Commentary (Rosen/Forscher): Current Combined Treatment of High-Grade Osteosarcomas

Modern Therapy for Osteogenic Sarcoma: Reinventing the Wheel at the Mayo Clinic

In this issue of ONCOLOGY, Damron and Pritchard discuss combined therapy for high-grade osteosarcoma. This is a nice review of the current status of osteogenic sarcoma, certainly from the point of view of modern surgical management, and for the general practitioner. However, for those of us who treat this disease medically, the review is somewhat naive and simplistic in its discussion of chemotherapy. It is therefore important to correct various misconceptions about the chemotherapy of osteogenic sarcoma, and discuss it in greater detail in an effort to be useful to treating physicians.

The original experience of the Mayo Clinic with adjuvant high-dose methotrexate cited by the authors (where there was no difference in survival in those patients who received high-dose methotrexate and those who did not) is a prime example of how one can use randomized studies to draw the wrong conclusions [1]. That original study used high-dose methotrexate at doses which were considered inadequate in light of the currently recommended dose of 12 gm/m². Pritchard and Damron now conclude that because of the complications associated with the administration of high-dose methotrexate, there is "continued interest in either eliminating methotrexate altogether or lowering its dose intensity." This statement shows a considerable lack of understanding of the chemotherapeutic management of this disease. The precise reason for the failure of their earlier study with adjuvant methotrexate was that too low a dose of methotrexate was used, and although it was completely ineffective, it was still potentially just as toxic in the hands of those without extensive experience in administering it. It has been the experience of those of us who have successfully treated osteogenic sarcoma with neoadjuvant chemotherapy, and have observed the effect of chemotherapy on primary tumor and the subsequent survival rates following various chemotherapy regimens over several years, that high-dose methotrexate with leucovorin rescue is still the most important regimen that we use in the treatment of osteogenic sarcoma.

Our experience in treating over 300 patients with preoperative chemotherapy, as well as the experience of the German/Austrian Cooperative Osteogenic Sarcoma Group, the Scandinavian Sarcoma Study Group, and the experience of the French and Italian investigators who have been prolific in this field, points to the fact that, in order for high-dose methotrexate to be effective in the treatment of osteogenic sarcoma, one must achieve a minimum peak serum concentration of methotrexate [2-6]. That peak serum concentration for most investigators who have been extensively involved in the treatment of this disease appears to be somewhere above 1,000 micromolar (10-3M) at the completion of the high-dose methotrexate infusion, which is usually 4, or sometimes 6, hours.

In order to achieve these drug levels, it is necessary to give the minimum dose of 12 gm/m² to patients with osteogenic sarcoma. Indeed, some of us have found that when the peak serum concentration is suboptimal, the dose must be increased to even more than 12 gm/m².

Furthermore, to achieve these peak serum levels that correlate with 100% tumor necrosis and good survival, it is suggested that patients not receive copious amounts of intravenous hydration (as has been practiced in the past and to which we have always objected) because of the fact that it can abrogate the effect of high-dose methotrexate on the primary tumor. While fluid restriction appears to be important during the first 24 hours, fluid hydration, on the other hand, might be needed after 24 hours to help patients clear the drug if they are not doing so adequately on their own. The pharmacokinetics of effective and safe high-dose methotrexate administration have been extensively worked out, and have been published both recently and more than 10 years ago (also cited in the authors' current review of treatment for osteogenic sarcoma) [7].

Adequate Methotrexate is Essential

When administered in the proper fashion, high-dose methotrexate is the least toxic of all the drugs that we use in the treatment of osteogenic sarcoma. The exciting thing about the chemotherapy for osteogenic sarcoma today is the fact that our French and German colleagues have really pinned down what has been our experience in the past: the fact that high-dose methotrexate needs to be administered in a fashion that will produce a minimum peak serum methotrexate concentration that will lead to effective treatment (as is alluded to above, in the range of .001M). This pharmacokinetic parameter can help all of us make the treatment effective for each individual patient. Contrary to the opinion of Damron and Pritchard, doxorubicin is not the most essential drug in the treatment of this disease. As noted above, it is high-dose methotrexate with leucovorin rescue, which needs to be administered frequently and at optimal high doses (not reduced doses).

The drug with the highest response rate in metastatic osteogenic sarcoma is high-dose ifosfamide (Ifex). In our experience, high-dose ifosfamide at the dose of 18 gm/m² has led to response rates of 67% to 75% in patients with measurable, evaluable disease. The lower response rate was observed in patients who had had prior treatment with cisplatin (Platinol) plus doxorubicin (Adriamycin), or BCD and high-dose methotrexate. It should be noted that this high response rate to single-agent, high-dose ifosfamide is about three times the response rateof ilower doses of ifosfamide (10 gm/m²) reported by other investigators when ifosfamide was being studied as a phase II agent. It is our feeling that, like high-dose methotrexate, high-dose ifosfamide should be given in its maximally effective dose, which usually calls for doses of 14 gm/m² to 18 gm/m² as a single agent.

Regarding Doxorubicin

Early experience with doxorubicin showed that there was a definite dose- response curve to this agent in studying patients with metastatic evaluable disease. The dose of 90 mg/m² gave the highest response rate (approximately 30%), with lower response rates at 60 mg/m². All these responses were obtained by giving doxorubicin by intravenous push and not via continuous infusion. Although continuous infusion may hopefully cut down on the degree of cardiac toxicity noted by many investigators, there is really no evidence that continuous infusion doxorubicin is as effective as IV push chemotherapy in the treatment of osteosarcoma.

It is our current practice to give only two doses of single agent doxorubicin-100 mg/m² in two divided doses of 50 mg/m²/day for 2 consecutive days. We run the drug in over a period of 1 hour. Toxicity is not a problem at this dose level with the support of granulocyte colony stimulating factor (G-CSF, Leukine, Prokine). A patient's total doxorubicin dose is kept to no more than 350 mg/m² (see below).

Cisplatin combined with doxorubicin is perhaps the most toxic combination that we use today. This drug combination produces irreversible renal toxicity and ototoxicity, as well as severe nausea and vomiting in many of our patients. We originally introduced this combination into the T-10 chemotherapy protocol as alternative chemotherapy for those patients who did not have a complete response to preoperative chemotherapy using high-dose methotrexate with leucovorin rescue. Our experience over the years has shown that treating such patients with the maximally tolerable dose of cisplatin combined with doxorubicin did not significantly alter the poorer survival that we obtained in those patients who did not have 100% tumor necrosis following preoperative high-dose methotrexate. We currently feel that cisplatin combined with doxorubicin is an effective treatment, but we limit it to only two doses in our osteogenic sarcoma regimen, and hope to obtain a complete response rate in the majority of patients through the better utilization of high-dose methotrexate.

Not a Simple Recipe

It is important to make these specific points to clarify the fact that chemotherapy for osteogenic sarcoma is really not as simple as following a recipe by putting in all the ingredients that are available in the drug "line-up." All of the drugs have to be used in their optimally established dosage regimens in order to be maximally effective. Although many studies look good with only 2 or 3 years of follow-up, it is really only those in which patients have had complete responses to preoperative chemotherapy using high-dose methotrexate, as discussed above, in which durable survival rates of 70% to 80% have been maintained.

A sufficient follow-up time is also needed to assess any new trends in the surgical management of this disease. It is rather disturbing that the authors at the Mayo Clinic consider a preliminary report about survival with marginal excision in patients who have had a good response to preoperative chemotherapy "enticing." While effective chemotherapy can certainly produce a substantially high cure rate in this disease, we have no long-term evidence that it can make up for poor or marginal surgery. Effective chemotherapy can shrink the primary tumor and facilitate limb-salvage surgery; however, surgical margins must be sufficiently clear to avoid a local recurrence. We have seen local recurrences in marginal excisions occur years after surgery in patients who have had a good response to preoperative chemotherapy. Thus, a good response to preoperative chemotherapy will not lessen the need for adequate surgical margins; in the absence of clear margins, chemotherapy may only delay a local recurrence rather than prevent it.

A tumor that has been unresponsive to chemotherapy, of course, will demonstrate a local recurrence much sooner if only a marginal excision is performed. Thus, the early lack of local recurrences in patients with marginal excisions following a good response to preoperative chemotherapy must be viewed with extreme caution. Experience has shown that patients who have had a good response to preoperative chemotherapy (100% necrosis) do develop local recurrences following marginal excisions, though that recurrence may occur as late as 2 to 5 years following surgery.

Aggressive Treatment for Stage III Disease

The value of the synthesis of good chemotherapy and good surgery for osteogenic sarcoma is stressed in the recent good survival rates that have been reported for patients with stage III (or metastatic lung) disease at presentation [8]. Patients who fall into this category should be treated as aggressively as those with primary tumor alone (stage I). Aggressive preoperative chemotherapy followed by limb-salvage surgery when appropriate, continued chemotherapy, and bilateral thoracotomies can lead to cure in a large percentage of patients. However, it is important to take an absolute curative approach to these patients. This means a radical surgical procedure for the primary tumor. In our experience with these stage III patients, the majority of those who fail to survive did so due to the development of either a local recurrence in the primary tumor area owing to a lack of aggressiveness of the surgical oncologist, or due to the fact that patients did not have adequate thoracic surgery at the proper time in their postoperative chemotherapy course. Even after a complete response to chemotherapy on CT scan, occult residual disease must be removed at thoracotomy to prevent pulmonary recurrences. This may require operating on an apparently "negative" chest by a thoracic surgeon experienced in finding residual small calcified or scarred nodules.

Summary

Chemotherapy for osteogenic sarcoma, although highly successful, requires considerable skill in its administration. Drug doses and regimens should be based upon the positive experiences that have now accumulated in patients who were given neoadjuvant chemotherapy for primary tumors. That experience has dictated that high-dose methotrexate is the most important drug in the treatment of osteogenic sarcoma, and it must be used at the maximally effective dose, as defined above. The same is true of all the other drugs we use. The timing and coordination of curative therapy, which is epitomized in the successful management of the patient with pulmonary metastatic disease, requires the close coordination of the team of treating medical oncologists, orthopedic oncologists, and thoracic oncologists.

References:

1. Edmonson JH, Green SJ, Ivins JC, et al: A controlled pilot study of high dose methotrexate as postsurgical treatment for primary osteosarcoma. J Clin Oncol 2:152-156, 1984.

2. Rosen G: Neoplasms of the bone and soft tissue, in Holland JF, and Frei E (eds): Cancer Medicine, 3rd Ed, pp 1825-1858. Philadelphia, Lea & Febiger, 1993.

3. Graf N, Winkler K, Betlemovic M, et al: Methotrexate pharmacokinetics and prognosis in osteosarcoma. Universitatsklinik fur Kinder- und Jugendmedizin, Homburg Saar, Germany. J Clin Oncol 12(7):1443-1451, 1994.

4. Saeter G, Alvegard TA, Elomaa I, et al: Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high dose methotrexate: A Scandinavian Sarcoma Group study. J Clin Oncol 9(10):1766-1775, 1991.

5. Delepine N, Delepine G, Desbois JC: A monocentric therapy study: An approach to optimize the results of the treatment of osteosarcoma by protocols based upon HDMTX, associated with systematic conservative surgery, in Humphrey GB (ed): Osteosarcoma in Adolescents and Young Adults, pp 327-331. Boston, Kluwer Academic Publishers, 1993.

6. Ferrari S, Sassoli V, Orlandi M, et al: Serum methotrexate (MTX) concentrations and prognosis in patients with osteosarcoma of the extremities treated with a multidrug neoadjuvant regimen. J Chemother 5(2):135-141, 1993.

7. Rosen G, Nirenburg A: Chemotherapy for osteogenic sarcoma: An investigative method, not a recipe. Cancer Treat Rep 66:1687-1697, 1982.

8. Rosen G, Holmes CE, Forscher CA, et al: The role of thoracic surgery in the management of metastatic osteogenic sarcoma, in Ginsberg RJ, Faber, LP (guest eds): Chest Surgery Clinics of North America: Current Perspectives in Thoracic Oncology, vol 4(1), pp 75-83. Philadelphia, WB Saunders, 1994.