With the expansion of the knowledge base for modern chemotherapy of cancer, the efficacy as well as the rationale of the use of combinations of drugs for the therapy of neoplasia became of paramount importance. The ideal situation in which application of the basic knowledge devel- oped to the present time is seen with rapidly growing neoplasms, particularly leukemias, in which neoplastic cells occur systemically but with easy access to the therapeutic agents through the vascular circulation. Here are considered examples of this more idealized treatment as well as the therapy of solid neoplasms, where delivery of the drug to the neoplastic cell becomes a major therapeutic hurdle.
Treatment of Leukemias
Many “protocols” have been devised, that is, therapeutic regimens for the treatment of specific neoplastic conditions, and more are being studied. Figure 20.16 shows an older example of such a protocol, termed the L-2 protocol by Clarkson and Fried (1971). The entire protocol extends over approximately 4 months, during which various combinations of drugs are given inter- spersed with several rest periods. These latter intervals are necessary in order to allow the host to recover from the toxic effects of the various chemicals given. Obviously, during these rest peri- ods the neoplastic population expands. The estimated changes in cellular populations during the course of therapy are seen in the upper portion of the figure. The assumption is made that the initial size of the leukemic population is 3 × 1012 cells, which is the approximate cell number found in many severe, untreated cases of acute lymphoblastic leukemia in children. The choice of the drugs given at the various periods is made partly on the basis of their mechanism of ac- tion, their toxicity, and their known efficacy from past experience in producing remissions in the disease. The reader is referred to the original publication (Clarkson and Fried, 1971) for a more detailed discussion of the protocol.
Several major challenges still remain in the treatment of acute lymphoblastic leukemia in children despite the fact that more than 70% of those treated today by regimens somewhat simi- lar to that seen in Figure 20.16 (Rivera et al., 1993) will be cured of their disease. Those children who relapse must be identified early in their disease and receive more effective therapy; children who respond well and in whom a cure can be expected should be identified so that their treat- ment may be modified to decrease short- and long-term toxicity (Holcenberg and Camitta, 1981). Today most acute lymphoblastic leukemias are of the pre-B type (approximately 85%), while most of the remaining are of the T-cell variety. The cure rate for children with the pre-B immunophenotype exhibit a cure rate in excess of 70% (Camitta et al., 1997; Rivera et al., 1993). However, cures in B-cell leukemias are relatively rare, while children with T-cell leuke-
Figure 20.16 Part I of the intensive treatment protocol (L-2) used in the treatment of acute lymphoblastic leukemia. The numbers associated with the vertical arrows at the top of the figure indicate the theoretic leukemic cell number in the patient at that particular time. (Modified from Clarkson and Fried, 1971, with permission of the authors and publisher.)
mias may have cure rates in excess of 40% when aggressive chemotherapy regimens employing high doses of rotating chemotherapeutic agents are employed (cf. Amylon, 1990). Follow-up of patients exhibiting complete remission for extended periods of time can now be monitored by molecular techniques in which residual leukemic cells can be detected in bone marrow (Cam- pana et al., 1991; Roberts et al., 1997).
In adults over 40 years of age, chemotherapy for leukemia generally is not nearly so effec- tive as in children (cf. Freireich, 1984). On the other hand, the chemotherapy of acute myeloge- nous leukemia in adults has advanced to the stage at which a significant number of patients have been in remission from the disease for more than 5 years; such individuals represent true cures of this disease (Lister and Rohatiner, 1982; Hoelzer, 1994). Much greater success has been achieved with combination chemotherapy for Hodgkin disease, originally using a multidrug reg- imen of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP). This regimen (De- Vita et al., 1980) has resulted in a cure rate for all stages of Hodgkin disease of up to 70% or better at 10 years. Addition of radiotherapy to combination chemotherapy may result in 10-year survivals of up to 95% in some series (Prosnitz and Roberts, 1992). Treatment of acute leukemia in adults has also included the use of bone marrow transplantation in patients given lethal doses of radiation and/or chemotherapy to eliminate all neoplastic cells in the bone marrow and organ- ism as a whole (cf. Thomas, 1992; Geller, 1993). Treatment of children with non-Hodgkin lym- phoma by combination chemotherapy with or without combined radiotherapy results in a very high rate of cure, in excess of 80% (Link et al., 1997). Therapy for the non-Hodgkin lymphomas may be quite effective in adults as well, where in certain cell types of this disease a 5-year cure rate of 60% to 80% has been produced (cf. Armitage, 1993; Lilleyman and Pinkerton, 1996).
Unfortunately, the efficacy of these various therapeutic regimens is not without some risk. At least two of the agents in the MOPP protocol, procarbazine and nitrogen mustard, are alkylat- ing agents. It is now apparent that a significant number of patients treated with these com- pounds, especially those given radiation as well, later develop second malignancies, one of the most common of which is acute myeloid leukemia. The incidence of this latter neoplasm may be as high as 5% in patients treated for Hodgkin disease with MOPP and radiation (Grünwald and Rosner, 1982). In some series the risk of a second malignancy after treatment for Hodgkin dis- ease may be in excess of 15% 15 years after the therapy itself (Tucker et al., 1988; Robinson et al., 1994). As pointed out in Chapter 11, secondary neoplasms have also been reported after chemotherapy and radiation therapy for a number of different types of human neoplasms, in- cluding carcinomas, myelomas, and even nonneoplastic diseases (Boffetta and Kaldor, 1994). On the other hand, one must recall that patients having had one cancer are at a greater risk of developing a second malignancy than are members of the population never exhibiting clinical neoplasia (Carter, 1984), and the highly significant increase in secondary malignancy seen in Hodgkin’s disease may in part be related to the abnormal immune function see in these patients (cf. Chapter 19).
Chemotherapy of Solid Neoplasms (Other Than Lymphomas)
Although many of the conclusions drawn on the basis of the L-1210 leukemia model and the combination therapy, especially the latter, also apply to the treatment of solid tumors, it is clear that a rapidly dividing, continuously circulating cell population such as that seen in leukemias is significantly different from a slowly growing neoplasm, with variable doubling times and with erratic growth. In addition, unlike the growth characteristics of leukemias, in most solid neo- plasms the cell growth is most rapid at the periphery of the neoplasm, with necrotic regions in the center and an intermediate zone in which cells are viable but nondividing. Some neoplasms, especially scirrhous tumors or neoplastic cells embedded in radiation-induced fibrous tissue, may represent difficult anatomical sites for drugs to permeate, leading to “compartmentaliza- tion” of some neoplastic cells within the host.
Some model experimental neoplasms have been studied (cf. Looney et al., 1977). How- ever, no specific test system like those mentioned above for leukemias has been devised or stud- ied in an attempt to establish new strategies of treatment of solid tumors. The human tumor stem cell assay (HTSCA) has been useful in predicting negative responses of individual neoplasms to chemotherapy. On the other hand, several solid neoplasms in both children and adults have been effectively treated with chemotherapy as the principal therapeutic modality. In children suffering from Wilms tumor, there is now a greater than 80% expectation of cure with a combination of surgery, radiation, and chemotherapy (D’Angio et al., 1991). Chemotherapy of breast cancer in adults has been largely carried out after primary surgical and/or radiotherapy (Bonadonna and Valagussa, 1983; Carbone, 1981). During the last two decades, cytotoxic and hormone therapy of metastatic breast cancer has shown some evidence of effectiveness for specific regimens (Fos- sati et al., 1998), and the endocrine treatment of breast cancer in women has been used exten- sively with a variety of different modalities (Santen et al., 1990). Postsurgical treatment of breast cancer with antiestrogens, particularly tamoxifen, has been most efficacious in reducing the risk of recurrence and death from breast cancer as well as offering some effective palliation for pa- tients with metastatic breast cancer (Osborne, 1998). In addition, tamoxifen given together with surgery and/or radiation therapy is effective in the treatment of very early breast cancer, espe- cially preventing the development of invasive neoplasia (Fisher et al., 1999). In a similar vein, combination chemotherapy has been found effective in the treatment of advanced and metastatic colorectal cancer with relatively nontoxic combinations of fluorouracil, leucovorin, and levami- sole. In this combination, leucovorin, a normal metabolite of folic acid, augments the activity and toxicity of fluorouracil, while levamisole appears to augment the immune system (Moertel,1994). The treatment of small-cell lung cancer, which has an extremely poor prognosis, has been improved by combination chemotherapy, allowing for remissions of a year or more in a signifi- cant number of patients (Bunn and Carney, 1997). Even greater success has been achieved in the chemotherapy of choriocarcinoma (Lewis, 1980) and testicular cancer (Einhorn, 1990), in which
80% to 90% of patients are cured by chemotherapy in the former case, and over 50% in the latter. A variety of techniques for chemotherapy, including intraarterial and intracavitary chemo- therapy, chemotherapy in combination with hyperthermia, and a variety of drug delivery systems are being used (cf. Markman, 1984). A unique therapy for osteogenic sarcoma in younger indi- viduals involved the administration of high, essentially lethal doses of methotrexate, with subse- quent rescue by the administration of leucovorin, the reduced form of the normal vitamin (folic acid) (Rosenberg et al., 1979). This single-drug therapeutic regimen combined with surgery ap- peared to result in cure rates of up to 40% to 50% in such individuals. More recently, the use of combination chemotherapy involving several drugs has resulted in 5-year survival rates of more than 70% of patients with nonmetastatic osteogenic sarcoma (cf. Grem et al., 1988).
Unfortunately, the problem of destroying every single tumor cell within the host is much more difficult in solid tumors than in leukemias, largely because of the low growth fraction and because most effective chemotherapeutic agents hit cells only during DNA synthesis and mito- sis, as well as the barriers to drug delivery to the neoplastic cell placed by the static environment of the tissue itself. Nonetheless, with a better understanding of the dose and scheduling in multi- stage cancer chemotherapy (Sweetenham, 1995) and the development of new chemotherapeutic agents (e.g., Hanauske, 1996), as well as the potential for individualizing chemotherapy to par- ticular patients or small groups of patients (Cree and Kurbacher, 1997), there is still room for progress to be made in combination drug therapy of neoplasia.