although approval does not necessarily occur concomitantly; e.g., Oncaspar^® was approved by the EMA 22 years after being approved by the FDA). Some formulations, including Suprefact^®, Mepact^®, Myocet^®, DC Bead^®, HepaSphere^®, Leptoprol^®, Apealea^®, LifePearl^®, Embozene Tandem^®, DC Bead LUMI^®, QuiremSpheres^®, Hensify^®, NanoTherm^®, and BioPearl^®, are authorized for use only in Europe, and Viadur^®, Vantas^®, Asparlas^®, and Marqibo^® only in the United States. Much of this percentage mismatch is attributable to the DEM-TACE microspheres, which have been approved as medical devices in Europe and the United States, but the drug-loading feature has yet to be approved by the FDA [177]. Overall, drug products represent 66.7% of the total number of approved formulations for cancer therapy, whereas medical devices represent the remaining 33.3%. However, these data are not uniform among the distinct types of cancer therapy; whereas 100% of the products approved for peptide-based therapy are drug products, the trend is reversed in the case of radiotherapy, where medical devices account for 100% of the approved formulations.

In conclusion, despite the lessons learned during these three decades that have allowed us to acquire a profound technological and pharmacological understanding of the development of novel formulations that have led to important advances in the treatment of cancer, there is still a long way to go to continue to improve the field of cancer therapy.