Adjuvant Chemotherapy for Micrometastases
One of the most important roles of cancer chemotherapy is as adjuvant therapy to eradicate or suppress minimal residual disease after primary field treatment with surgery or irradiation. Failure of primary field therapy to eradicate tumor is due principally to occult micrometastases of tumor stem cells outside the primary field. These distant micrometastases are more likely to be present in patients with positive lymph nodes at the time of surgery (eg, breast cancer), in patients with tumors known to have a propensity for early hematogenous spread (eg, osteogenic sarcoma, Wilms’ tumor), and in patients with certain pathologic or molecular risk factors (eg, high proliferative index, vascular invasion, oncogene amplification). Given specific risk factors, the risk of recurrent or metastatic disease can be extremely high (> 80%). Only systemic therapy can adequately prevent micrometastases.
Chemotherapeutic regimens that have been shown to be effective in inducing regression of advanced cancers may be curative when combined with surgery for high-risk “early” cancer. More data are now available to support the use of adjuvant therapy in several neoplasms. Prolongation of survival times has been shown for women (especially premenopausal women) with breast cancer and positive or negative axillary lymph nodes (stages I, II, and III) from combination chemotherapy following surgical resection; there are several useful regimens. Node-negative patients are treated with CMF (cyclophosphamide, methotrexate, and fluorouracil) or variants, whereas high-risk, node-positive patients are generally treated with regimens that include doxorubicin. Neoadjuvant (preoperative) and perioperative chemotherapy are also used and may improve surgical resectability or time to disease progression. The antiestrogen tamoxifen is used routinely either with or without antecedent chemotherapy if receptors for estrogen and progesterone are present. The role of amplification of the c-erbB-2 or Her-2/neu oncogene in tamoxifen-resistant breast cancer is a subject of current research. In postmenopausal women, tamoxifen alone may be used. The main challenge in treating women with node-negative (stage I) breast cancer is to identify prognostic factors to determine which patients are at higher risk and therefore more likely to benefit from adjuvant therapy.
Adjuvant chemotherapy with fluorouracil plus levamisole is now indicated in Dukes C (node-positive) colon cancer and has been shown to reduce the risk of cancer recurrence. Earlier clinical trials employing semustine (methyl-CCNU) appeared to result in an increased risk of both leukemia and renal insufficiency. The omission of semustine from combination regimens still results in enhanced cure rates with decreased local and overall tumor recurrence.
Other tumors that have been shown to respond to adjuvant therapy include osteogenic sarcoma, ovarian cancer, and malignant melanoma. Adjuvant therapy remains investigational and unproved for a number of common tumors, including non-small-cell lung cancer and pancreatic cancer. Patients with Hodgkin’s disease or testicular carcinoma do not benefit from adjuvant therapy.
Although adjuvant therapy has been shown to reduce the rate of recurrence for some cancers, there is still a high failure rate (up to 80% in high-risk breast cancer despite adjuvant therapy). In most cases, tumor recurrence signifies incurability. There is clear evidence of a dose-response effect of adjuvant chemotherapy in some cancers; however, doses have been limited by bone marrow toxicity. Current studies are investigating the use of dose-intense chemotherapy regimens with or without autologous bone marrow or peripheral blood progenitor cell rescue in the high-risk adjuvant setting for patients with carcinoma of the breast, testis, and ovaries. Otherwise incurable patients with testicular cancer have been cured by this intensive treatment approach. Nonrandomized studies suggest efficacy with tolerable side effects of high-dose chemotherapy with stem cell support in the setting of high-risk breast cancer (more than ten positive lymph nodes). Multicenter trials are now in progress comparing aggressive adjuvant hemotherapy with autologous bone marrow transplantation for high-risk breast cancer. The use of marrow transplantation for high-risk ovarian cancer remains controversial, though long-lived responses in otherwise incurable patients have been documented. Patients with advanced ovarian cancer at high risk for recurrence may now be considered for treatment in a multicenter randomized study comparing transplantation with standard adjuvant chemotherapy. Young patients with high-risk malignancies should be considered for entry into clinical trials investigating this aggressive, potentially curable therapy.
Random Posts
Leave a Reply
You must be logged in to post a comment.