The history of chemotherapy (chemotherapy, chemotherapy) in oncology has been evolving for more than 70 years. During this time, multiple drugs have been updated, multiple regimens have emerged, and chemotherapy has become increasingly effective and less toxic.
Currently, chemotherapy seems to be the “old guard” in the lung cancer field compared to the rapidly changing targeted therapies and immunotherapies. But the reality is that most patients will still choose chemotherapy for a variety of reasons. It can be argued that chemotherapy is irreplaceable as a cornerstone of lung cancer treatment, both now and in the future.
In fact, when you look at it, chemotherapy has never stopped moving forward, even though it doesn’t dominate the headlines as often as targeted and immunotherapy, which are the two “fresh meat”.
New drugs
Chemotherapy drugs have evolved over the past 70 years, resulting in three generations of drugs.
- First generation: methotrexate, cyclophosphamide, and fluorouracil were used in the 1940s and 1950s, ushering in a new era of chemotherapy;
- Second generation: In the 1960s and 1970s, adriamycin and cisplatin were used to expand the “landscape” of chemotherapy;
- Third generation: paclitaxel, gemcitabine, vincristine, irinotecan and many other new drugs were used in the clinic, and the chemotherapy effect reached a new level, and gradually formed the overall pattern today.
Many people may think that “one generation is stronger than the next” and that the later wave should “beat the former wave to death”, but this is not the case. The three generations of drugs have different ranges of application and toxicities, and for different patients and tumor types, each may have its own strengths, and each has its own winning field.
While no disruptive chemotherapy drugs have been introduced in recent years, the pace of new drug development has never stopped, and we believe that as quantitative changes accumulate, qualitative changes will eventually occur.
New regimens
In the beginning, chemotherapy regimens generally used only a single drug, and one drug was a regimen. As clinical experience was gained and clinical studies were conducted, physicians discovered that better outcomes might be achieved with multi-drug combinations. This is certainly not an arbitrary combination, and as human understanding of tumors has become more sophisticated, it has become clearer how to rationally match and complement each other’s strengths.
We know that cells proliferate by dividing, and for proliferating cells, the entire proliferative cycle is divided into two phases: interphase (subdivided into G1, S, and G2 phases) and metaphase (M phase). The cells that are temporarily out of the proliferative cycle are called “stationary phase” (G0 phase).
Researchers have found that some chemotherapeutic agents work at specific stages of the proliferation cycle and are effective at killing rapidly proliferating tumor cells, so they are called “cycle-specific chemotherapeutic agents”; others do not target specific proliferative stages but are “generalists”, so they are called “non-specialists”. “They are called “non-cycle-specific chemotherapeutic agents”. The scientific combination of these two classes of drugs can be more effective in containing tumors.
In addition, traditional chemotherapy is usually administered for only 4-6 cycles and then it is over. In recent years, the profession has developed the concept of “maintenance therapy,” which means that after a certain cycle of chemotherapy, if the tumor has not progressed, you can continue with another chemotherapy regimen that is less toxic.
For example, patients with advanced lung adenocarcinoma who are “negative” for driver genes such as EGFR and ALK (no targeted drugs) can be maintained on pemetrexed alone after 4 to 6 weeks of pemetrexed and platinum-based dual-agent chemotherapy.
Maintenance therapy fills the “window” in the fight against tumors and does not give the remaining tumor cells a “break”, potentially leading to longer disease remission.
New use of old drugs
Some chemotherapy drugs are effective, but their use is limited for a variety of reasons (e.g., high toxicities, high starting concentrations). In this case, the “old” drug can be rejuvenated by finding a more appropriate dose, a better dosage form, and a more scientific route of administration.
Changing the route of administration: Chemotherapy drugs are usually administered systemically by intravenous infusion, but sometimes, to increase the concentration of the drug in the tumor site, local intratumoral injections can be used to concentrate the drug around the cancer site.
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Choosing the right dosage form: The dosage form affects the concentration, stability, and duration of action of the drug in the body. For example, an extended-release dosage form allows the drug to remain at a relatively stable concentration for a long time and prolongs the dosing interval. Sustained release simply means that the drug is released gradually over time, rather than all at once. For example, paclitaxel is a very common chemotherapy drug, which is insoluble in water and needs to be dissolved in castor oil, but castor oil can cause allergic reactions. To overcome this, scientists have developed new dosage forms such as liposomal paclitaxel and albumin-bound paclitaxel.
Combination therapy
In recent years, there has been a proliferation of new therapies beyond the traditional “old triad” (surgery, chemotherapy, and radiation), including anti-angiogenic drugs that target tumor neovascularization, targeted drugs that target specific genetic loci, and immunotherapy that targets the immune environment in the body. The efficacy of these new therapies has gradually been proven and has even surpassed chemotherapy. Chemotherapy has also begun to join forces with these “new meat”, such as chemotherapy + anti-angiogenic therapy, chemotherapy + targeted therapy, etc., and some of them have already begun to show results.
What’s promising is that some studies have shown that chemotherapy drugs can stimulate the immune system to fight tumors, which means that if immune checkpoint inhibitors, which have been a big hit recently, are combined with chemotherapy, chemotherapy can expand the proportion of patients who respond to immune checkpoint inhibitors and expand the population that benefits from them, which could be an added benefit.
Precision chemotherapy
We know that many traditional chemotherapy drugs cannot “distinguish” between cancer cells and normal cells, and often “kill a thousand enemies at the expense of 500”, so how to improve the “precision” of chemotherapy has been explored. The first step in the process is to improve the accuracy of chemotherapy, which has been explored by medical doctors.
One of the current “new weapons” is antibody drug conjugates (ADCs), which are “antibodies” that target tumors and are “assembled” with chemotherapy drugs. “The antibody is responsible for finding and targeting the tumor cells, and the chemotherapy drug is responsible for killing the tumor, as the “scope” (antibody) and the bullet (chemotherapy drug) of a sniper rifle.
In the past decade, studies have suggested that drug-targeted genetic testing of patients could help predict the efficacy of chemotherapy drugs, but most have failed in further validation. However, medical doctors are still tirelessly exploring markers to predict the efficacy of chemotherapy, and perhaps new discoveries will be made in the near future.
Co-authors: Dr. Yue-Li Sun Dr. Wen-Feng Lai, Guangdong Provincial People’s Hospital, Guangdong Lung Cancer Institute