Oral Metronomic Chemotherapy with Low Dose Immunotherapy

Maximum Tolerated Dose (MTD)

MTD is the highest dose of a drug that can be given to a patient without causing unacceptable side effects. It is determined through clinical trials and is typically used in conventional chemotherapy protocols.

Characteristics of MTD Regimens:

• •Administered in high doses to maximize the killing of rapidly dividing cancer cells.
• •Followed by a rest period to allow the patient’s healthy cells to recover from the toxic effects.
• •Aims to achieve maximum tumor cytotoxicity but often comes with significant toxicity to normal tissues.

Oral Metronomic Chemotherapy with Low-Dose Immunotherapy in Oral Cancer Treatment

Maximum Tolerated Dose (MTD)

MTD is the highest dose of a drug that can be given to a patient without causing unacceptable side effects. It is determined through clinical trials and is typically used in conventional chemotherapy protocols.

Characteristics of MTD Regimens:

• Administered in high doses to maximize the killing of rapidly dividing cancer cells.
• Followed by a rest period to allow the patient’s healthy cells to recover from the toxic effects.
• Aims to achieve maximum tumor cytotoxicity but often comes with significant toxicity to normal tissues.

Metronomic Chemotherapy

Metronomic therapy involves the administration of low doses of chemotherapy drugs at regular, frequent intervals (e.g., daily or weekly) without extended breaks. It contrasts with MTD, where high doses are given in cycles.

Key Features of Metronomic Therapy:

• Low Dose: Reduces the toxic side effects associated with high-dose regimens.
• Continuous Administration: Maintains a steady therapeutic effect over time.

Targets Tumor Microenvironment:

• Inhibits angiogenesis (formation of blood vessels that supply the tumor) by targeting endothelial cells.
• Modulates the immune system to enhance anti-tumor activity.
• Reduces tumor resistance over time by avoiding high-dose toxicity-induced adaptations.

Metronomic chemotherapy refers to the continuous, low-dose administration of chemotherapeutic agents at regular intervals. This approach contrasts with conventional high-dose chemotherapy cycles. The primary goals of metronomic chemotherapy are to:

1. Target the Tumor Microenvironment: Inhibit tumor angiogenesis (formation of new blood vessels that supply the tumor).
2. Reduce Toxicity: Minimize the severe side effects associated with high-dose chemotherapy.
3. Enhance Immune Modulation: Improve the immune response against cancer.

In oral cancer, metronomic regimens often include drugs like methotrexate, cyclophosphamide, or fluoropyrimidines delivered orally or intravenously in low doses. Oral administration provides convenience for patients and is particularly suited for outpatient settings.

Low-Dose Immunotherapy

Immunotherapy enhances the body’s immune response to cancer. When combined with metronomic chemotherapy, low-dose immunotherapy:

• Stimulates Immune Surveillance: Encourages immune cells to recognize and destroy cancer cells.
• Reduces Immunosuppression: Counteracts the immune-suppressive effects of the tumor microenvironment.

Agents commonly used include:

• Checkpoint Inhibitors (e.g., PD-1/PD-L1 inhibitors): These block proteins that suppress immune activity, allowing T-cells to attack cancer cells more effectively.
• Cytokines or Vaccines: Boost specific immune responses.
• Adjuvants: Enhance the overall effectiveness of the immune response.

Benefits in Oral Cancer

• Control of Local and Distant Disease: Particularly useful for managing advanced or recurrent cases of oral cancer.
• Improved Quality of Life: Low doses reduce side effects like mucositis, nausea, and fatigue.
• Enhanced Accessibility: Oral delivery and outpatient administration make the treatment accessible and cost-effective.
• Synergy Between Therapies: Metronomic chemotherapy reduces tumor burden and angiogenesis, creating an environment where immunotherapy can be more effective.

Current Applications

Oral metronomic chemotherapy with low-dose immunotherapy is especially valuable for:

1. Advanced and Recurrent Oral Cancer: Where curative surgery or high-dose chemotherapy is not feasible.
2. Palliative Care: To prolong life and improve quality without aggressive treatment.
3. Adjuvant Therapy: Supporting primary treatments like surgery or radiation therapy.

Challenges

1. Selection of Patients: It may not be suitable for aggressive, rapidly growing tumors that require high-dose treatments.
2. Treatment Monitoring: Requires careful follow-up to assess efficacy and adjust therapy.
3. Resistance: Long-term low-dose regimens may lead to adaptive resistance mechanisms.

In oral metronomic chemotherapy combined with low-dose immunotherapy for oral cancer, specific drugs are chosen based on their mechanisms of action, tolerability at low doses, and synergy with immunotherapy. Here’s an overview of commonly used agents:

Chemotherapy Drugs in Metronomic Regimens

1.Methotrexate

• A folate antagonist that inhibits DNA synthesis and cell division.
• Commonly used in low doses for oral and head & neck cancers.
• Administered orally or intramuscularly.

2.Cyclophosphamide

• An alkylating agent that targets rapidly dividing cancer cells.
• At low doses, it suppresses regulatory T cells (Tregs) that dampen the immune response, enhancing the effectiveness of immunotherapy.

3.Capecitabine

• A prodrug converted to 5-fluorouracil (5-FU) in tumor tissues.
• Inhibits DNA synthesis in tumor cells with relatively low systemic toxicity.

4.Celecoxib (Adjunctive)

• A COX-2 inhibitor used to reduce inflammation and angiogenesis.
• Not a chemotherapy agent but often combined in metronomic regimens for oral cancers.

Immunotherapy Drugs

1.Checkpoint Inhibitors

• Nivolumab (PD-1 inhibitor): Enhances T-cell response by blocking PD-1, a receptor that cancer cells exploit to evade immune detection.
• Pembrolizumab (PD-1 inhibitor): Similar to Nivolumab, approved for head & neck cancers including oral cancer.
• Atezolizumab (PD-L1 inhibitor): Blocks PD-L1, allowing T-cells to attack cancer more effectively.

2.Cytokines

• Interleukin-2 (IL-2): Boosts T-cell activity, enhancing immune surveillance.
• Interferon-alpha (IFN-α): Stimulates immune system activity against tumor cells and inhibits tumor growth.

3.Adjuvants and Vaccines

• Immune adjuvants like BCG (Bacillus Calmette–Guérin) are sometimes used to stimulate immune response in combination with other therapies.
• Experimental cancer vaccines targeting specific oral cancer antigens.

4.Monoclonal Antibodies

• Target specific cancer markers or pathways. For example, Cetuximab targets the EGFR pathway in head & neck cancers.

Synergy Between Chemotherapy and Immunotherapy

• Metronomic chemotherapy reduces immunosuppressive cells like Tregs and myeloid-derived suppressor cells (MDSCs), enhancing the effectiveness of checkpoint inhibitors.
• Inhibiting angiogenesis through low-dose chemotherapy also makes the tumor environment less hospitable, aiding immune cell infiltration.

Challenges and Ongoing Research

• Identifying the optimal combination of drugs.
• Managing potential low-grade but chronic toxicities.
• Evaluating effectiveness in clinical trials for long-term survival benefits.