The rationale for combining chemotherapeutic agents is founded on the knowledge that single-agent regimens often result in drug resistant recurrence. "Tumors usually consist of mixed populations of malignant cells, some of which are drug-sensitive while others are drug-resistant. Chemotherapy kills drug-sensitive cells, but leaves behind a higher proportion of drug-resistant cells. As the tumor begins to grow again, chemotherapy may fail because the remaining tumor cells are now resistant."•
"Combination chemotherapy accomplishes three important objectives not possible with single-agent therapy: (1) It provides maximum cell kill within the range of toxicity tolerated by the host for each drug; (2) it offers a broader range of coverage of resistant cell lines in a heterogeneous tumor population; and (3) it prevents or slows the development of new drug-resistant cell lines."•
Mutation can enhance evolutionary strategies that promote or confer resistance to toxins. Some of these strategies including: drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition. Many of these strategies are conserved across the animal kingdom. Microbial antibiotic drug resistance is a good example of how robust these strategies are.
Principles used to select drugs for inclusion in combination chemotherapy regimens:
- Drugs known to be active as single agents should be selected for combinations. Preferentially, drugs that induce complete remissions should be included.
- Drugs with different mechanisms of action should be combined in order to allow for additive or synergistic effects on the tumor.
- Drugs with differing dose-limiting toxicities should be combined to allow each drug to be given at full or nearly full therapeutic doses.
- Drugs should be used in their optimal dose and schedule.
- Drugs should be given at consistent intervals. The treatment-free in- terval between cycles should be the shortest possible time for recovery of the most sensitive normal tissue.
- Drugs with different patterns of resistance should be combined to minimize cross-resistance.•
Currently, combination chemotherapy is standard treatment for most advanced cancers. However, evidence supporting the benefit of combination therapy is mixed. In the case of breast cancer, an analysis of 12 trials, involving 2317 randomized women, compared the effect of combination chemotherapy to the same drugs given sequentially in women with metastatic breast cancer. The authors concluded, "Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analyzed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression."@
|CAF chemotherapy regimen|
|Days 1 & 8||Doxorubicin|
|Days 1 & 8||5-fluorouracil|
|Repeat cycle every 28 days for 6 cycles.|
Combination chemotherapy is
given in courses or cycles. The number of cycles vary by type
of cancer, the cytotoxic drugs used, and the patients response to therapy.
Combination therapy regimens may be documented by acronym, e.g. CAF (Cyclophosphamide
+ Adriamycin® (Doxorubicin)+ Fluorouracil) is a combination regimen used to treat HER2-negative breast cancer.
Adjuvant chemotherapy is hormonal, cytotoxic or targeted therapy administered after surgery or radiation. It is intended to prevent relapse and improve survival.
Induction or neoadjuvant chemotherapy is the first treatment, often as part of a standard set of treatments that include surgery, chemotherapy or radiation. It is intended to suppress metastases and reduce tumor burden prior to definitive treatment. Disadvantages of induction regimens rest on the fact that definitive treatment is delayed.@
Induction chemotherapy in the context of liquid (leukemia) tumors, is given to induce a remission. This term is commonly used in the treatment of acute leukemias.
Consolidation chemotherapy involves repetitive cycles of chemotherapy after remission is achieved. The goal of this therapy is to sustain a remission. Consolidation chemotherapy may also be called intensification therapy. This term is commonly used in the treatment of acute leukemias.
Maintenance chemotherapy refers to using single drugs or combinations of drugs at lower doses on a long term basis for patients who are in remission or to prevent the growth of residual or remaining cancer cells. The continued cytotoxic effect has been shown to improve survival in acute lymphoblastic leukemia.
Palliative chemotherapy is a type of chemotherapy that is given specifically to address symptom management without expecting to significantly reduce the cancer.