From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)

10. Discussion

In spite of its severe side effects, chemotherapy remains a main treatment option for cancer. As early as 1963, the disappointing efficacy of chemotherapy was reported (4). However, between 1984 and 1985, at the peak of aggressive chemotherapy, >6,000 articles were published in medical journals regarding treatment of cancer with chemotherapy; none of these studies reported on novel strategies that could cure advanced solid tumors in combination with chemotherapy (3). Grade 3 and 4 side effects can be life threatening. One of the many types of cytostatic drug that produce such side effects are molecular derivatives of nitrogen mustard, which is a toxin that was used during World War I. Examples, still in use, are melphalan, chlorambucil, cyclophosphamide, ifosfamid and others.

Evidence-based medicine is currently the gold standard for the approval of novel drugs. The quality of criteria for clinical studies has steadily increased since the introduction of cytostatic drugs; however, some drugs originally approved many years ago are still in use. Recommendations for updates of standard therapy come from medical oncology societies. There is no guarantee, however, that such recommendations are devoid of conflicts of interest; therefore, it remains the individual responsibility of a medical oncologist to decide which drugs to apply or not. Medical ethics should be respected.

To change the direction of cancer therapy is not easy, as healthcare is a huge market. At present, immunological products, such as MAbs and checkpoint inhibitors have successfully entered the market; however, this is only a small portion of the potential of immunotherapy. In the future, immunotherapy may be a discipline in its own right, including immune diagnosis, immunotherapy, immune monitoring and immunological follow-up. Furthermore, two cancer vaccines, ATV-NDV and VOL-DC, which combine OVs with TAAs, have been entered into clinical application. After >30 years, integrating OVs into cancer immunotherapy may soon become mainstream (101).

11. Conclusions

The present review compared chemotherapy and biological therapies, including immunotherapy and OV therapy.

Systemic forms of cancer treatment are necessary at the transition phase of cancer, when it turns from a localized into a systemic form of disease with metastases. Systemic forms of cancer treatment can be prophylactic (e.g. in a post-operative situation) or therapeutic. The primary aim of chemotherapy is to reduce tumor burden, whereas the aim of immunotherapy is to generate systemic protective anticancer immunity. The focus is either on the tumor or on the tumor-bearing host organism and its immune system.

The aim of this review was to present novel concepts, which may reduce side effects from systemic cancer treatment. This is necessary because chemotherapy often exhibits relatively low tumor specificity and high toxicity. Targeted therapy with chemically designed SMIs has higher tumor specificity than conventional chemotherapy; however, the side effects are similar. The majority of novel concepts are derived from biological types of therapy (Tables I–III); some of these biological therapies exert considerable side effects. Conversely, conventional immunotherapy, including vaccination and OV therapy, exerts only mild side effects and is well tolerated. It is suggested that the reason for this difference is physiological: Immunological self-tolerance and immunological memory.

An important difference between chemotherapy and immunotherapy or OV therapy is the dose-response curve. While in the case of cytostatic drugs the curve is linear, in the case of biological and physiological therapies it is bell-shaped. The reason for this difference appears to be due to the complementarity of specific cognate molecular lock-and-key interactions. This is exemplified with interactions between antigens and antibodies, as well as between pMHC and TCR in cases of T-cell-mediated immune responses.

Notably, a combination of cancer immunotherapy and OV therapy was successful in a randomized controlled study (77,78). This previous study evaluated the efficacy of post-operative vaccination with ATV-NDV in patients with stage IV CRC following resection of liver metastases. The results revealed that in patients with colon cancer a significant 10-year survival benefit of as much as 30% was detected. The magnitude of the effect is similar to that obtained in patients with melanoma treated with ICB (59). The side effects of these two approaches, however, were different: Grade 0-2 for the vaccination study compared with grade 1-4 for the ICB study.

With regards to future developments, it has been suggested to combine vaccines, OVs and immune checkpoint inhibitors to prime, expand and facilitate effective tumor immunotherapy (102,103). The main conclusions of this review are: i) It may be beneficial for immunotherapy to be included in standard care. Rules of evidence-based medicine should be adjusted to the needs of individualized immunotherapy studies, as well as to multimodal therapy studies in general. ii) Recommendations for the use of cytostatic drugs that produce severe side effects and low efficacy should be reviewed by societies of internal medicine.

Acknowledgments