Portal de Periódicos da CAPES

THE CLASSIC: Osteogenic Sarcoma

2005; Lippincott Williams & Wilkins; Volume: &NA;; Issue: 438 Linguagem: Inglês

10.1097/01.blo.0000183424.18268.1a

1528-1132

Stanford Cade, G Westbury,

Bone Tumor Diagnosis and Treatments

Stanford Cade was born in St. Petersburg, received his early schooling in Antwerp, and entered the Medical School of the University of Brussels in 1913. In 1914, he joined the Belgian Army, and at the fall of Antwerp, he was evacuated to England where he resumed his medical studies. He qualified at Westminster Hospital, where he was appointed to the Surgical Staff in 1924. He was a broadly experienced general surgeon, but developed a special and overriding interest in the treatment of malignant diseases not only by surgery but also by radiotherapy and, in due course, chemotherapy. He was, thanks to the encouragement of Ernest Rock Carling, one of the pioneers of the use of radium, especially for oral cancer. His enormous experience in this field is encapsulated in his book Malignant Disease and Its Treatment by Radium, first published in 1940 with a four-volume second edition in 1948, which remains a classic. He also wrote extensively on breast cancer, melanoma, and tumors of the musculoskeletal system. The approach discussed in his 1955 paper on the primary management of osteogenic sarcoma by irradiation formed a rational and humane basis of management that was widely followed until the concept was superseded by advances in cytotoxic therapy and limb conservation surgery. Cades’s hospital career was interrupted by the Second World War in which he served in the medical branch of The Royal Air Force, making significant contributions to the safety of fighter pilots and reaching the rank of Air Vice-Marshal. He was knighted in 1945. He retired from the active staff of Westminster Hospital in 1960 and was subsequently Consulting Surgeon, until his death in 1973. DEFINITION The term osteogenic sarcoma was first used by Ewing to describe a disease entity that has many characteristics. Its significance is that the tumor is derived from bone and its origin is from osteoblasts, not from associated structures such as the bone-marrow or the endothelial cells of the blood vessels. It is, in fact, the only malignant tumour derived from bone or bone forming tissue. METHODS OF TREATMENT The time-honoured, established and universally accepted method of treatment of osteogenic sarcoma is amputation or, occasionally, misguided local excision of the tumour. Dissatisfaction with the results of this treatment has resulted in the search for other therapeutic measures, the use of Coley’s fluid and, later, radiotherapy. In spite of surgical ablation, death of the majority of patients occurs from widespread metastases, mostly in the lungs. An analysis of the survival rates and the time of survival shows that most patients die within the first year, and that 80 percent of deaths occur within the first 2 years, irrespective of treatment. Attempts at radiotherapy were first made in inoperable or irremovable tumours and in postamputation recurrences, and later as a preoperative treatment. Greater confidence in the possible achievements of radiation have gradually led to the prolongation of such treatment, to longer periods of observation after radiotherapy and before amputation, and finally to radiotherapy as the sole method of treatment in a few and carefully selected cases. There is now abundant evidence that radiotherapy can alter the course of an osteogenic sarcoma, produce changes in the growth itself, arrest or slow down its course. It is, however, more difficult to produce evidence that control of the disease is achieved in cases where subsequent amputation is undertaken. The rationale of the treatment also needs very careful analysis. The fact that most patients die of pulmonary metastases regardless of early amputation as the sole treatment indicates that osteogenic sarcoma metastasises not only often but also early; probably most patients when first treated have already developed metastases. A large proportion of such patients can be given palliation with relief of symptoms without ablation of limbs. Control of the disease for a few moths or 1 year results in a natural selection of the favourable, less malignant, nondisseminated cases who can still be offered delayed amputation but with greater hope of escaping metastases and of enjoying prolonged survival than if the whole group was treated by early amputation. Thus a considerable number of patients are spared the mutilation and disturbance of a major surgical procedute without in any way prejudicing their chances of survival. It is customary to refer to osteogenic sarcoma as a “radioresistant” tumour. This, of course, is quite true if the response to radiation from conventional X-rays at 250 k.V. is considered. It is a fallacious argument if a much higher tumour dose, e.g., 8000 to 10,000r, can be reached. This can be done by supervoltage radiation with large telecobalt units, or X-rays at 2 million to 4 million volts (the Van de Graaf generator, the 4 million volt linear accelerator, the 2000 curie cobalt unit). Whereas very little could be achieved with conventional X-rays, unless treatment was prolonged over many months (Baclesse, 1950, 1952), considerable encouragement was obtained with teleradium, and later with supervoltage X-rays, by the use of which regression of tumour could be obtained with only slight damage to normal tissues. CHANGES FOLLOWING RADIOTHERAPY When radium or supervoltage X-rays are used with skill and accuracy, marked changes are noted in the majority of tumours. A small number of cases prove primarily radioresistant and in these no benefit is achieved. The postradiation effects can be studied clinically, radiologically, and histologically. Clinical Changes Except in the primarily resistant cases, the tumour diminishes in size and occasionally disappears completely. The rate of shrinkage varies with the type of tumour, osteolytic tumours regressing more rapidly than the osteoblastic type. Concomittant with this, there is relief from pain. Most patients obtain relief within 2 weeks and require little if any sedatives. Further clinical evidence of improvement is the return of function, with greater mobility of the neighbouring joint, absorption of excess synovial fluid, and improved muscle tone. Regression of the tumour leaves most patients with a functionally useful limb. Radiological Changes The arrest of active growth is followed by changes similar to those of repair following injury. Osteolytic lesions show recalcification and reossification. In osteoblastic lesions, the new bone increases in density and further spread of the tumour does not occur. The interstices between the sun-ray spicules and between the intervening layers in the “onion peel” type of new bone become filled with bone to form a solid mass not unlike callus, which gradually shrinks in size. The radiological appearance eventually is that of an osteoma. Histological Changes The postradiation changes in osteogenic sarcoma are similar to those seen in soft tissues, e.g., the uterus, the tongue, and the breast. Mitoses are rarely seen; abnormal mitoses, monstrosities, and giant cells occur; fibrosis follows. The stroma shows newly formed fibrous tissue that gradually replaces the tumour by a mass of scar tissue which eventually consolidates, and in some cases undergoes ossification. Careful examination of numerous sections from amputation specimens following radiotherapy show that the histological changes depend primarily on the tissue dose; they vary also according to the time that has elapsed since radiation. In radiosensitive tumours that respond satisfactorily to big total doses, such as 7000r–9000r spread over 8 to 12 weeks of treatment, the changes are characteristic; mitosis is arrested, the typical spindle-shaped tumour cell disappears, and the polymorphism of the stroma is gradually altered to a network of fibrous tissue. In some sections only pigment is shown, in some residual tumour cells, less active and possibly not capable of surviving; with very big doses, there remains merely a connective tissue network with no cellular elements. This network gradually fills up with new bone, which undergoes calcification and ossification and eventually resembles an osteoma or callus. These changes are as marked and as convincing as the histological changes reported in carcinoma of the cervix and in carcinoma of the breast. It must be realised that as osteogenic sarcoma is generally a bulky tumour, the histological changes following radiotherapy show variations in the same tumour from total destruction to areas where viable cancer cells are still seen. ILLUSTRATIVE CASES The following six cases have been selected from a total of 49 patients with osteogenic sarcoma treated with supervoltage at 2 million volts to total doses of up to 9000r. They illustrate, both histologically and radiologically, the changes that occur in osteogenic sarcoma following radiotherapy to high doses. Satisfactory response to radiation may lead to partial or complete regression of the local tumour and an apparent arrest of the disease; but only a proportion of cases escape subsequent blood borne metastatic spread. THE ILL-EFFECTS OF RADIATION In osteogenic sarcoma, as in other tumours, radiation may be followed by severe after-effects: telangiectasis, intense fibrosis, atrophy of the normal cellular tissue, disappearance of fat, and endarteritis obliterans. These effects are nearly always due to some error in technique, too rapid an over-all time of treatment, too high a dosage rate or an attempt to achieve a high tissue dose with conventional X-rays at 250 k.V. The effect of such treatment is shrinkage of the limb, flexion deformities, loss of function, severe damage to skin and subcutaneous tissue resulting in changes suitably described as “leathering.” They are, in fact, similar to the changes in the pelvis described as “plaster of Paris pelvis,” following injudicious radiotherapy for cancer of the uterus. Such changes are nevertheless unimportant if amputation of the limb is to be undertaken, and the radiotherapeutic treatment is only a preoperative measure. CORRELATION BETWEEN DOSE AND EFFECT In the past much of the difficulty in the radiotherapy of bone tumours was due to lack of suitable apparatus and to consequent underdosage. Clinically, it was observed at Westminster Hospital during the past 25 years that the results occasionally obtained with teleradium were better than those with conventional X-rays at 200–250 k.V. It seemed, too, that not only the total dose mattered but that the quality of radiation was also of importance. Bone affects the dose distribution by reducing the dose reaching the soft tissues beyond it, and by raising it in the soft tissues within the bone (the Haversian canals and their contents) by virtue of the greater energy absorption in the mineral bone itself. The work of Wilson (1945, 1950) and of Spiers (1949, 1951) showed that the use of wavelengths of gamma rays and of X-rays generated at one or more million volts resulted in an absorption of energy in the soft tissue nearly equal to that of bone. In practice the 2 MeV apparatus has facilitated the treatment of bone tumours and has given better results with much less damage to normal tissues. The correlation between dose and clinical response to radiotherapy in bone tumours was studied by Woodard and Coley (1947) and is shown in Table 4. It is, therefore, of great practical importance to aim at a dose far in excess of what can be achieved with X-rays at 250 k.V. by conventional methods. Treatment must of necessity be prolonged over 10 to 12 weeks, gamma rays of X-rays at 2 to 4 million volt should be used, and the average total dose aimed at should be 8000r to 8500r. In some cases where a decision as to early amputation has been reached before radiotherapy is begun, the dose can be deliberately raised to 9000r or 10,000r. The correlation between dose and effect on tumour is well recognised. In the series treated by radium at Westminster Hospital (1925–1950), the successful cases received between 8000r and 9000r (S. Cade, 1952). Similarly F. Baclesse at the Foundation Curie in Paris quotes a small series of nine cases where survival up to 15 years followed radiotherapy to a total dose of 9000r (A. Baclesse, 1950, 1952). Histological examination of specimens taken from limbs amputated several months after radiotherapy also showed that with the very high tissue dose the tumours were profoundly affected, some of them showing complete absence of active malignant tissue, others marked variation from the appearance seen in the biopsy sections taken before radiation. RESULTS OF TREATMENT The period under review, 1925–1955, can be divided into two: the radium period 1925–1950, during which 84 patients were treated with teleradium units ranging from 2 to 10 gm.; and the period 1951 to date when 49 patients were treated with the 2 MeV Van de Graaf generator. In every case there has been undoubted histological proof, mostly confirmed by more than one pathologist. Of the 84 patients treated between 1925 and 1950, there are ten survivors for periods varying from five to 30 years. These ten patients with prolonged survival periods include 2 cases, one of the femur, the other of the humerus where only teleradium was used and the limbs were not amputated. The other eight patients had some form of surgery—4 amputations, 2 excisions, and 2 fenestration operations on the maxilla. The second series consists of 49 patients treated by the 2 MeV X-rays from 1951 to date. No five-year survivals are yet available. The analysis of these patients is of considerable interest. Of the total, 21 patients were submitted to amputation or disarticulation following radiotherapy, and these are shown in Table 6. The remaining 28 patients were treated by supervoltage only, none being submitted to surgery. A study of these two Tables shows the period between radiotherapy and surgery, the results obtained, and the length of survival. Table 8 summarises the method of treatment and results in the 49 patients treated with supervoltage radiotherapy. THE RATIONALE OF RADIOTHERAPY IN OSTEOGENIC SARCOMA The following is still asked by some surgeons and radiotherapists: (1) Why take the trouble to spend weeks in radiotherapeutic treatment if the limb is to be amputated eventually? Why not amputate at once? (2) Does not the delay in amputation increase the chances of pulmonary metastases? Thirty years experience, and the observation of a carefully studied series, of 133 patients have led to the following conclusions: (1) Delay in amputation does not seem to be as harmful in osteogenic sarcoma as in the common epithelial neoplasms of the breast, stomach, tongue, uterus. (2) Very early amputation in no way prevents the development of metastases. (3) The observations of A. B. Ferguson (1940), based on the analysis of 400 cases of osteogenic sarcoma, showed that whereas in early amputation only 5% of five-year freedom from symptoms was achieved, in the late amputation series, 34% were free of symptoms for five years. (4) To continue to ablate limbs as has been the practice from the early days of surgery is unlikely to lead to any improvement in results. It is the very poor and disappointing results of amputation that dictate an urgent policy of trying some other form of treatment. (5) Radiotherapy with gamma rays or X-rays generated at 2 to 4 MeV have been shown to produce regression of tumours, histologically, radiologically and clinically. (6) Radiotherapy delays amputation by a few months; during this period a number of patients already show evidence of pulmonary metastases; these patients would not in any case by controlled by ablation of limbs and thus are spared unnecessary mutilation. This, too, forms a natural selection of cases, those with early metastases receiving palliative radiotherapy and only the more promising cases being submitted to amputation. (7) A small proportion of patients escape surgery altogether and survive many years with a normal limb. (8) In patients with osteogenic sarcoma of the vertebrae, skull, and sacrum radiotherapy remains in fact the only possible form of treatment. It seems justifiable, therefore, to give patients the additional benefit of radiotherapy. For the past 20 years many reports on the effect of radiation on bone sarcoma have been published. The most important are as follows: J. C. Bloodgood (1935), Baltimore; B. L. Coley (1935), New York; M. Friedman (1933), New York; G. Hilton (1937), University College, London; R. F. Phillips (1934), St. Bartholomew’s Hospital, London; J. S. Fulton (1939), Glasgow; A. Lacassagne (1930), Paris; A. B. Ferguson (1940), New York; E. Poppe (1949), Oslo; Helen Q. Woodard and B. L. Coley (1947), New York; F. Baclesse (1952), Paris; S. Cade (1934–1939, 1947, 1952, 1955). Preoperative radiotherapy is an accepted method of treatment in cancer of the uterus, in the breast, in the larynx, and in soft tissue sarcoma and there is no reason why it should not be applicable to bone sarcoma. SUMMARY AND CONCLUSIONS A series of 133 patients with histologically proved osteogenic sarcoma is reviewed. All these patients have been treated by radiotherapy either with radium or with supervoltage X-rays at 2 MeV. Regression of the tumour was obtained in a proportion of cases, and a few were spared amputation. In most cases treated by radiotherapy, amputation was postponed for periods varying from two to 18 months. Pulmonary metastases occur very early, mostly within the first six months, and the majority of deaths occur within one year. No speculative theories are submitted to explain the benefit of radiotherapy in osteogenic sarcoma; it is probably the same as in soft tissue tumours, both epithelial and mesodermal in origin. Radioresistance of osteogenic sarcoma is not a contraindication to treatment by radiotherapy, but indicates the need of supervoltage apparatus and dictates the policy of slow treatment protracted over eight to 12 weeks. ACKNOWLEDGMENTS I thank my colleagues at Westminster Hospital for their help in the care of these patients. To Drs. F. M. Allchin, T. M. Prosser and K. A Newton of the Radiotherapy Department; to Mr. E. P. Brockman and Mr. H. E. Harding, orthopaedic surgeons; to Drs. G. Lumb and D. H. Mackenzie for pathological studies; to Dr. Hansell for the illustrations; to Miss P. Wheatley, M. B. E., for the care of all the patients, their records and follow-up over many years; and to Messrs. G. D. Leach and E. V. Wilmot of the Imperial Cancer Research Fund for the photomicrographs.