The past 20 years has seen an increasing trend toward the use of oral chemotherapy for the treatment of patients with a variety of malignancies. The advantages of oral chemotherapy include lower treatment cost, compared with that of intravenous (IV) administration, and more convenient treatment for patients. Several oral drugs are now used routinely for cancer treatment, and others are under investigation. Hormonal agents, such as tamoxifen, flutamide, and megestrol acetate, and antimetabolites, such as hydroxyurea, which are available only in oral formulation, have proven both safe and efficacious. Several other oral drugs, including etoposide and cyclophosphamide, have been shown to be useful and often as effective as their IV formulations, and more data on the bioavailability of these agents have become available. In addition, several new and promising oral agents (platinum compounds, fluorinated pyrimidines, topoisomerase I inhibitors, and others) are likely to be introduced into clinical practice in the near future. It is possible that eventually, oral combination chemotherapy will be an accepted and standard approach for the treatment of patients with many types of cancer. [ONCOLOGY(Suppl 4):43-50, 1998]
In the past 20 years, there has been an increasing trend toward the use of oral chemotherapy for the treatment of patients with a variety of malignancies. There are several advantages of oral chemotherapy. The cost of treatment is usually far lower than that of intravenous administration, which also requires the presence of a physician and/or nurse in an office or hospital setting. Oral administration is more convenient for patients, permitting them to remain at home while taking their medications and eliminating the need for venous access.
The acceptance of oral chemotherapy has been limited by several actual or perceived problems. Some drugs have shown erratic gastrointestinal absorption when administered orally, leading to concern about adequate dosing. Poor patient compliance with a multiday oral regimen has been a potential problem. There has also been a perception by some physicians and patients that intravenous treatments are “stronger” and more effective than oral treatments.
The use of oral therapy for severe chronic disease is not new. For example, digitalis preparations and diuretics are commonly used to treat congestive heart failure, as are oral antiarrhythmic agents for cardiac arrhythmias, oral cytotoxic agents for severe rheumatologic disorders, and oral antibiotics for serious infections. Furthermore, hormonal agents, such as tamoxifen (Nolvadex), flutamide (Eulexin), and megestrol acetate (Megace), and antimetabolites such as hydroxyurea (Hydrea), which are available only in oral formulation, have proven both safe and efficacious therapy for cancer patients. Several other oral drugs have been proven useful and often equivalent to their intravenous formulations, and more data are now available concerning the bioavailability of these agents. Physicians are beginning to feel more confident about using oral therapy.
Several oral drugs are now routinely used in the treatment of cancer patients, and others are being investigated. This brief review will illustrate the variety of oral medications now used in clinical practice, provide a few specific examples of recent clinical results, and discuss some of the promising agents being developed.
Tables 1 and 2 show the classes of selected oral agents and examples of their use against several neoplasms. Some of these are considered standard therapy, such as procarbazine (Matulane) and prednisone as part of the MOPP regimen (mechlorethamine/vincristine/procarbazine/prednisone) for advanced Hodgkin’s disease, and melphalan (Alkeran) with prednisone for multiple myeloma.
Etoposide (VePesid) has proven useful for a broad spectrum of malignancies, including small-cell lung cancer, germ cell neoplasms, non-Hodgkin’s lymphoma, Hodgkin’s disease, and acute leukemia. Etoposide inhibits the activity of topoisomerase II, which regulates the replication of DNA. Intracellular levels of topoisomerase II are substantially higher in proliferating cells, particularly during the G2 phase of the cell cycle,  making these cells more sensitive to the cytotoxic effects of etoposide. In addition, the binding of etoposide to topoisomerase II is reversible, suggesting that prolonged etoposide exposure enhances cytotoxicity.
The schedule dependency of etoposide has been demonstrated by several investigators. Preclinical studies with several animal tumors showed that frequent small doses or divided daily doses were superior to higher, less frequent doses.[3,4] Cavalli et al were the first to suggest the greater efficacy of etoposide in the treatment of small-cell lung cancer when the drug was ad- ministered orally for 3 days weekly compared with a 1-day intravenous schedule.
Slevin et al unequivocally demonstrated the importance of etoposide scheduling in a comparison of a 24-hour continuous infusion schedule (500 mg/m2) versus daily infusion for 5 days (100 mg/m2/d) in patients with extensive stage small-cell lung cancer. Response rates were 10% and 89%, respectively (P < .001). Survival of patients receiving the 5-day schedule was also significantly improved. Pharmacokinetic data from this study demonstrated that duration of exposure, rather than peak serum level or total exposure (as measured by plasma area under the curve [AUC]), was the most important determinant of the cytotoxicity of etoposide. The authors speculated that a serum etoposide level of about 1 mg/
mL was sufficient to achieve therapeutic efficacy.
Extended Schedules of Oral Etoposide
When Slevin’s scheduling studies were initiated, etoposide was available only as an intravenous agent. Prolonged administration schedules were therefore cumbersome and impractical. The introduction of an oral etoposide formulation facilitated further exploration of etoposide scheduling. In addition to the usual benefits of an oral agent (ie, greater ease of administration, reduced cost), the prolonged administration of etoposide offered the possibility of increased efficacy and/or reduced toxicity.
In 1989, my colleagues and I began a series of trials using extended schedules of oral etoposide. We empirically chose a 21-day schedule and demonstrated in a phase I study that a daily dose of 50 mg/m2 was the maximum tolerated dose when given for 21 consecutive days. Using this dose and schedule, etoposide serum levels > 1 mg/
mL are maintained from 10 to 12 hours on each day of treatment. Phase II trials using this 21-day schedule, as well as other prolonged oral schedules, have been reported in patients with several types of cancer.
In our initial phase II trial, 22 patients with recurrent or refractory small- cell lung cancer were treated with oral etoposide (50 mg/m2/d
´ 21). All patients had been previously treated with combination chemotherapy, and 18 of 22 had previously received intravenous etoposide given on 3- or 5-day divided dose schedules. The overall response rate with oral etoposide was 45%, and median duration of response was 4 months (range, 1.5 to 9.5 months). Patients were more likely to respond to oral etoposide if they had responded to initial induction therapy and had not received chemotherapy for more than 90 days prior to disease progression. Myelosuppression was the most common toxicity but was severe in only 19% of courses. The overall response rate observed with oral etoposide in this setting is higher than that reported with intravenous etoposide in recurrent small-cell lung cancer (10% to 15%), and is similar to results obtained with various combination chemotherapy regimens in this setting.
Extended-schedule oral etoposide has also been used as initial therapy for small-cell lung cancer. Clark and associates attempted to reduce toxicity by shortening the duration of administration, and demonstrated similar response rates (55% to 65%) using schedules of 10, 14, or 21 days’ duration. Myelosuppression was reduced with the shorter schedules. This approach was particularly beneficial for small-cell lung cancer patients considered too elderly or medically unfit to receive intensive combination chemotherapy. Clark et al treated these patients with single-agent oral etoposide, 50 mg bid for 14 consecutive days, followed by a 1-week rest. The response rate was high, and median survival was similar to that reported in some trials using combination regimens. Thus, extended-schedule oral etoposide, alone or in combination with other drugs, offers a viable and well-tolerated treatment option for elderly, unfit patients who have traditionally fared poorly when given treatment with intensive combination chemotherapy.
Based on the promising results achieved in the phase II study of small- cell lung cancer, we evaluated the efficacy and toxicity of the same 21-day regimen in 25 patients with previously untreated stage IIIB or IV non-small-cell lung cancer. Of 22 evaluable patients, 5 (23%) had partial responses and 6 had stabilization of disease. The median response duration was 5 months, and median survival of the entire group was 5 months (range, 1 to 19+ months). Severe myelosuppression occurred in only 6% of cycles. Two other phase II studies using identical schedules of oral etoposide in patients with previously untreated non-small-cell lung cancer have been reported; response rates were 7% and 46%, respectively.[12,13]
Etoposide is highly active for the treatment of lymphoma, and has demonstrated marked activity as a component of several salvage regimens. We investigated the same 21-day oral etoposide regimen as therapy for 25 patients with refractory lymphoma. Patients had either non-Hodgkin’s lymphoma (indolent or aggressive histology) or Hodgkin’s disease, and were considered incurable, having failed previous standard multidrug treatment. Eighty-four percent of patients had received two or more previous chemotherapy regimens, and 36% of patients had previously received etoposide. Patient characteristics are shown in Table 3.
Overall, 15 patients (60%; 95% confidence interval, 41% to 77%) had partial responses, including 5 of 9 patients who had previously received intravenous etoposide. Median response duration was 8 months in patients with low-grade non-Hodgkin’s lymphoma and 3 months in those with intermediate or high-grade lymphoma (Table 4). One patient with large-cell lymphoma, included as a partial responder in our initial report eventually achieved a complete response after seven courses of oral etoposide and remains free of disease 5 years later. Myelosuppression was again the major treatment-related toxicity; however, most patients who developed severe myelosuppression were able to continue with subsequent courses when the etoposide dose was reduced by 25%. Other side effects were rare, with the exception of total alopecia.
Interestingly, two patients who had experienced disease progression during or immediately following treatment with combination regimens containing intravenous etoposide had clinically significant, immediate responses to oral etoposide. This finding provides direct evidence that the increased cytotoxicity produced by extending the duration of etoposide exposure can be clinically important in some patients.
Table 5 summarizes results of phase II published studies of extended-schedule oral etoposide in several types of cancer. These results demonstrate the activity of extended-schedule oral etoposide in a variety of refractory malignancies. [9-24] Of particular interest are the results in breast and ovarian cancer, where consistent activity was seen in refractory patients.[15-19] Intravenous etoposide given according to the standard schedule has been considered relatively inactive in both of these malignancies.
A novel and potentially important use of extended-schedule etoposide was recently reported by Cooper and Einhorn. Patients with refractory germ cell tumors completing salvage therapy, either with high-dose or standard-dose regimens, received daily oral etoposide, 50 mg/m2 for 21 days every 4 weeks for three courses. Of 23 patients (74%) who began oral etoposide therapy while in complete remission, 17 (74%) remain disease-free with a median follow-up of 36 months. Maintenance therapy with oral etoposide decreased relapse rates as compared with previous Indiana University data, which indicated that approximately 50% of patients relapsed after achieving a complete remission following various salvage regimens without maintenance therapy.
As is evident in Table 5, most phase II trials of extended-schedule oral etoposide have used the originally defined 21-day regimen with the “maximally tolerated dose” of 50 mg/m2/d. Although this regimen has proven to be generally tolerable, myelosuppression has been the major toxicity in all of the trials and is severe in 10% to 20% of patients. Patients who have poor performance status, coexistent medical illnesses, or have received extensive previous chemotherapy are more susceptible to this toxicity. Myelosuppression can be substantially reduced by either lowering the daily etoposide dose or shortening the administration schedule. Limited data suggest that cytotoxicity is preserved with either approach, although the relative efficacy of the various schedules is unclear.
1. Edwards CM, Glisson BS, King CK, et al: Etoposide-induced DNA cleavage in human leukemia cells. Cancer Chemother Pharmacol 20:162-168, 1987.
2. Sullivan DM, Chow KC, Glisson BS, et al: Role of proliferation in determining sensitivity to topoisomerase II-active chemotherapy agents. NCI Monogr 4:73-78, 1987.
3. Dombernowsky P, Nissen NI: Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP16-213 (NSC-141540) in L1210 leukemia. Acta Pathol Microbiol Scand 81:715-724, 1973.
4. D’Incalci M, Erba E, Vaghi M, et al: In vitro cytotoxicity of VP16 on primary tumor and metastasis of Lewis lung carcinoma. Eur J Cancer Clin Oncol 18:377-380, 1982.
5. Cavalli F, Sonntag RW, Jungi F, et al: VP16-213 monotherapy for remission induction of small-cell-lung cancer: A randomized trial using three dosage schedules. Cancer Treat Rep 62:473-475, 1978.
6. Slevin ML, Clark PI, Osborne RJ, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 7:1333-1340, 1990.
7. Hainsworth JD, Johnson DH, Frazier SR, et al: Chronic administration of oral etoposide: A phase I trial. J Clin Oncol 7:396-401, 1989.
8. Hande KR, Krozely MG, Greco FA, et al: Bioavailability of low-dose oral etoposide. J Clin Oncol 11:374-377, 1993.
9. Johnson DH, Greco FA, Strupp J, et al: Prolonged administration of oral etoposide in patients with relapsed or refractory small cell lung cancer: A phase II trial. J Clin Oncol 8:1613-1617, 1990.
10. Clark PI, Cottier B: The activity of 10-,14-, and 21-day schedules of single-agent etoposide in previously untreated patients with extensive small cell lung cancer. Semin Oncol 19(suppl 14):36-39, 1992.
11. Waits TM, Johnson DH, Hainsworth JD, et al: Prolonged administration of oral etoposide in non-small-cell lung cancer: A phase II trial. J Clin Oncol 10:292-296, 1992.
12. Saxman S, Logie B, Stephens D, et al: Phase II trial of daily oral etoposide in patients with surgically unresectable non-small cell lung cancer. Invest New Drugs 9:253-256, 1991.
13. Miller AA, Tolley EA, Niell HB, et al: Pharmacokinetics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer. J Clin Oncol 11:1179-1188, 1993.
14. Hainsworth JD, Johnson DH, Frazier SR, et al: Chronic daily administration of oral etoposide in refractory lymphoma. Eur J Cancer 26:818-821, 1990.
15. Garrow GC, Hainsworth JD, Johnson DH, et al: Prolonged administration of oral etoposide in previously treated epithelial ovarian cancer: A phase II trial (abstract). Proc Am Soc Clin Oncol 11:236, 1992.
16. Hoskins PJ, Swenerton KD: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 12:60-63, 1994.
17. Marzola M, Zucchetti M, Colombo N, et al: Low-dose oral etoposide in epithelial cancer of the ovary. Ann Oncol 4:517-519, 1993.
18. Calvert AH, Lind MJ, Millward MM, et al: Long-term oral etoposide in metastatic breast cancer. Clinical and pharmacokinetic results. Cancer Treat Rev 19 (suppl C):27-33, 1993.
19. Martin M, Lluch A, Casado A, et al: Clinical activity of chronic oral etoposide in previously treated metastatic breast cancer. J Clin Oncol 12:986-991, 1994.
20. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17(suppl 2):36-39, 1990.
21. Smit EF, Sutedja T, van Zandwijk N, et al: A phase II study of daily oral etoposide for 21 days q 5 weeks in malignant mesothelioma. Proc Eur Conf Clin Oncol 6:171, 1991.
22. Ajani J, Dimas P, Pazdur R, et al: Phase II trial of oral etoposide in untreated patients with advanced gastric carcinoma (abstract). Proc Am Soc Clin Oncol 12:217, 1993.
23. Kampe CE, Lowenbraun S, Foster J, et al: Oral etoposide in treatment of advanced refractory sarcomas. J Natl Cancer Inst 84:1836-1837, 1992.
24. Wierzbicki R, Ezzat A, Abdel-Warith A, et al: Phase II trial of chronic daily VP-16 administration in unresectable hepatocellular carcinoma. Ann Oncol 5:466-467, 1994.
25. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 13:1167-1169, 1995.
26. Murphy PB, Hainsworth JD, Greco FA, et al: A phase II trial of cisplatin and prolonged administration of oral etoposide in extensive-stage small cell lung cancer. Cancer 69:370-374, 1992.
27. Johnson DH, Hainsworth JD, Devore R, et al: Carboplatin plus oral etoposide in the management of unresectable non-small-cell lung cancer: Preliminary results of a Vanderbilt trial. Oncology 49(suppl 1):57-62, 1992.
28. Miller AA, Herndon JE, Hollis DR, et al: Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small cell lung cancer: A randomized phase III study of the Cancer and Leukemia Group B. J Clin Oncol 13:1871-1879, 1995.
29. Faylona EA, Loehrer PJ, Ansari R, et al: Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: A Hoosier Oncology Group trial. J Clin Oncol 13:1209-1214, 1995.
30. Grunberg SM, Crowley J, Livingston R, et al: Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 11:1598-1601, 1993.
31. Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12:2005-2012, 1994.
32. Young WA, Greco FA, Greer JP, et al: Aggressive non-Hodgkin’s lymphoma in the elderly: An effective, well-tolerated treatment regimen containing extended-schedule etoposide. J Natl Cancer Inst 86:1346-1347, 1994.
33. Bonadonna G: Evolving concepts in the systemic adjuvant treatment of breast cancer. Cancer Res 52:2127-2137, 1992.
34. Cooper RG: Adjuvant chemotherapy for breast cancer: 20 years’ experience using CVFMP chemotherapy. Semin Oncol 15(suppl 3):29-34, 1988.
35. Ozer H, Anderson JR, Peterson BA, et al: Combination trial of subcutaneous recombinant alpha 2b interferon and oral cyclophosphamide in follicular low-grade lymphoma. Med Pediatr Oncol 22:228-235, 1994.