HIGH DOSE METHOTREXATE (HDMTX) WITH CITROVORUM FACTOR RESCUE

Methotrexate is one of the oldest chemotherapy drugs, ever used, for the treatment of cancer. In 1948 Sidney Farber at Harvard’s Childrens Hospital in Boston gave a drug, Aminopterin, to children with Acute Leukemia and stopped temporarily their disease, returning them to a perfectly normal condition. This was the beginning of the era of Chemotherapy of Cancer.

Methotrexate, which Farber selected 2 years later, as a less toxic agent is, like the original Aminopterin, a Folic Acid Inhibitor. It prevents the vital vitamin, Folic Acid, of the vitamin B group, from performing its crucial role of supporting life by helping to produce DNA with all its genes and ensure growth and replication of practically all cells in any organism. This applies to cells of plants, animals, bacteria and, of course, of all cancers,

Should we prevent the Folic Acid from acting when needed, a multiplying cell is interrupted in the process if making DNA and as a result promptly dies. This is how Methotrexate helps destroy various cancers and explains the wide range of effectiveness of the High Doses.

Methotrexate is among the oldest FDA approved chemotherapy agents. Chemically it is real Folic Acid modified just enough to make it useless as a vitamin. As a result, whenever Methotrexate penetrates a cell, the latter is fooled to engage it, instead of the real vitamin. The latter, even if present, can not be activated by the cell which dies when it tries to make DNA with the help of folic (folinic) acid.

Folic Acid on the other hand can easily be activated chemically in the laboratory and can be given as a drug (“Leukovorin”) to the patients after treatment with Methotrexate. By timing properly the administration of the Methotrexate and the activated Folic Acid (known as Citrovorum Factor, alias, Tetrahydrofolic Acid, or generically as “Leukovorin”) the effect of Methotrexate can be stopped immediately and completely. In this fashion Methotrexate can be allowed to work for a while on the cancer cells, but stopped before it starts damaging seriously the sensitive normal cells.

This process was named “Rescue” (of the patients from the side effects of MTX). Eventually the concept of “Rescue” from chemotherapy was enlarged to include special transfusions of blood cells like platelets, granulocytes, antibiotics and most recently Stem Cells and Bone Marrow Transplants, which are all designed to replace the normal blood cells destroyed by the chemotherapy. The “Rescue does not attack the Cancer itself. The actual treatment is done by the high-dose chemotherapy.

The ability to modify the effects of Methotrexate with Citrovorum Factor (“Leukovorin”) makes High Dose MTX chemotherapy unique. Methotrexate is the only drug for which we have a real ANTIDOTE. This means a drug which can reverse the poisonous (toxic) effects of another chemical and thus prevent or reverse all side effects.

In the mid-sixties, Dr. Isaac Djerassi, still working with Sidney Farber in Boston, realized that the main reason Methotrexate fails to stop many cancers is that not enough molecules of this drug penetrate the “skin” (membrane) of the cancer cells while it easily enters the normal dividing, and therefore, sensitive, cells like bone marrow, hair, mouth and intestinal linings (mucosa).

By giving much higher doses of Methotrexate and by dripping it in the vein during many hours to maintain a high blood concentration it finally penetrates the cancer cells. This requires very high doses of the drug. The only way to do it safely is to follow the Methotrexate with the antidote Leukovorin (Citrovorum Factor). The patient suffers very few, if any, side effects. This is how the High Dose Methotrexate with Citrovorum Factor Rescue treatment was designed in 1964 and helped produce some of the earliest permanent cures of Acute Leukemia and Non-Hodgkins Lymphoma in children in the 60’s. (see references).

Stronger doses of Methotrexate helped Farber, Jaffe, Frei and Djerassi to produce remissions and then cures of the most vicious cancer in children, the Osteogenic Sarcoma (cancer of the bone).

In 1967 Djerassi treated an 11 year old girl with Brain Glioma who is alive today along with 18 other patients, mostly adults, with the same disease. It turned out that the High Dose Methotrexate can penetrate the BLOOD - BRAIN BARRIER .

Meanwhile, major anticancer effectiveness was observed by Djerassi when using High Dose Methotrexate and Rescue in Cancers of the Lung, the Ovaries, the Stomach, the Bladder, the Breast and especially Mesothelioma (the “Asbestos cancer”). Equally impressive were the results in various Sarcomas such as Leiomyosarcoma, Fibrosarcoma, and Lipoma.

The effectiveness of the High Dose Methotrexate was further enhanced by the ability of combining this drug with other, more routine chemotherapeutic agents. The earliest combination, recommended and still used by Djerassi and others, was High Dose Methotrexate followed by 5-fluorouracyl (5-FU), initially for Breast Cancer and more recently for Colon Cancer. The benefit of combining HDMTX with Adriamycin, Mitomycin and 5-FU in Breast Cancer, or combining Cytoxan, Adriamycin, mitomycin with HDMTX, followed 48 hours later by cisplatinum for Ovarian Cancer, or HDMTX followed by Cisplatin for Mesothelioma, or non-small cell cancer of the Lung, was impressive.oxHosH Hos

The reason for the marked synergistic effect of HDMTX with small doses of the other drugs was suggested by Goldman from the University of Virginia in the 70’s, when he proposed that it is due to HDMTX stopping DNA repair of mild damage caused by ineffective drugs. HDMTX depletes the cell from active Folic Acid. The latter is essential for the repair and survival of the cancer cells. In the absence of Folic Acid even a minor and survivable damage of the DNA in the cancer cell becomes, indeed, lethal for the cancer which otherwise would have survived the treatment and continue to grow.

The use of the original dose-schedules of HDMTX is now a routine in many Centers around the world, who are capable of carrying them out safely and successfully. All those interested in utilizing the newest and most advanced dose-schedules and combinations, however, are well advised to contact the Djerassi group in Philadelphia for details on recent improvements of the technique.

Intensive and specialized support is the basis for the safe use of the newer HDMTX dose-schedules. Innovative uses of platelet transfusions and multiple third generation antibiotics, all in a prophylactic mode, are the basis of such support. The importance of this supportive system can not be overemphasized.

REFERENCES FOR THE USE OF HIGH DOSE METHOTREXATE

A. Publications by Dr. Djerassi

1. Djerassi, I., Aabir, E., Royer, G. and Treat, C.: Long-Term Remissions in Childhood

Acute Leukemia: Use of Infrequent Infusions of Methotrexate; Supportive Roles of

Platelet Transfusions and Citrovorum Factor. Clinical Pediatrics, 5:502-509, 1966.

2. Djerassi, I., Abir, E., Trat, C., Royer, G.: A New Method for Maintenance of

Remission in Children with Acute Leukemia. J. Ped. 69:977, 1966.

3. Djerassi, I.., Abir, E., Treat, C. and Royer, G: Use of Methotrexate for Long-Term

Maintenance of Remissions in Acute Leukemia; Supportive Role of Platelet

Transfusions and Citrovorum Factor. Abstract, XIth Congress of the International

Society of Haematology, Sydney, August, 1966.

4. Djerassi, I., Royer, G., Treat, C. and Abir, E.: Survival of Children with Acute

Lymphatic Leukemia - Role of Methotrexate and Intensive Supportive Management..

Proc. American Assoc. Cancer Research, 8:14, 1967.

5. Djerassi, I., Farber, S., Abir, E. and Neikirk, W.: Continuous Infusion of

Methotrexate in Children with Acute Leukemia. Cancer 20, 233-242, 1967.

6. Djerassi, I., Royer, G., Treat, C., and Carim, H.: Management of Childhood

Lymphosarcoma and Reticulum Cell Sarcoma with High Dose Intermittant

Methotrexate and Citrovorum Factor. Proc. ASCO 9:70, 1968.

7. Djerassi, I., Rominger, C.F., Kim, J.S., Turchi, J.J., and Meyer, E.C.:

Methotrexate-Citrovorum Factor in Patients with Lung Cancer. Proc. AACR

11:21, 1970.

8. Jaffe, N., Farber, S., Traggis, D., Geiser, C., Das, L., Kim, J., Frauenberger, G.

and Djerassi, I.: Favorable Response of Metastatic Osteogenic Sarcoma to Pulse

High Dose Methotrexate Citrovorum Administration (HDMC). Proc. AACR

13:27, 1972.

9. Djerassi, I., Suvansri, U. and Kim, J.S.: Long Remissions in Acute Lymphocytic

Leukemia: Pulse Methotrexate and a Four (4) Drug Combination. Proc. AACR

13:94, 1972.

10. Djerassi, I., Rominber, C.J., Kim, J.S., et al: Phase I Study of High Doses of

Methotrexate with Citrovorum Factor in Patients with Lung Cancer. Cancer 30:

22-30, 1972.

11. Jaffe, N., Farber, S., Traggis, D., Djerassi, I., et all: Favorable Response of

of Metastatic Osteogenic Sarcoma to Pulse High Dose Methotrexate with

Citrovorum Frescue and Radiation Therapy. Cancer 31:1367-1373, 1973.

12. Djerassi, I., Kim, J.S. and Suvansri, U.: “Pulse” Methotrexate and Citrovorum

Factor “Rescue” in Common Solid Tumors (including Lung and Pancreas Cancer)

of the Adult. Proc. AACR 15:73, 1974.

13. Djerassi, I.: High-Dose Methotrexate (NSC-740) and Citrovorum Factor

(NSC-3590) Rescue: Background and Rationale. Cancer Chemotherapy

Rep6:3-6, 1975.

14. Djerassi, I. and Kim, J.S.: Methotrexate-Citrovorum Factor in the Management

of Non-Hodgkin’s Lymphoma - 4 Year Unmaintained Remissions. Proc. AACR

16:151, 1975.

15. Djerassi, I., Kim, J.S., and Suvansri, U.: Chemotherapy, Supportive Care, and

Immunotherapy of Cancer - from Research Tools to Therapeutic Modalities.

Fundamental Aspects of Neoplasia, edited by A. Arthur Gottlieb, Otto J. Plescia,

and David H. L. Bishop., Springer-Verlag New York, Inc., 1975.

16. Djerassi, I. and Kim, J.S.: Methotrexate and Citrovorum Factor Rescue in the

Management of Childhood Lymphosarcoma and Reticulum Cell Sarcoma

(Non-Hodgkin’s Lymphomas). Cancer 38:1043-1051, 1976.

17. Kim, J.S., Djerassi, I., et al.: Pulse High Dose Methotrexate with a Drug

Combination (BOMB) for Remission Maintenance in Acute Leukemia.

Proc. AACR 14:144, 1976.

18. Djerassi, I., Kim, J.S., Nayak, N.: Activity and Toxicity of Methotrexate-

Citrovorum in Adults with Solid Tumors: Value of a New CF Rescue Dose

Schedule. Proc. AACR 17: 143, 1976.

19. Djerassi, I., Kim, J.S., et al: High Dose Methotrexate with Citrovorum Factor

Rescue: A New Approach to Cancer Chemotherapy. In: Recent Advances in

Cancer Treatment, edited by H.J. Tagnon and M.J. Staquet, Raven Press, New York, 201-225, 1977.

20. Djerassi, I., Kim, J.S. and Shulman, K.: High Dose Methotrexate Citrovorum

Factor Rescue in the Management of Brain Gliomas. Cancer Treatment Reports,

61:4, 1977.

21. Djerasso. O/. Coiesielka, W. and Kim, J.S.: Removal of Methotrexate by

Filtration-Absorption Using Charcoal Filters or by Hemodialysis. Cancer

Treatment Reports, 61:4, 1977.

22. Djerassi, I., Kim, J.S., Nayak, N., Ohanissian, H., Adler, S. and Hsieh, S.:

New “Rescue” with Massive Doses of Citrovorum Factor for Potentially Lethal

Methotrexate Toxicity. Cancer Treatment Reports 61:4, 1977.

23. Kim, J.S. and Djerassi, I.: Dose response of Osteogenic Sarcoma and Lung

Cancer to Methotrexate-Citrovorum (MTX-CF). Proc. AACR 18:123, 1977.

24. Djerassi, I., Kim, J.S., et al.: Massive Dose Citrovorum Factor Rescue (CFR)

and Charcoal Filtration Following High Dose Methotrexate (HDMTX). Proc.

AACR 18: 123, 1977.

25. Djerassi, I.: Working Concepts of High Dose Methotrexate (HDMTX) and

Citrovorum Factor (CF) Rescue. Chemioterapia Oncologica II, 111, 1978.

26. Djerassi, I., Kim, J.S.: High Dose Methotrexate (HDMTX) in Acute Leukemia.

Chemioterapia Oncologica - Anno II - n. 2 - Giugno 1978 High Dose Methotrexate

International Workshop - June 13-14, 1978.

27. Djerassi, I., Kim, J.S., and Ohanissian, H.: High Dose Methotrexate (HDMTX)

and Citrovorum Factor Rescue (CFR) in Solid Tumors. Chemioterapia Oncologica

- Anno II - n.2 - Giugno 1978 High Dose Methotrexate International Workshop,

June 13-14, 1978.

28. Djerassi, I., Ohanissian, H., and Kim, J.S.: Supportive Care as Part of the Rescue

of High Dose Methotrexaate (HDMTX). Chemioterapia Oncologica - Anno II -

n.2 Giugno 1978 High Dose Methotrexate International Workshop, June 13-14, 1978.

29. Djerassi, I., Ohanissian, H., Kim, J.S., Mills, K., and Joshua, H.: A New Approach

to Massive Methotreate Citrovorum Rescue - A Non-Toxic Dose Schedule for

Methotrexate Resistant tumors in Poor Risk Patients. roc. ADCO 20:398, 1979.

30. Kim, J.S. and Djerassi, I.: response of Pancreas Cancer to High Dose Methotrexate

- Citrovorum Factor Rescue. Proc. AACR 20: 195, 1980.

31. Djerassi, I., Mills, K., Ohanissian, H. and Kim, J.S.: Elimination of the Hazards

of High-Dose Methotrexate (MDMTX) with Improved Citrovorum Factor Rescue

(CF). Proc. ASCO 20:361, 1980.

32. Djerassi, I.: New Frontiers for High-Dose Methotrexate When Used With

Equimolar Citrovorum Rescue. chemioterapia Oncologica, AnnoV n. 1 - Marzo,

1981.

33. Djerassi, I., Mills, K., Ohanissian, H. and Kim, J.S.: High-Dose Methotrexate

with Rescue: An Effective Treatment for Refractory Neoplasms. In: Controversies

in Oncology. Edited by Peter Wiernik. John Wiley & Sons, Inc., Publishers,

pp. 325-352, 1982.

34. Djerassi, I., Kim, J.S. and Reggev, A.: Response and Long-Term Survival in

Astrocytoma with Massive Doses of Methotrexate (MDMTX). Proc. ASCO, 1983.

35. Reggev, A. and Djerassi, I.: Rescue from High Dose Methotrexate (HDMTX) with

5-Methyltetrahydrofolic Acid (5-MTHF). Proc. AACR, 1983.

36. Kim, J.S. and Djerassi, I.: Prolonged Remissions in Adult Acute Leukemias and

Poor Risk Childhood ALL with the MTX-BOMB Protocol. Proc. AACR, 1983.

37. Djerassi, I., Kim, J.S., and Reggev, A.: Response of Astrocytoma to High Dose

Methotrexate with Citrovorum Factor Rescue. Cancer 55:2741-2747, 1985.

38. Djerassi, I., Kim, J.S., Kassarov, L. and reggev, A.: Response of Mesothelioma

to large Doses of Methotrexate with CF Rescue (HDMTX-CF) Used Alone or

with Cisplatinum. Proc. ASCO 4:191, 1985.

39. Djerassi, I., Rominger, C.J., Kim, J.S., Kassarov, L., Patel, A. and Ahmad, N.:

Astrocytoma Responding to High Dose Methotrexate CF Rescue (HDMTX-CF),

Alone or Combined with Simultaneous Small Doses of Radiation. Proc. AACR

26:171, 1985.

40. Djerassi, I. and Kim, J.S.: High Dose Methotrexate for Remission Maintenance

in Acute Leukemia and Non-Hodgin’s Lymphoma. In Methotrexate in Cancer

Therapy. Editors Kiyoji Kimura and Yeu-Ming Wang, Raven Press, New York,

pp. 141-147, 1986.

41. Djerassi, I., Kim, J.S., Kassarov, L., Reggev, A., Gandhi, V., and Srivastava, B.:

High Dose Methotrexate (HDMTX) with Citrovorum Factor (CF) in Astrocytoma.

ASCO., 1988.

42. Djerassi, I., M.J. Suh, A. Lee and C.D. Kim: Obtjective Response of Poor Risk

Astrocytoma to a Combination of High Dose Methotrexate (HDMTX) with

Cisplatinum and/or BCNU. Proc. ASCO, Vol. 10, p. 126, 1991.

43. Djerassi, I., Suh, M.J., Kim, J.S., Kim, C.D.: High Dose Methotrexate in Grade

III Astrocytoma. Proc. ASCO, 1992.

44. Djerassi, I., Suh, M.J., Kim, J.S., Reggev, A., Kassarov, L., Kim, C.D.: Survival

of Astrocytoma Patients Whose Treatment Included High Dose Methotrexate with

Citrovorum Rescue. Proc. ASCO, Vol. 12, p. 181, 1993.

B. Publications by Others (grouped by institution of origin)

a. HARVARD

1. Frei, E., Jaffe, N. Tattersal, M., Pitman, s. and Parker, L.: Seminars in Medicine

of the Beth Israel Hospital, Boston - New Approaches to Cancer Chemotherapy

with Methotrexate, The New England Journal of Med., Vol, 292, No. 16,

pp. 846-851, 1975.

2. Jaffe, N., Frei, E., Traggis, D., and Bishop, Y.: Adjuvant Methotrexate and

and Citrovorum-Factor Treatment of Osteogenic Sarcoma. The New England

Journal of Med., Vol. 291, No. 19, pp. 994-997, 1974.

3. Jaffe, N.: Recent Advances in the Chemotherapy of Metastatic Osteogenic

Sarcoma. Cancer, Vol. 30, No. 6, pp. 1627-1631, 1972.

4. Jaffe, N., et al.: Favorable Response of Metastatic Osteogenic Sarcoma to

Pulse High-Dose Methotrexate with Citrovorum Rescue and Radiation Therapy.

Cancer, Vol. 31, No. 6, pp. 1367-1373, 1973.

5. Jaffe, N., et al.: Weekly High-Dose Methotrexate-Citrovorum factor in

Osteogenic Sarcoma. Pre-Surgical Treatment of Primary Tumor and of Overt

Pulmonary Metastases. Cancer, Vol. 39, No. 1, pp. 45-50, 1977.

6. Ervin, T., and Miller, D.: Improved Survival in Patients with Advanced

Squamous Carcinoma of Head and Neck Responding to Preoperative High-

Dose Methotrexate-Leukovorin (HD-MTX). Proc. AACR 21:141, 1980.

7. Skarin, A.T., Greene, H., Canellos, g.P., takovorian, R, Frei, E.: High-Dose

Methotrexate with Citrovorum Factor Rescue (HD-MTX) Alternating with

Combination Chemotherapy (M-CAV-CME) In Small Cell Lung cancer

(SC Lung Ca.). Proc. ASCO 20: 328, 1979.

8. Henderson, I.C., Canellos, G.P., Blum, R.H., Skarin, A.T., Mayer, R.J.,

Parker, L.M. and Frei, E.: Prolonged Disease-Free Survival In Advanced

Breast Cancer (BC) Treated with “Super-CMF” - Adriamycin: An Alternating

Regimen employing High Dose Methotrexate (M) with Citrovorum Factor

(CF)( Rescue. ASCO 20: 327, 1979.

9. Skarin, a., Canellos, G., rosenthal, D. case, D., Moloney, W., and Frei, E.:

Therapy of Diffuse Histiocytic (DH) and Undifferentiated (DU) Lymphoma

with High Dose Methotrexate and Citrovorum Factor Rescue (MTX/CF),

Bleomycin, (B), Adriamycin (A), Cyclophosphamide (C), Oncovin (O), and

Decadron (D) (M-BACOD). ASCO 21; 463, 1980.

9a. Pitman, S.W., and Frei, E.: Weekly Methotrexate-Calcium Leucovorin Rescue:

Effective of Alkalinization on Nephrotoxicity; Pharmacokinetics in the CNS; and

Use in CNS Non-Hodgkin’s Lymphoma. Cancer Treatment reports, Vol. 61,

No. 4, pp. 695-701, 1977.

b. YALE

10. Hryniuk, W., and Bertino, J.: Treatment of Leukemia with Large Doses of

Methotrexate and Folinic Acid: Clinical-Biochemical Correlates. The Journal

of Clinical Investigation. Vol. 48, pp. 2140-2155, 1969.

11. Capizzi, R.L., DeConti, C., Marsh, J. C.. and Bertino, J.R.: Methotrexate

Therapy of Head and Neck Cancer: Improvement in Therapeutic Index by the

Use of Leucovorin “Rescue”. Cancer Research 30, pp. 1782-1788, 1970.

12. Bertino, J., Mosher, M., and DeConti, R.: Chemotherapy of Cancer of the

Head and Neck. Cancer, Vol. 31:5, pp. 1141-1149, 1973.

c. SLOAN-KETTERING MEMORIAL

13. Rosen, G., Suwansirikul, S., Kwon, c., Tan, C., Wu., J., Beattie, E., , and

Murphy, M.: High-Dose Methotrexate with Citrovorum Factor Rescue and

Adriamycin in Childhood Osteogenic Sarcoma. Cancer 33:4,p.1151-1163,1974.

14. Rosen, G., Nirenberg, A., and Caparros, B.: Evaluation of High Dose

Methotrexate (HDMTX) with Citrovorum Factor Rescue (CFR) Single Agent

Chemotherapy in Osteogenic Sarcoma (OSA). Proc. AARC 21:177, 1980.

15. Cheng, B., Magill, G., and Golbey, R. High Dose Methotrexate Therapy

in Carcinoma of the Pancreas. Proc. ASCO.

16. Nikrui, N., Magill, G., Ochoa, M., and Golbey, R.: High Dose Methotrexate

(HDMTX) Therapy in Carcinoma of the Cervix. Proc. AACR 17:173, 1976.

17. Sklaroff, R., and Yagoda, A.: Methotrexate in the Treatment of Penile

Carcinoma. Cancer 45:2, pp. 214-216, 1980.

18. Yagoda, A., Watson, r., Whitmore, W.: Phase II Trial of Methotrexate in

Urinary Bladder Cancer. Poroc. ASCO 21:427, 1980.

18a. Rosen, G., et al.: Pontine Glioma-High-Dose Methotrexate and Leucovorin

Rescue. JAMA 230:8, p. 1149-1152, 1974.

d. ROSWELL PARK

19. Wang, J., Freeman, a., and sinks, L.: Treatment of acute Lymphocytic Leukemia

by High Dose Intravenous Methotrexate. Cancer research 36: 6, pp. 1441-1444,

1976.

20. Barlow, J., Piver, M., and Lele, S.: High Dose Methotrexate with “Rescue”

Plus Cyclophosphamide as Initial Chemotherapy in Ovarian Adenocarcinoma.

Cancer 46:6, pp. 1333-1338, 1980.

21. Brecher, M., Thomas, P., sinks, L. and Freeman, A.: Updated Results on the

Treatment of Childhood Non-Hodgkin’s Lymphoma (NHL). Proc. ASCO 20:

438, 1979.

e. M.D. ANDERSON

22. Kimball, J., Herson, J., Sullivan, M.: Favorable response to Maintenance

Therapy of Second or Subsequent remissions in childhood Acute Lymphocytic

Leukemia. Cancer 46:5, pp. 1093-1097, 1980.

23. Yap, H.Y., et al.: High-Dose Methotrexate for Advanced Breast Cancer.

Cancer Treatment Reports, Vol. 63, No. 5, 1979.

f. NATIONAL CANCER INSTITUTE (NIH)

24. Fisher, R., et al.: Pro-MACE-MOPP Combination Chemotherapy:

Treatment of Diffuse Lymphomas. Proc. ASCO 21: 468, 1980.

g. UNIVERSITY OF CHICAGO/VANDERBILT UNIVERSITY

25. Stein, R., Collins, R., Ultmann, J.: Diffuse Histiocytic Lymphoma (DHL):

B-Cell Origin by Lukes-Collins Criteria Predicts Favorable Response to

Comla (Cyclophosphamide, Oncovin, Methotrexate, Leucovorin, Cytosine

Abrabinoside) Chemotherapy. Proc. ASCO 21:469, 1980.

h. UNIVERSITY OF WASHINGTON

26. Bleyer, W.A.: The Clinical Pharmacology of Methotrexate - New

Applications of an Old Drug: Cancer 41:1, pp. 36-51, 1978.

i. UNIVERSITY OF NORTH CAROLINA

27. Neijstrom, E., et al.: High Dose Methotrexate (HDMTX) with Leucovorin

Rescue (LR) for CNS Prophylaxis in Patients with Small Cell Lung Cancer

(SCLC). Proc. ASCO 21:456, 1980.

j. MISCELLANEOUS

28. Tornyos, K., and Faust H.: High Dose Oral Methotrexate (MTX) with

Citrovorin Factor (CF) Rescue in Squamous Cell Cancer of the Lung.

Proc. ASCO 18:316, 1977.

29. Eilber, F.R., and Isakoff, W.: High Dose Methotrexate Therapy for

Disseminated Malignant Melanoma. Proc. ASCO 17:262, 1976.

29a. Isacoff, W.H.: High Dose Methotrexate therapy of solid Tumors:

Observations Relating to Clinical Toxicity. Medical and Pediatric Oncology

2:319-325, 1976.

30. Shehata, W., and Meyer, r.: The enchancement Effect of Irradiation by

Methotrexate. Cancer 46:6, pp. 1349-1352, 1980.

C. Specially Significant Publications

(Ovarian, Breast, Stomach, Mesothelioma, Leukemia, Lymphoma)

1. Barlow, J., Piver, M. Lele, S.: High Dose Methotrexate with “Rescue” Plus

Cyclophosphamide as Initial chemotherapy in Ovarian Adenosarcoma. Cancer

46:6, pp. 1333-1338, 1980.

2. Yap, H.Y., et al.: High Dose Methotrexate For Advanced Breast Cancer.

Cancer Treatment Reports Vol. 63, No. 5, 1979.

3. J.A. Wils, R.C. Coombes, J. M. Bliss, et al.: Phase I-II Study of Sequential High

Dose Methotrexate and 5-Fluorouracil Combined with Epirubicin (FEMTX) at

Different Dose Levels in Advanced Gastric Cancer. The Netherlands, 1994.

4. S. Tiong Ong and Nicholas J. Vogelzang: Chemotherapy in Malignant Pleural

Mesothelioma: A Review. J. of Clinical Oncology, Vol 14, no 3, pp 1007-1017

March, 1996.

5. Gaston K. River, M.D., Donald Pinkel, M.D., Joseph V. Simone, M.D., et al.:

Treatment of Acute Lymphoblastic Leukemia - 30 Years’ Experience at St. Jude

Children’s Research Hospital. The New England J. of Medicine, Vol 329, no 18,

pp 1289-1295, Oct., 1993.

6. Jean-Yves Blay, Thierry Conroy, Christine Chevreau, et al.: High Dose Methotrexate

for the Treatment of Primary Cerebral Lymphomas: analysis of Survival and Late

Neurologic Toxicity in a Retrospective Series. J. of Clinical Oncology, Vol 16, No 3,

pp 864-871, March, 1998.