This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jaffe, N. Articles by Gorlick, R. Search for Related Content PubMed PubMed Citation Articles by Jaffe, N. Articles by Gorlick, R. Social Bookmarking                            What's this?

High-Dose Methotrexate in Osteosarcoma: Let the Questions Surcease—Time for Final Acceptance

The University of Texas M. D. Anderson Cancer Center, Houston, TX

Richard Gorlick

Children's Hospital at Montegiore, Bronx, NY

Osteosarcoma is the most common primary malignant bone tumor affecting children and adults. The etiology is unknown, although a higher incidence occurs in patients with bilateral retinoblastoma, Paget's disease of bone, the Li Fraumeni syndrome, and those who have received therapeutic radiation. The biologic behavior is consistent with the premise that silent pulmonary micrometastases are present in at least 80% of patients at diagnosis. These metastases are not visible on imaging studies, but in the absence of effective systemic therapy, they generally surface 6 to 9 months after surgical ablation of the primary tumor. If untreated, they will be responsible for the patients demise within 2 to 3 years of their appearance. Historical controls reveal a survival of 5% to 20%.

There are currently four major classes of chemotherapeutic agents with established efficacy that are used in the therapy of this malignancy: doxorubicin, cisplatin, ifosfamide/high-dose cyclophosphamide, and high-dose methotrexate with leucovorin rescue (MTX-L). Doxorubicin and MTX-L were discovered first in the early 1970s. Doxorubicin, and the other agents when discovered later, were accepted without query; not so for MTX-L. It was initially subjected to intense scrutiny,^1,2 rebuffed intermittently,³ and later incorporated with variable degrees of indifference or enthusiasm into therapeutic regimens seemingly for want of a more effective agent. During this interminable period of probation (still extant⁴), support for its efficacy and confirmation of its activity emanated from various publications. It was shown to be effective in eliminating overt pulmonary metastases, improving the opportunity for limb salvage, healing pathologic fractures, and enhancing the effect of radiation therapy for palliation and control of inoperable tumors.⁵ When administered postoperatively as the sole agent after ablation of the primary tumor, it increased survival to 40%,⁶ and in combination with other agents (pre- and postoperative therapy), it increased survival to 65% to 75%.^6-12

A regimen devoid of MTX (non–methotrexate-based therapy) has been documented, inter alia, among the "major poor prognostic factors."¹⁰ The authors of this article stipulate that the major poor prognostic factors were as follows: "[age] older than 30 years, large absolute or relative tumor volume, tumor location in the proximal humerus, no neoadjuvant chemotherapy, non–methotrexate-based therapy, poor histologic response to preoperative chemotherapy...... and so on."

Using serum MTX concentrations to monitor MTX levels, the regimen has been successfully administered safely and effectively to patients in numerous investigations.^6-12 MTX is usually administered over 4 to 6 hours, and it is generally considered that a mean peak serum MTX threshold greater than 700 to 1,000 µmol/L at the completion of the infusion is required for successful therapy. This was found to be correlated significantly with prognosis.^8,11,12 (In N.J.'s experience, superior results are more likely to be achieved with levels in excess of 1,500 µmol/L). Unfortunately, for reasons undetermined at the present time, there is inter- and intrapatient variability, and consistent high levels with each course are infrequent (hence the desirability to attain a more than adequate threshold level at 4 to 6 hours). This variability, inter alia, may account for the diverse and conflicting results in published studies.^13,14 When administered as a so-called block of therapy or an intensified course, an optimum schedule comprises four to eight doses at 10- to 14-day intervals; when administered in combination with other agents, generally doxorubicin, the interval between courses may be reduced to 3 to 4 weeks.

MTX should be administered with appropriate attention to the pretherapy requirements and diligent monitoring of the decay curve. Infection and pathologic accumulation of fluid (ascites and pleural and pericardial effusions) where MTX may sequestrate and result in a prolonged delay in excretion are contraindications. MTX levels in excess of an institute's specific designated values at specified times portend potential toxicity and should be treated immediately by increasing intravenous hydration and augmenting the dose of leucovorin. The decay curve has wide variability: 24 hours, 30 to 300 µmol/L; 48 hours, 3 to 30 µmol/L; and 72 hours, less than 0.3 µmol/L. A dose of 10 mg of leucovorin is usually administered intravenously 24 hours after initiation of the MTX infusion. Subsequent doses are adjusted and administered according to the MTX levels obtained at 24, 48, and 72 hours. Algorithms are available for this purpose and should be consulted. Generally, these doses are administered as 10 mg of leucovorin intravenously or orally every 6 hours; however, levels in excess of 50 µmol/L at 24 hours, 10 µmol/L at 48 hours, and 0.5µmol/L at 72 hours portend potential toxicity and are usually treated with an increase in the dose; for example, 100 mg/m² administered intravenously every 3 hours. Elevations or reductions in the doses continue to be implemented throughout the period of rescue in accordance with the algorithms until the MTX level is 0.1 µmol/L (some centers will discontinue leucovorin at 0.3 µmol/L).

One of the earliest signs of toxicity is oliguria followed by anuria, presumably resulting from MTX precipitation in the renal tubules. Reduced renal clearance is generally accompanied by gastrointestinal, hematologic, and hepatic dysfunction. Toxicity can become excessive, but with appropriate early recognition and management, the patient will usually recover. Additional measures to abort life-threatening toxicity comprise hemodialysis using a high-flux dialyzer and carboxypeptidase-G2. This cleaves MTX into inactive metabolites. Irreversible toxicity, however, is rare, and several centers now advocate treatment on an outpatient basis.¹⁵ Patients should be cautioned to avoid over-the-counter medication that may interfere with MTX excretion (eg, ibuprofen, aspirin, and acetaminophen). Certain antibiotics, such as penicillin, may cause a similar problem.

MTX is cell cycle specific for the S phase. It acts by inhibiting the conversion of dihydrofolate to tetrahydrofolate and prevents the transfer of 1- carbon donors. This surceases the folate pool, thwarts the formation of purine and thymidine, and ultimately disrupts DNA replication. However, the dose of MTX in osteosarcoma is many-fold the conventional dose, and it probably operates via a different mechanism. One simplistic possibility resides in the transport mechanism. MTX and leucovorin share a common carrier, called the reduced folate carrier, for entry into cells. This transport mechanism is present in normal cells but not in resistant cancer cells. High-dose MTX enters normal cells via the carrier mechanism and, by virtue of its high extracellular concentration, also resistant malignant cells through diffusion over time (concentration x time). Leucovorin also enters normal cells via the carrier mechanism, but unlike MTX, is prohibited from entry into malignant cells because of its relatively extracellular low serum concentration and the absence of a carrier mechanism. It rescues normal cells while malignant cells, in the absence of intracellular leucovorin, self-destruct.

The ability of MTX-L to destroy malignant osteosarcoma cells led to intensive investigations to determine its metabolic and biochemical activities. Studies evaluated blood, urinary, and cerebral spinal fluid levels in children after high-dose MTX infusions, examined age-related different pharmacokinetics, and discovered contaminants and specific metabolites during therapy and degradation and clearance of the antifolate.^16,17 Age may be important in terms of effective dosage.¹⁷ Nonetheless, the mechanism of action of MTX-L in osteosarcoma remains an enigma.

Attempts to enhance the efficacy of MTX-L in osteosarcoma by extending the period of administration from 4 or 6 hours to 24 hours or prolonging the interval before initiating the rescue program have not been successful.¹⁸ Similarly, administering a high MTX dose by the intra-arterial route, which produces a higher local concentration as opposed to the intravenous route, does not enhance the efficacy of its therapeutic application (Jaffe et al,¹⁹ also republished in this issue of the Journal of Clinical Oncology). Others have administered MTX in even higher doses, seemingly without increasing its efficacy. Thus the regimen seems to have reached the limits of its utility with the conventional intravenous high dose (10 to 12.5 g/m²).

Despite the enigma of its mechanism of action, successes achieved with the regimen in osteosarcoma spawned attempts to develop new and similar agents to treat the disease. This led to the rational synthesis of folate analogs that differ from MTX in transport, metabolism, and intracellular targets. These include trimetrexate and pemetrexed. Trimetrexate with simultaneous leucovorin has shown some promising activity in the context of phase II trials of patients with recurrent disease, but it remains unknown whether it can add to the efficacy of upfront MTX-L. Similarly, pemetrexed administered with simultaneous folic acid supplementation is in the midst of phase II testing in osteosarcoma as part of Children's Oncology Group clinical trials.

With the republication of the study comparing intra-arterial and intravenous MTX-L after a quarter century¹⁹ and 36 years after the first demonstration of its efficacy,²⁰ it is appropriate to recognize and finally affirm its contribution to the treatment of osteosarcoma.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Norman Jaffe, Richard Gorlick

Final approval of manuscript: Norman Jaffe, Richard Gorlick

REFERENCES

1. Muggia FM, Louie AC: Five years of adjuvant chemotherapy: More questions than answers. Cancer Treat Rep 62:301-305, 1978[Medline]

2. Edmonson JH, Green SJ, Ivans JC, et al: A controlled pilot study of high-dose methotrexate as per surgical adjuvant treatment for primary osteosarcoma. J Clin Oncol 2:152-156, 1984[Abstract]

3. Carter SK: Adjuvant chemotherapy in osteogenic sarcoma: The triumph that isn't? J Clin Oncol 2:147-148, 1984[Medline]

4. Link MP, Gebhardt MC, Meyers PA, in Pizzo PA, Poplack DG (eds): Osteosarcoma: Principles and Practices of Pediatric Oncology (ed 5). Philadelphia, PA, Lippincott Williams & Wilkins, 2006, pp 1074-1115

5. Jaffe N, Link M, Traggis D, et al: The role of high-dose methotrexate in osteogenic sarcoma in sarcomas in soft tissue and bone in childhood. Natl Cancer Inst Monogr 56:201-206, 1981

6. Goorin AM, Delorey M, Gelber RD, et al: The Dana Farber Cancer Institute/The Children's Hospital adjuvant chemotherapy trials for osteosarcoma: Three sequential studies. Cancer Treat Symp 3:155-159, 1985

7. Rosen G: Role of chemotherapy in the treatment of primary osteogenic sarcoma: A five-year follow-up of T-10 neoadjuvant chemotherapy, in Kimura K, Wang Y-M (eds): Methotrexate in Cancer Therapy. New York, NY, Raven Press, 1986, pp 227-238

8. Bacci G, Gherlinzoni F, Picci P, et al: Doxorubicin-methotrexate high dose versus doxorubicin-methotrexate moderate dose as adjuvant chemotherapy for osteosarcoma of the extremities: A randomized study. Eur J Cancer Clin Oncol 22:1337-1345, 1986[CrossRef][Medline]

9. Meyers PA, Gorlick R, Heller G, et al: Intensification of preoperative chemotherapy for osteogenic sarcoma: Results of the Memorial Sloan Kettering (T-12) protocol. J Clin Oncol 16:2452-2458, 1998[Abstract]

10. Kim MS, Cho WH, Song WS, et al: Time dependency of prognostic factors in patients with stage II osteosarcomas. Clin Orthop Relat Res 463:157-165, 2007[Medline]

11. Delepine N, Delepine G, Jasmine C, et al: The importance of age and methotrexate dosage: Prognosis in children and young adults with high grade osteosarcoma. Biomed Pharmacother 42:257-262, 1988[Medline]

12. Graf N, Winkler K, Betlemovic M, et al: Methotrexate pharmakinetics and prognosis in osteosarcoma. J Clin Oncol 12:1443-1451, 1994[Abstract]

13. Bramwell VH, Burgers M, Sneath R, et al: A comparison of two short intensive adjuvant intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: The first study of the European Osteosarcoma Intergroup. J Clin Oncol 10:1579-1591, 1992[Abstract/Free Full Text]

14. Souhami RL, Craft AW, Van der Eiken JW, et al: Randomized trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European Osteosarcoma Intergroup. Lancet 350:911-917, 1997[CrossRef][Medline]

15. Anderson PM, Pearson M: Novel therapeutic approaches in pediatric and young adult sarcomas. Curr Oncol Rep 8:310-315, 2006[CrossRef][Medline]

16. Wang YM, Lantin E, Sutow WW: Blood, urinary and cerebral spinal fluid methotrexate levels in children after high methotrexate infusion. Clin Chem 22:1053-1056, 1976[Abstract/Free Full Text]

17. Wang Y-N, Sutow WW, Romsdahl MM, et al: Age related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma. Cancer Treat Rep 63:405-410, 1979[Medline]

18. Cohen H, Jaffe N: Pharmacokinetic studies of 24-hour infusions of high-dose methotrexate. Cancer Chemother Pharmacol 1:61-64, 1978[Medline]

19. Jaffe N, Prudich J, Knapp J, et al: Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol 1:428-431, 1983[Abstract]

20. Jaffe N: Recent advances in the chemotherapy of metastatic osteogenic sarcoma. Cancer 30:1627-1631, 1972[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jaffe, N. Articles by Gorlick, R. Search for Related Content PubMed PubMed Citation Articles by Jaffe, N. Articles by Gorlick, R. Social Bookmarking                            What's this?