Low Dose Chemotherapy
There has long been a perception in the world of medical oncology that large dosages of chemotherapy are necessary to eradicate every last tumor cell. That being said, this strategy has not consistently resulted in long-lasting complete cures for most cancer patients. It's important to remember that improving the dosage of standard regimens alone does not always result in better regression or higher overall survival rates.
One major drawback of this aggressive strategy is the possibility of overtreatment leading to a decline in quality of life. The majority of solid tumors will eventually relapse, even in situations where overt damage is avoided. Achieving a balance between providing cancer patients with high-quality treatment and preserving their quality of life is critical.
Prioritizing the idea that "more is better" when it comes to medication administration has historically resulted in a lack of attention to other important factors, like when and how long to administer cytotoxic chemotherapy. In this case, metronomic chemotherapy—the continuous administration of relatively modest doses of cytotoxic agents—may not directly target tumor cells, as is mainly seen with the cyclic Maximum Tolerated Dose (MTD) strategy. Rather, metronomic chemotherapy inhibits angiogenesis and vasculogenesis, which has an indirect effect on tumor cells. Thus, low-dose metronomic (LDM) chemotherapy has several advantages over the MTD approach, including:
decreased toxicity,
treatment response independent of the resistance profile of the tumor cell population, and
the possibility of long-term combination therapy with targeted drugs.
Using traditional chemotherapeutics, low-dose metronomic (LDM) chemotherapy offers a novel strategy for addressing resistance to maximum-tolerated dose (MTD) chemotherapy. The results of several studies have demonstrated the many benefits of LDM chemotherapy, exhibiting a therapeutic index that combines exceptional anticancer effectiveness with a toxicity profile better than that of MTD chemotherapy.
Executive Summary
Introduction to Metronomic or Low Dose Chemotherapy: Metronomic chemotherapy is a new approach to cancer treatment that challenges the traditional "more is better" mindset. Instead of using high doses of chemotherapy drugs, it uses lower doses given more frequently. This method aims to balance effective treatment with better quality of life for patients. It works differently from traditional chemotherapy by targeting the blood vessels that feed tumors rather than directly attacking cancer cells.
How Metronomic Chemotherapy Differs from Conventional Treatment: Unlike conventional chemotherapy, which uses high doses with long breaks between treatments, metronomic chemotherapy uses lower doses given more consistently. This approach keeps a steady level of the drug in the patient's body, rather than causing it to spike and drop. Metronomic chemotherapy also tends to have fewer side effects, making it easier for patients to tolerate over long periods.
How Metronomic Chemotherapy Works: This treatment method works in several ways to fight cancer. It prevents the formation of new blood vessels that feed tumors, boosts the immune system's response to cancer, and can cause tumors to become dormant. Interestingly, it can also make cancer cells dependent on the chemotherapy drug, so that when the drug is withdrawn, the cancer cells die.
Combining Low Dosde Chemotherapy with Other Treatments: Researchers are exploring how to combine metronomic chemotherapy with other cancer treatments, especially immunotherapy. Early studies show that this combination approach could be more effective than either treatment alone. For example, in breast cancer and lung cancer, combining metronomic chemotherapy with immunotherapy drugs has shown promising results.
Clinical Experience in Different Cancers: Metronomic chemotherapy has been tested in various types of cancer, including breast, prostate, ovarian, kidney, lung, and blood cancers. In many cases, it has shown promising results, especially for patients who have not responded well to traditional treatments. For instance, in breast cancer, combining metronomic chemotherapy with other drugs has led to longer survival times for some patients.
Benefits and Challenges: The main benefits of metronomic chemotherapy include fewer side effects, the ability to overcome drug resistance in some cases, and the potential for long-term use. However, challenges remain in determining the best drug combinations and dosing schedules for different types of cancer. More research is needed to fully understand how to best use this treatment approach.
Future Prospects: Metronomic chemotherapy is gaining recognition as a valuable treatment option in cancer care. It's now recommended in some treatment guidelines, particularly for advanced breast cancer. As research continues, it's likely that metronomic chemotherapy will become more widely used for various types of cancer, offering patients a potentially more tolerable and effective treatment option.
Difference from conventional chemotherapy
Lower doses than the Maximum Tolerated Dose (MTD) are used in metronomic chemotherapy, providing a more continuous and prolonged treatment plan. This is not the case with traditional cytotoxic medications, which are usually given based on bone marrow recovery at MTD at predetermined intervals (e.g., weekly, fortnightly, or every three weeks).
Metronomic therapy keeps the drug's plasma concentration constant, whereas conventional therapy causes it to rise and fall. Interestingly, metronomic therapy targets particularly the endothelial cells within the expanding tumor vasculature, whereas conventional therapy targets the tumor cells themselves as they proliferate.
Conventional therapy aims to directly treat cancer by either stopping or eliminating tumor cells from proliferating too quickly. On the other hand, metronomic chemotherapy offers a unique approach to cancer treatment by focusing on angiogenesis as a means of controlling the disease.
The benefit of using metronomic chemotherapy is that it can maintain a low blood level of the drug without causing major toxic side effects, which can minimize the requirement for supportive care. On the other hand, conventional therapy presents questions regarding toxicity, particularly when it is given at MTD.
Furthermore, traditional chemotherapy is generally more successful in treating the original tumor than in treating its metastases. Cytotoxic agents frequently only provide palliative effects in patients with advanced cancer, despite combination regimens at MTD.
Mechanisms of Action
Among the many targeted therapies available, metronomic chemotherapy is unique in that it affects tumor cells and their surrounding tissue directly as well as indirectly. Its effects include promoting immune responses to cancer, preventing tumor angiogenesis, and causing tumor dormancy.
The primary mechanism by which metronomic treatment suppresses tumor angiogenesis is its anti-angiogenic properties. Notably, its in-vivo actions include:
inhibiting endothelial cell migration,
sustaining a decrease in the quantity and survival of bone marrow-derived endothelial progenitor cells (CEPs),
boosting the expression of thrombospondin-1, an endogenous angiogenesis inhibitor.
preventing activated endothelial cells from proliferating and/or from undergoing apoptotic induction.
Since endothelial toxicity is a common problem in anti-cancer therapy, it is critical to establish clear criteria for the metronomic classification of chemotherapy. These include dynamic contrast-enhanced magnetic resonance imaging or contrast-enhanced ultrasonic examinations indicating:
altered endothelial cell function,
strong differential cytotoxicity between cancer cells and endothelial cells, and
demonstrable inhibition of angiogenesis in both in vitro and in vivo settings.
Metronomic chemotherapy stimulates both the innate and adaptive immune systems, which goes against the widely held belief that chemotherapy causes immunological suppression. This is in addition to its anti-angiogenic properties. Studies have demonstrated that some cytotoxic medications, such as taxanes, cyclophosphamide (CPA), and anthracyclines, have immune-stimulating properties. In metronomic therapy, the impact on regulatory T cells (Treg) is especially noteworthy because of their suppressed activity and lower population, which enhance the immune response against antigens linked with tumors.
Moreover, metronomic chemotherapy promotes dendritic cell development, enhancing its therapeutic profile by including an immunostimulatory layer. Studies demonstrating the stimulation of dendritic cell maturation at non-toxic concentrations of particular chemotherapeutic agents provide evidence for this.
Another aspect of the effectiveness of metronomic chemotherapy is tumor dormancy, which is accomplished by immune-surveillance mechanisms, death of malignant cells, and inhibition of angiogenesis. Furthermore, because lower doses of cytostatic medications cause antiproliferative responses without initiating caspase activity cascades linked to cellular apoptosis, this therapy may induce senescence.
The "four-dimensional effect" theory explains the effectiveness of regimens with sporadic drug interruptions by postulating a drug-driven deprivation/dependency phenomenon. This idea states that tumor cells develop a dependence on chemotherapeutic medicines over time and that abrupt withdrawal or substitution therapy may cause cell death. This theory aids in explaining situations in which several medications are administered at different times.
Evidence for Efficacy
Although the original goal of mCT was to target tumor endothelial cells to combat tumor resistance, more recent research has shown that it can also trigger tumor cytotoxicity pathways and anti-tumor innate and adaptive immunity. Consequently, integrating mCT with other pharmacological substances—particularly immune checkpoint inhibitors—has been investigated recently.
Metronomic chemotherapy and immune checkpoint inhibitors
Because of its diverse immunomodulatory properties, mCT is a great option to work along with immune checkpoint inhibitors (ICI). Recent developments in immunotherapy, especially concerning ICI, have shown that they can modulate immune cell activation and cytotoxic activity to augment the body's natural anti-tumor immunological response. Targeting T cell surface receptors such as programmed cell death (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) and their ligands, PD-L1 or PD-L2, has been the main emphasis. Notably, exceptional results for a range of cancers, such as melanoma, lung cancer, and hematological malignancies, have been noted.
Even with the great advancements in cancer immunotherapy, only a small percentage of patients can benefit from immune checkpoint-blocking antibodies while treating various cancer types. The investigation of combining immunotherapy with chemotherapy has produced encouraging results to prevent immunological tumor evasion and increase the response rate to immune checkpoint inhibitors.
Research has investigated the anti-tumor response in triple-negative breast cancer (TNBC) by comparing the effectiveness of three different cyclophosphamide regimens. Interestingly, their results showed that in comparison to traditional MTD or daily metronomic dosing, the administration of cyclophosphamide at 140 mg/kg every 6 days in murine orthotopic models led to greater suppression of tumor growth.
In patients with metastatic or incurable, locally advanced TNBC, the TONIC trial evaluated the efficacy of nivolumab, an anti-PD-1 monoclonal antibody, after short-term induction with mCT (cyclophosphamide, cisplatin, or doxorubicin), irradiation, or no induction. The study's objective response rate (ORR) was found to be 20%, with the cisplatin (ORR 23%) and doxorubicin (ORR 35%) groups exhibiting the most noteworthy responses. Together with a notable increase in tumor-infiltrating T cells and an upregulation of genes linked to PD-1/PD-L1, these cohorts showed an elevated response rate. Similarly, an up-regulation of CD8+ T cells was seen in patients with small cell lung cancer (SCLC) receiving treatment with both nivolumab and low-dosage albumin-paclitaxel.
Clinical Translation Opportunities and Challenges
Cancer patients for whom traditional chemotherapy was no longer effective have benefited therapeutically from mCT. Particularly, after mCT administration, favorable results were shown in the treatment of metastatic breast cancer, non-small cell lung cancer (NSCLC), and colon-rectal carcinoma. Furthermore, it has been shown that mCT and non-traditional cytotoxic medicines, like anti-angiogenic medications, can effectively overcome host toxicity while maintaining therapeutic efficacy.
Clinical Experience in Breast Cancer
In breast cancer research, cyclophosphamide (CP) and methotrexate (MTX) have emerged as viable options for metronomic therapy. The oral metronomic administration of CP and MTX combined (CM) among patients with pretreatment metastatic breast cancer was the subject of initial research. In one trial, a 50 mg daily dose of CP and 2.5 mg twice daily, for two days a week, of MTX were used. The results showed a significant clinical benefit (defined as at least 24 weeks of objective response and stable illness) of 31.7% and an encouraging objective response rate (ORR) of 20.9%. Interestingly, a noteworthy 15.7% of patients in the long-term follow-up reported persistent clinical benefit that lasted more than a year.
Comparable disease control and controllable toxicity profiles were also shown in another study's trials, which tested CP either by itself or in conjunction with MTX. Furthermore, in metastatic patients, the combination of metronomic CP and MTD liposomal doxorubicin demonstrated encouraging outcomes, with a 75% clinical benefit rate and a median overall survival (OS) of 6.4 months.
Both CP and MTX offer a wide range of combination regimens with specific agents. In a different research, a group of patients who were resistant to taxanes and anthracyclines was tested with bevacizumab and trastuzumab (particularly in HER-2-positive patients), in addition to the CM combination. This group of patients achieved an overall survival (OS) of 13.6 months.
Among patients with pretreated breast cancer, the combination of CP with bevacizumab and capecitabine demonstrated the highest clinical benefit rate (68%). In a phase I dose-escalation study, vandetanib was also included in CM-based metronomic therapy. A 10% partial response was seen in the remaining 20 patients, despite side effects causing a loss of treatment adherence in 1/3 of the patients.
Celecoxib, a selective cyclooxygenase-2 inhibitor, was tested on 15 individuals with CM in a different trial. At 46.7%, the clinical benefit rate was noteworthy, and no significant toxicities were recorded. By combining CM with fulvestrant, another study adopted a novel strategy that produced a sustained clinical benefit. Together, these results highlight the encouraging results and promise of these various combination schedules in improving the treatment of breast cancer.
Clinical Experience in Castration-Resistant Prostate Cancer (CRPC)
Metronomic cyclophosphamide was one of the first drugs to be investigated as a treatment for CRPC, and it is still the drug of choice, either alone or in combination with other drugs. A seminal investigation on the application of CP in CRPC comprising 30 hormone-refractory prostate cancer (HRPC) patients was carried out in 1993. Remarkably, 18 of these individuals showed both a therapeutic benefit and a reduction in symptoms. Ten years later, a study with eight metastatic HRPC patients receiving CP showed a striking 62.5% clinical benefit rate and two patients with prostate-specific antigen (PSA) responses greater than 50%.
Analyzing a larger group of 80 patients who had CP, a good 34.5% overall response rate was noted. A phase II experiment looked at the combination of CP and corticosteroids to see if it could be an effective way to treat pretreated CRPC with cyclophosphamide. Interestingly, 15 out of 36 patients (42%) had a significant >50% PSA response, which is noteworthy given the proven efficacy of DES in hormone-refractory illness, and the median overall survival was 16.4 months.
Furthermore, the combination of celecoxib and CP, which is well-known for its antiangiogenic properties, was investigated. Thirteen (45%) out of a cohort of 29 older adults demonstrated a confirmed PSA drop of 50% or more. Celecoxib and CP were used in a significant study that showed that 14 out of 32 patients had a PSA drop of more than 50%. These results add to the continuing investigation into efficacious therapeutic approaches concerning cyclophosphamide therapy.
Clinical Experience in Ovarian Cancer
In a trial, metronomic chemotherapy and the potential antiangiogenic drug bevacizumab were assessed for ovarian cancer. A noteworthy development was the smooth integration of bevacizumab into the first-line standard of care in a phase III trial. Three patient groups receiving carboplatin and paclitaxel were compared in the study: the first group did not get bevacizumab, the second group received bevacizumab initially, and the third group received bevacizumab continuously throughout treatment. According to the results, adding bevacizumab significantly increased the median progression-free survival (PFS) by about 4 months. In particular, the bevacizumab group's median PFS was 14.1 months, while the control group's median PFS was 10.3 months. These findings highlight the beneficial effects of bevacizumab in improving ovarian cancer therapy results.
Both CP and bevacizumab were investigated in terms of potential therapy options for pretreated platinum-resistant ovarian cancer. Prominent research presented a regimen consisting of 50 mg/day of CP with 10 mg/kg of intravenous bevacizumab given every two weeks. Remarkably, the overall survival (OS) was 7 months and 17 months, and the progression-free survival (PFS) was 4.5 months and 7 months.
Similar results were presented, with 66 patients showing an extraordinary OS of 20 months. A retrospective analysis of bevacizumab and CP found a median progression time of 5.5 months. Further research with patients who had a median of 8 previous chemotherapy treatments showed that the same combination of bevacizumab plus CP had a total response rate of 53.3%.
Additionally, encouraging outcomes were seen when bevacizumab was used with other traditional treatments. For example, biweekly bevacizumab administration combined with topotecan in cycles of 1, 8, and 15 days throughout 28-day administrations produced a PFS of 7.8 months and an OS of 16.6 months. A study also investigated bevacizumab in conjunction with weekly paclitaxel, topotecan, and pegylated liposomal doxorubicin. The results showed that the median progression-free survival (PFS) was 3.4 months when chemotherapy was administered alone, but it increased to 6.7 months when bevacizumab was added.
Clinical Experience in Renal Cell Cancer
When faced with resistance to targeted medicines, a compelling option for additional clinical research emerged: investigating the possible increase of their efficacy by metronomic scheduling, as suggested by preclinical studies. Metronomic regimens were shown to be effective in preclinical research. In this research, dormancy was induced and maintained by pairing metronomic topotecan with pazopanib and testing against human RCC cell lines.
A further study examined a combination therapy consisting of six cycles of metronomic capecitabine and sorafenib combined with the maximum tolerated dose (MTD) of gemcitabine, and then metronomic sorafenib. These patients had an impressive median progression-free survival (PFS) of 11.1 months. Twenty of the 44 people had a partial reaction, and 17 had stable disease.
In a different trial, etoricoxib + pioglitazone taken daily, together with three times a week low-dose interferon and twice-day oral capecitabine every three weeks, showed promising results. Despite a 48.8% incidence of Grade 4 toxicity, the overall survival (OS) and PFS for the entire sample were, respectively, 26.9 and 7.2 months. A recent research investigated the combination of interferon α and metronomic cyclophosphamide (CP), and in 40% of the 30 patients, they saw a clinical effect that lasted longer than 24 weeks. This novel method resulted in a median OS of 13.2 months.
Clinical Experience in Lung Cancer
Metronomic regimens have been scrutinized in the context of non-small cell lung cancer, where they are utilized as a salvage therapy in addition to being the primary method for weak patients. In salvage therapy, the adaptable oral etoposide has garnered significant attention. One notable trial compared the standard intravenous regimen with oral etoposide at a dose of 100 mg twice a day for the palliative treatment of small cell lung cancer (SCLC). The results showed an overall survival (OS) of 4.8 months and a 9.8% 1-year survival rate in the etoposide group.
Clinical Experience in Multiple Myeloma
Given the crucial role that vasculogenesis plays in the pathophysiology of multiple myeloma, it is reasonable to employ antiangiogenic medications with metronomic regimens. A study created a regimen of oral thalidomide (200 mg daily), prednisone, and cyclophosphamide (50 mg twice daily for 21 days) in 28-day cycles for patients with relapsed or refractory multiple myeloma (RRMM). With an 85.8% clinical benefit, including a 20% full response, 5.7% near complete response, 13% partial response, and 22.9% stable disease, the outcomes for 35 patients were encouraging. Notably, toxicities in grades 3 and 4 were recorded, with hematological problems being the most frequent.
Further research looked at thalidomide in combination with prednisone and cyclophosphamide. Lenalidomide, cyclophosphamide, and prednisone were prescribed in a 28-day cycle according to a study. The overall response rate was a remarkable 94% with a median follow-up of 28 months, and the median progression-free survival was 161 months.
A prospective phase 1/2 trial examined the efficacy of a metronomic combination of dexamethasone, cyclophosphamide, and lenalidomide in the setting of RRMM patients. The median values for overall survival and progression-free survival were reported to be 29.0 months and 12.1 months, respectively. A further phase 2 research evaluated the low-dose daily administration of pomalidomide and cyclophosphamide in patients with RRMM; the results showed a 14-month progression-free survival rate of 67%.
Studies on myeloma patients have shown that thalidomide and lenalidomide are effective medications with more tolerable levels of toxicity. Their extensive application emphasizes how crucial they are to the management of multiple myeloma, especially in posttransplantation treatment for maintenance.
Conclusion
Preclinical and clinical research results have established metronomic chemotherapy as a novel therapeutic strategy for certain cancers. In cancer treatment, metronomic chemotherapy has quietly made a quiet debut, limited to later therapeutic tiers and nearly entirely in palliative care.
Since the early 1920s, more and more people have been using mCHT; breast cancer was the first to use it, but other cancers, particularly lung cancer and pediatric malignancies, quickly followed.
The three main tenets of mCHT are (1) its multi-modal modes of action, (2) its low incidence of adverse effects, and (3) its simple administration method. Each of these elements has had a major role in the widespread application of mCHT in a number of additional cancer types (ovarian, head and neck, AML, GBM).
In the Advanced Breast Cancer (ABC)-European Society of Medical Oncology (ESMO) guidelines for metastatic breast cancer, mCHT is now advised. It has also been incorporated into other national guidelines, even in nations like Vietnam where the routine application of this technique is relatively new. Researchers across the world too are in complete agreement that mCHT is a completely new treatment option rather than just a different method of delivering chemotherapy.