Chemotherapy in bone tumors

Historically, before the era of chemotherapy, survival in osteosarcomas was in the order of 20%. In 1977 the use of chemotherapy revolutionized treatment and the present 5-year survivals are 60 to 76 %.

At present the standard approach to the treatment of osteosarcoma has been neoadjuvant therapy followed by definitive resection and then adjuvant chemotherapy. This approach has been more traditional than empirical. Still the availability of comparison tissue at the time of definitive resection has been an important tool in prognostication. Good necrosis in post-resection specimens is an important indicator of good prognosis in osteosarcoma as well as Ewing’s sarcoma patients. Even so it should be born in mind that historically, 20% of patients had been cured by their disease and even now up to 24 to 40% percent are not cured of their disease. This means that 44 to 64% of patients ultimately do no benefit from chemotherapy. This makes the case for the approach of primary wide resection and reconstruction followed by chemotherapy. Many factors influence this decision. An important determinant of poor survival is a delay in chemotherapy. Hence a patient who undergoes high risk surgery through an irradiated bed may be at risk of postoperative infection and ultimately have a delay in chemotherapy. Yet an older patient who can’t tolerate high dose chemotherapy and ultimately be under-dosed for his specific tumor may benefit from a primary resection followed by adjuvant chemotherapy. This latter approach has the added advantage of performing surgery in a healthy patient as opposed to the patient under chemotherapy who is less able to heal and as a result have delayed chemotherapy.

The typical agents used can be classified into cell cycle specific and cell cycle non-specific agents. Cell cycle specific agents include methotrexate and doxorubicin. These interfere with cell division and hence affect cells that are actively proliferating. In any cell population there are quiescent cells. These cells would not be affected by cell cycle specific agents. For this purpose the cell cycle non-specific agents are used. Cisplatin and cyclophosphamide directly damage the DNA of a cell and so even quiescent cells are affected. This Goldie – Coldman model of chemotherapeutic administration is the most commonly used in the treatment of osteosarcomas and Ewing’s sarcomas.

Chemotherapy as the sole agent in the treatment of osteosarcoma has been reported to have inferior results. The complications with this approach include increased local recurrence and metastases. Cure was convincingly achieved in only 10% of patients. Recently, it has been discovered that bisphosphonates may have important anticancer properties which are presently being investigated clinically in some centers. Similarly, Liposomal Muramyl Tripeptide Phosphatidyl Ethanolamine (L-MTP-PE) has shown promise in multi-center evaluations as an experimental drug in osteosarcoma. The overall effect (ie. survival improvement over standard therapy) has been modest. There was no statistical difference in survival for metastatic disease. There was modest improvement in survival for localised disease and then only in overall survival. It is being evaluated for relapsed disease.