Commentary (Healey): Current Combined Treatment of High-Grade Osteosarcomas

There are few success stories in solid tumor oncology that match osteogenic sarcoma. Drs. Damron and Pritchard have chronicled this story, and present a multidisciplinary overview of the current management of conventional osteogenic sarcoma. However, only by amplifying their summary somewhat can the reader get a true perspective on the complexities of modern management of the disease and an understanding of where the field is headed.

To help the reader achieve such understanding, I would like to expand upon certain aspects of the diagnosis of osteogenic sarcoma, and also on the chemotherapy and surgery for this malignancy. First, it is critical to recognize how successful we have become with the management of this disease. The 10-year disease-free survival rate at Memorial Sloan-Kettering Cancer Center is 72% [1]. With current regimens, a disease-free survival rate of greater than 80% is anticipated.

From such lofty levels, it is extremely difficult to show improvement with any new diagnostic or therapeutic program. Multi-institutional studies will be necessary to advance the field further. Conventional osteogenic sarcoma should be dealt with only in that setting. High-risk cohorts, such as patients with large proximal tumors, metastatic disease, or tumors unresponsive to routine treatment constitute appropriate groups for small, single-institution studies. The patient's and society's interests are best served by caring for osteogenic sarcoma patients in centers with concentrated multidisciplinary expertise and a patient volume large enough to maintain a level of excellent care.

Diagnosis

Diagnosis of osteogenic sarcoma can be aided by modalities other than alkaline phosphatase and MRI. The lactate dehydrogenase (LDH) for example, is at least as predictive of outcome as the alkaline phosphatase [2]. It probably is a surrogate for tumor size. Thallium scan, reflecting both tumor cellularity and blood flow, is an excellent indicator of disease and chemotherapy response [3]. When normalized for blood pool images seen with technetium scan, thallium scan is of even greater value.

Plain radiographs, however, remain the most specific diagnostic test for osteogenic sarcoma. Such imaging also has value in showing bone normalization during the chemotherapy process, identifying fractures, depicting overall bone dimension, and showing the growth potential of the physis [4]. Plain radiographs also are necessary for proper interpretation of the pathologic specimen. They should be the primary imaging technique, and MRI used selectively thereafter.

Tumor location is of great prognostic significance. At our institution, femoral lesions were 3 times as likely to suffer relapse as were proximal humeral lesions [2]. At the Mayo Clinic, local recurrence rates varied dramatically by location, with nearly a 25% local recurrence rate for pelvic lesions, and more conventional levels of recurrence for tumors in other locations.

Staging

Tumor staging is well described in the article, though refinements have been suggested, based on follow-up studies. For instance, we now know that skip metastases within the same bony compartment actually behave in a manner similar to distant metastases [5]. Tumors that extend outside of the bony compartment but are contained within the periosteum represent an intermediate stage between IIA and IIB.

Follow-up radiographic imaging is very difficult when searching for local recurrence. Since prostheses and metal implants obscure appropriate MRI and CT images, arteriography continues to have a role in this difficult situation. Finally, molecular diagnostic studies promise to have great importance in identifying subclasses of tumors, and perhaps in guiding therapy in the future [6].

About the Natural History and Chemotherapy

It would be advisable, I believe, to lay to rest the historic controversy of potential change in the natural history of osteogenic sarcoma. In actuality, there is not and never was any significant change, though there was a recent observation in Scandinavia [7] that the average age at diagnosis is higher now than it was a decade ago. The natural history controversy forced the multi-institutional osteosarcoma study as a randomized trial [8]. We in orthopedic oncology owe a large debt to the 9 patients who represented the unfortunate excess mortality needed to prove that chemotherapy was necessary in osteogenic sarcoma, a conclusion that was apparent to many before this trial began.

Multi-agent chemotherapy is the cornerstone of current management, and Pritchard and Damron appropriately stress the importance of doxorubicin dose intensity. I would add that the other effective agents, methotrexate and ifosfamide, are probably very much dose-dependent in their effects on this disease.

Current Surgical Approaches

Many changes have occurred in the surgery of osteogenic sarcoma. Most important is the understanding of proper biopsy technique, which remains a serious problem, despite the fact that many investigators have stated in the literature that lesions should only be biopsied by those capable of handling the ultimate surgical procedure.

Advances in soft-tissue reconstruction, including free, vascularized soft-tissue transfer, have helped to solve many previously unmanageable situations [9]. Such surgery allows a more functional bone and joint reconstruction with lower complication rates, such as wound-healing difficulty and infection. More than any other factor, such surgery has reduced the need for amputation in recent years.

Difficult Problems

Reconstructive operations represent a complex, difficult set of problems not addressed in the article. Turniplasty is an effective, long-term, functionally sound approach. In essence, it is an extension of the amputation stump, retaining the function, excellent sensation, and a normal weight-bearing surface of the foot, rather than a standard amputation stump.

Expandable prostheses have become very popular. Unfortunately, as a rule, they are mechanically unsound, particularly in very small prostheses for young children. On the positive side, bone transport and the Ilizarov technique have the potential to preserve the articular surface, and are particularly suited for younger children.

Finally, optimal care of a patient with osteogenic sarcoma goes well beyond the initial management of the primary site. Late metastases are now a well-recognized phenomenon. Indeed, chemotherapy has changed the natural history of the disease [10]. Reconstructions may suffer long-term complications, and there is significant attrition of limbs following current forms of limb-sparing surgery. Some of our greatest surgical challenges are trying to recoup these failed prosthetic reconstructions. Innovative techniques are required to handle these problems.

In conclusion, Pritchard and Damron's approach of intensive chemotherapy, tumor resection with a wide surgical margin, reconstruction based on the extent of resection, and aggressive metastectomy (as many times as necessary) represents the state of the art.

References:

1. Springfield DS, Schmidt R, Graham-Pole MRB Jr, et al: Surgical treatment for osteosarcoma. J Bone Joint Surg 70:1124-1130, 1988.

2. Meyers PA, Heller G, Healey J, et al: Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial Sloan-Kettering experience. J Clin Onc 10:5-15, 1992.

3. Rosen G, Loren GJ, Brien EW, et al: Serial thallium-201 scintigraphy in osteosarcoma. Correlation with tumor necrosis after preoperative chemotherapy. Clin Orthop 302-306, 1993.

4. Fletcher BD: Response of osteosarcoma and Ewing sarcoma to chemotherapy; imaging evaluation. Am J Roentgenol 157:825-833, 1991.

5. Wuisman P, Enneking WF: Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg 72:60-68, 1990.

6. Wunder JS, Bell RS, Wold L, et al: Expression of the multidrug resistance gene in osteosarcoma. J Orthop Res 11:396-403, 1993.

7. Stark A, Kreicbergs A, Nilsonne U, et al: The age of osteosarcoma patients is increasing. An epidemiological study of osteosarcoma in Sweden 1971 to 1984. J Bone Joint Surg (Br) 72:89-93, 1990.

8. Link MP, Goorin AM, Horowitz M, et al: Adjuvant chemotherapy of high grade osteosarcoma of the extremity. Updated results of the Multi-institutional Osteosarcoma Study. Clin Orthop 8-14, 1991.

9. Aboulafia AJ, Malawer MM: Surgical management of pelvic and extremity osteosarcoma. Cancer 71:3358-3366, 1993.

10. Goorin AM, Shuster JJ, Baker A, et al: Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: Results from the multi-institutional osteosarcoma study. J Clin Oncol 9:600-605, 1991.