Micrometastases

The term adjuvant therapy refers to the use of chemotherapy or radiotherapy following surgical resection of a tumor mass. The rationale behind adjuvant chemotherapy is to eradicate micrometastases or other tumor cells that may have been missed during removal of the primary tumor. The recent results of five relatively large prospective trials (n = 344—1867) suggest that there is benefit from adjuvant chemotherapy. The largest study, the International Adjuvant Lung Trial (IALT),24 has led to the... 

IMA Any tumor thickness with no ulceration with one lymph node involved and micrometastases Or any tumor thickness with no ulceration with two to three lymph nodes involved and micrometastases 63-70% 57-63%... 

Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that postsurgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. 

Metastasis is a process by which malignant cells leave their primary site and spread to distant locations throughout the body. It is the formation of metastasis that makes cancer such a lethal disease. The presence of metastasis is therefore the main cause of morbidity and mortality in patients with cancer. While primary tumors are potentially resectable, most metastases are resistant to all current forms of cancer treatment. Approximately 30% of patients with newly diagnosed solid cancers (excluding nonmelanoma skin cancers) have clinically detectable metastases, while another 30% may have occult micrometastases (L2). Clearly, to reduce mortality from cancer, we have to be able to prevent or treat metastasis. 

Theoretically, preoperative ChT allows higher drug doses than when used with radiation, optimizing control of occult micrometastases. The disadvantage of excluding radiation is a reduced likelihood of control of bulky local/regional disease. 

Failure pattern analysis of the C ALGB and French trials showed that local persistence or failure still occurred in around 80% of patients despite the ChT however, the incidence of distant metastases as a first site of failure was significantly lower in the combined modality group, confirming the theoretical potential that ChT could effect distant micrometastases. Subsequent meta-analyses confirmed the superiority of induction ChT, using a cisplatin-based regimen, and RT over radiation alone (60,65). Thus, sufficient evidence was now in place to establish induction chemoradiation as a world-wide standard of care. To further improve outcome, steps would have to be taken to improve local disease control as well. 

The rationale for concurrent chemoradiation is that the ChT can augment local-regional control by both direct tumor cell killing and radiosensitization at the same time as it addresses systemic micrometastases. Unfortunately, this also has the potential to increase radiation-related mucosal acute toxicity, predominantly esophagitis and pneumonitis. Thus, some of the early trials of concurrent therapy used either attenuated dose ChT or split course RT to ameliorate potential cotoxicity. These trials showed that concurrent therapy is feasible and, as with the sequential approach, improves outcome. 

In the meantime, there is continued interest in exploiting the use of induction ChT along with concurrent chemoradiation to maximize the opportunity to control occult micrometastases. There are potential downsides to this approach, as the induction ChT could reduce patient tolerance for the subsequent concurrent component. The induction ChT can also potentially stimulate accelerated tumor cell repopulation so that an additional burden of avidly dividing tumor is placed upon the subsequent concurrent chemoradiation. 

Another approach to increasing patient exposure to ChT and potentially improving the control of micrometastases is to give ChT after concurrent chemoradiation. This so-called posterior or consolidative ChT can still be given in full dose and should not be confused with low-dose maintenance ChT. 

Spatial cooperation Radiation is more effective at controlling the primary bulky disease but is unable to affect distant micrometastases. Chemotherapy, on the other hand, can deal with micrometastases but is unable to affect the large primary tumor. The combination of both local (radiation) and systemic (chemotherapy) approaches then maximizes therapeutic impact. 

Nomoto S, et al. Chnical application of K-ras oncogene mutations in pancreatic carcinoma detection of micrometastases. Semin Surg Oncol 1998 15(l) 40-46. 

Adjuvant chemotherapy involves the use of antineoplastic drugs when surgery or radiation therapy has eradicated the primary tumor but historical experience with similar patients indicates a high risk of relapse due to micrometastases. Adjuvant chemotherapy should employ drugs that are known to be effective in the treatment of advanced stages of the particular tumor being treated. Adjuvant chemotherapy has played a major role in the cure of several types of childhood cancers as well as breast cancer, colorectal cancer, and osteosarcoma in adults. 

Rapid immunohistochemical study of frozen sections is necessary for intraoperative diagnosis in some cases. Rapid immunostaining is also helpful in confirming or excluding tumor clearance in resection margins or in detecting micrometastases in sentinel lymph nodes in breast cancer patients. Two methods to immunostain frozen sections are the enhanced polymer one-step staining (EPOS) system and the EnVision system both systems are detailed later. 

Saga, T., Neumann, R.D., Heya, T., Sato, J., Kinuya, S., Le, N., et al. (1995) Targeting cancer micrometastases with monoclonal antibodies a binding-site barrier. Proc. Nat. Acad. Sci. USA, 92, 8999-9003. 

One of the most important roles for effective cancer chemotherapy is as an adjuvant to initial or primary field treatment with other methods such as surgery or radiation therapy. Failures with primary field therapy are due principally to occult micrometastases outside the primary field. With the currently available treatment modalities, this form of combined-modality therapy appears to offer the greatest chance of curing patients with solid tumors. 

Indications for treatment Chemotherapy is indicated when neoplasms are disseminated and not amenable to surgery. Chemotherapy is also used as a supplement to surgery and radiation treatment to attack micrometastases. [Note Tumors most susceptible to current chemotherapy are undifferentiated and have high growth fractions.]... 

Treatment of occult micrometastases is continued after clinical signs... 

Finally, and most importantly, these cells must now be able to proliferate within the new organ parenchyma, if they are to give rise to a clinically relevant metastatic colony. To expand further, the micrometastases must develop a vascular network and evade destruction by host defenses. Malignant cells can then invade into the blood vessels, and start the metastatic process again. 

Lin, W. C., Pretlow, T. P., Pretlow, T. G. 2d and Culp, L. A. (1990a) Development of micrometastases earliest events detected with bacterial lacZ gene-tagged tumor cells. J. Natl. Cancer Inst. 82,1497-1503. 

Liotta, L. A., Vembu D., Saini R. K. and Boone C. (1978). In vivo monitoring of the death rate of artificial murine pulmonary micrometastases. Cancer Res. 38, 1231-1236. 

Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F. and Groom, A. C. (1998). Multistep nature of metastatic inefficiency— Dormancy of solitary cells after successfiil extravasation and limited survival of early micrometastases. Am. J. Pathol. 153, 865-873. 

---