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
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
Osteogenic Sarcoma (cancer of
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
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.
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
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.
A. Publications by Dr. Djerassi1. 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
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
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
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:
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
14. Djerassi, I. and Kim, J.S.: Methotrexate-Citrovorum Factor in the Management of Non-Hodgkin’s Lymphoma - 4 Year Unmaintained Remissions. Proc. AACR
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,
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
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.
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)
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.
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:
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.
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
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
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.