Aust. N . Z . .ISurg. . 1992.62.691-696
69 1
PERSONAL VIEW SURGICAL ONCOLOGY AND THE ROLE OF REGIONAL CHEMOTHERAPY F. 0. STEPHENS,* D. W. STOREY,.' J . F. THOMPSON" A N D F. W. MARSDEN' *Department of Surgery, The University of Sydney and 'Department of Surgical Oncology, South ' Wules, Australia The Royal Prince Aljired Hospital, Sydney, N ~ M
Introduction The discipline of surgical oncology has been struggling for the past 20 years to establish its proper place in the management of malignant disease and the role of the surgical oncologist in the treatment of cancer has been unclear. Surgeons have tended to feel. often correctly, that the person best equipped to undertake modern surgical care is a surgeon with specialized regional operative expertise and interest, and that it is beyond the capacity of one surgeon to cover all anatomical regions and systems. Medical oncologists have often regarded any surgeon who professed an interest in chemotherapy as an interloper. Radiotherapists have tended to be surprised and have sometimes become suspicious when a surgeon appeared to understand anything more than the most fundamental elements of radiobiology. The place of the surgical oncologist is in the process of becoming more clearly defined. There is no doubt that many cancers are well treated by operation or radiotherapy alone. There is also no doubt that the management of patients with widely disseminated malignant disease has been transformed by the increasingly sophisticated application of systemic chemotherapy. In either of these settings, the surgical oncologist has little to offer over and above that which can be provided by an appropriately trained regional surgeon and/or a medical oncologist or radiotherapist. There remains, however, a group of malignant diseases for which currently accepted radical operative surgery or radiotherapy give poor results and in which the pattern of failure is essentially locoregional. Examples are: advanced cancer of the head and neck; and some malignancies arising in the gastrointestinal tract.
Correspondence: Professor F.O. Stephens, Department of Surgical Oncology. Royal Prince Alfred Hospital, Misscnden Road. Camperdown. NSW 2050, Australia. Accepted for publication 9 April 1992.
There are other malignant diseases that have i propensity for widespread dissemination, but which in certain patients also show a consistent tendency to locoregional patterns of recurrence. Examples of these are melanomas in a limb, soft tissue or bone sarcomas and locally advanced breast cancers. Still other malignancies have patterns of spread, such as to the liver or peritoneal cavity. which tend to be associated with terminal illness yet are frequently seen without more widespread dissemination. Examples are colorectal, gastric, pancreatico-biliary and ovarian cancers and ocular melanomas. These diseases as a group are usually only partially sensitive to radiotherapy or chemotherapy. They present some of the most difficult problems in oncology. It is the regional nature of these diseases which makes it desirable for their management to be carried out by practitioners whose training allows them to plan and initiate appropriate multimodal regional therapy. This is the role of surgical oncologists. Thus surgical oncologists arc far from being merely surgeons who operate on cancer patients, although their possession of surgical skills and experience is extremely important and clearly differentiates them from their colleagues, the medical oncologists. They are in essence surgeons who provide fully integrated regional cancer management for conditions in which this is likely to be more effective than single modality treatment.
Regional chemotherapy An important concept in surgical oncology is the application of regional chemotherapy. This started with the observation by Klopp in 1950 that after accidental injection of nitrogen mustard into an artery rather than a vein there was a much increased tissue reaction in the distribution of the artery.' Klopp therefore postulated that intra-arterial delivery of an effective anti-cancer agent had the potential for a greater local effect than could be achieved by its systemic administration. After the development of effective systemic anticancer agents in the 1950s and 1960s, there was an
602
initial wave of enthusiasm for regional chemotherapy. Surgeons familiar with exposure and cannulation of arteries used these agents intra-arterially as suggested by Klopp. The results were poor and most surgeons abandoned the idea, even though improved results were being achieved by their medical colleagues who were using the same agents to treat patients with disseminated disease. In retrospect one reason for these initial disappointments is apparent; intra-arterial chemotherapy was mostly tried on tumours which were recurrent after operative treatment and/or radiotherapy had failed. The resulting impairment of blood supply defeated the very basis of intra-arterial therapy - that is achievement of a high local concentration of cytotoxic agents. The next logical step, the use of regional chemotherapy as the firstline treatment, was only taken up by a small number of determined individuals. Helman and Bennett in South Africa used this approach in advanced breast cancer in the 1960s.* Nervi ef a / . in Italy reported the application of such principles in head and neck cancers in 1970.3 Fujimoto in Japan first reported the use of regional chemotherapy in gastric cancer in 1976.4 Also in 1976 Morton in the USA reported the use of pre-operative intraarterial chemotherapy as the first treatment modality in the management of patients with limb sarcoma.5 Meanwhile, Creech and Krementz in the USA had established a similar concept for the treatment of locally recurrent limb melanoma by using a cardiopulmonary bypass pump to perfuse the isolated limb with melphalan.6 The University of Sydney Surgical Oncology Unit started similar treatments at about the same time for locally advanced breast cancer, locally advanced head and neck cancer, gastric cancer and locally advanced malignant neoplasms in limb^.^-'^ There was little appreciation by each of these surgical groups of the developments in other centres until 1982, when Karl Aigner in Germany arranged a meeting of many of those involved." From his efforts has arisen The International Society for Regional Cancer Treatment, which is now well established, with biennial conferences and an internationally recognized journal. At the most recent meeting of this Society, in June 1991, it was clear that important advances in regional cancer treatment continue to be made by surgical oncologists around the world. Contributions included discussions of advances in limb perfusion for melanoma, management of intraperitoneal malignancy by various forms of intracavity chemotherapy, hyperthermic cytotoxic perfusion of the isolated pelvis for pelvic recurrence, management of stage I11 breast cancer, management of limb sarcoma and management of hepatic metastases. There were reports of continuing developments in methods to further enhancing the regional to systemic drug
STEPHENS ET A L .
concentration advantage; these included drug delivery on albumin and starch microspheres, manipulation of the local circulation with pharmacological agents, and systemic haemofiltration to extract the agents from the general circulation and thus reduce systemic toxicity. Delivery of cytotoxic agents to hepatic malignancies using lipiodol as a locally concentrating agent or gelfoam as a locally embolizing agent seems to hold particular promise. The isolated perfusion technique has even been extended to the liver, where the vascular isolation techniques learnt in liver transplantation have allowed development of this daunting but nonetheless practicable procedure. 1 6 , " The surgical oncologist must draw on his or her skills as a surgeon in employing all of these techniques. First, establishing a regional intra-arterial delivery system often involves operative placement of a catheter or a portal device, and the more adventurous methods of isolated regional perfusion require vascular surgical skills of a high order. Second, in most of the applications the essence of the method is that the regional cytotoxic therapy is not the definitive treatment; rather it is given with the aim of destroying as many malignant cells as possible but particularly those cells at the periphery of the field which will be encompassed by subsequent radical surgery or radiotherapy. Ix
Induction chemotherapy In the past, most systemic chemotherapy has been applied as postoperative adjuvant therapy after local resection of solid tumours. The recognition that intra-arterial chemotherapy should be given before operation led to the concept of using adjuvant therapies in general before rather than after operative surgery. This approach has been referred to as neoadjuvant or preferably induction chemotherapy. The obvious question to be asked is whether systemic rather than regional chemotherapy could be used as induction treatment? This would obviate the need for the more complex techniques required for intra-arterial delivery. With the exception of stage Ill cancer of the breast, there has been little study of this important question. However, there now is enough understanding of the pharmacokinetics of drug delivery to suggest that intra-arterial induction therapy will prove to have a local advantage in those malignancies that are known to be poorly responsive to systemic agents at tolerable dosage. Investigation of this question, central to the role of intra-arterial chemotherapy, has been hampered by the lack of animal models that closely mimic the relevant human disease states. One successful model has been the Australian sheep, which develops squamous cell carcinoma on the exposed skin of nose and ears and thus lends itself to direct observation of the regional effects of intra-arterial therapy.
SURGICAL ONCOLOGY
This is an excellent model, but it is difficult to obtain affected sheep and although early studies have confirmed the superiority of regional over systemic treatment for some agents," progress in elucidating the details of the pharmacokinetics has necessarily been slow.
Local experience with regional chemotherapy The principle of using intra-arterial induction chemotherapy before any other treatment has been applied in the Department of Surgical Oncology at the University of Sydney since 1970.'-'O During the years when the department was essentially alone in Australia in offering this type of therapy, the pattern of patients treated was dictated by the level of acceptance or otherwise by the referring doctors, especially surgeons and general practitioners. Therefore in each group of patients there has been a mixture of moderately advanced lesions that would have been treated more conventionally in other centres, along with patients with very advanced lesions who had already been rejected by appropriately skilled regional surgeons. The patient mix was further varied when the senior author (FOS) moved, in 1984, from Sydney Hospital to the Royal Prince Alfred Hospital causing the disruption of established referral channels and reinforcing the already apparent predominance of very advanced lesions. There has been no possibility of controlled studies in this setting, but many lessons have been learnt (Table I). In each group of patients, the results have been better than would have been expected for the degree of advancement of the tumours and there were dramatic responses in some patients who were clearly beyond other modes of treatment. The delivery methods have vaned over time, with gradual replacement of operative cannula placeTable 1. Some of the lessons learned over 20 years experience in the use of induction regional chemotherapy 1 The intra-arterial cannula needs to be held securely in
place. 2 The position of the catheter, establishing that the flow through it is directed to the tumour site, must he checked (with Patent Blue dye and/or a radionuclide study) before each drug infusion. 3 The rate of infusion must be carefully monitored. Too rapid flow of some agents (e.g. Adriamycin) may result in excessive local tissue damage. 4 There must he appropriate and adequate monitoring of both therapeutic effects and side effects o f treatment, with adjustment of doses and timing of agents used if necessary. 5 An appropriate course of chemotherapy must be completed before subsequent radiotherapy and/or surgical resection, which will he required even when there is apparently total tumour response to chemotherapy.
693
ment by radiological techniques where possible.20 The chemotherapy regimens used have been based on three principles. ( I ) When more than one type of anti-cancer agent is known to be effective against the tumour being treated, then a regimen of multiple compatible agents is generally preferred to a single agent regimen. (2) The multiple agents selected usually do not have the same major side effects, thus avoiding compounding chemotherapy side effects. (3) The agents used act at different stages in the cell division process, thus achieving a 'broadside' action against dividing tumour cells.x-'" BREAST CANCER
Twenty-two patients with breast cancer were treated and all had advanced stage 111 lesions. Although there have been dramatic effects on gross advanced disease and local control was achieved in 17 of the patients," the fact remains that good results are also possible with systemic induction chemotherapy,'2 and patients tend to die of widespread metastatic disease. This condition is thus a good example of the potential value of induction chemotherapy in achieving local tumour control but possibly a poor example of the role of regional cytotoxic treatment, as systemic induction chemotherapy may have achieved similar results. HEAD AND NECK CANCER
Twelve patients with advanced squamous cell carcinoma of the lower lip were treated. All had lesions that were larger than 2 cm and that penetrated underlying muscle. Conventional management of these patients would have involved operative surgery and/or radiotherapy, with expected tumour eradication in about two-thirds of the case^.^^.^^ Cure was achieved in 11 of 12, which is an encouraging result. The one patient who was not cured had extensive involvement of the mandible and widespread involvement of skin and nodes on both sides of the neck. Total tumour eradication was also achieved in over 50% of 37 patients treated for locally advanced cancers of the tongue, floor of mouth, oropharynx and salivary glands. This is clearly better than would have been anticipated from standard therapy, even though randomized studies with matched controls were not performed. The difficulty of arranging appropriately randomized studies to show a significant difference in results using preoperative induction chemotherapy by intra-arterial or intravenous delivery is widely recognized, although a randomized study by Arcangeli et a / . appeared to show an advantage in using intra-arterial induction chemotherapy before radiotherapy. 2s
694
STEPHENS E T A L . GASTRIC CANCkR
For all adenocarcinomas of the gastrointestinal tract, from the oesophagus to the rectum, conventional treatment results are generally poor (with 5 year survival ranging from 45% for colon cancer to 2Y0 for cancer of the pancreas). Recurrent disease tends to be predominantly a locoregional problem. However, only gastric and hepatic cancers lend themselves readily to regional induction chemotherapy because only the stomach and liver have a single infusable artery of supply. the coeliac axis. With the exception of some Japanese experience, reported 5 year survival for patients who have been subjected to a radical gastrectomy with curative intent is rarely better than 30Y0.’~-~’The 35 patients treated with induction intra-arterial chemotherapy followed by radical gastrectomy included a few patients with disease that may have been confined to the submucosa, but most had advanced disease extending to the serosa, and more than half had local lymph node involvement. The 5 year survival of those with nodes free of cancer in the operative specimen was 72%, and for those with involved nodes it was 3 1 ‘/o. For the whole group the 5 year survival was 47%.’”.’’ As with the rest of the experience, many patients were referred because they were felt to have a poor prognosis. These results are therefore considered to be encouraging and a multicentre controlled study using a simplified delivery resimen is planned. LIMB SARCOMA
Osteosarcomas and advanced soft tissue sarcomas in limbs have, in the past, been treated by amputation because of the high risk of local recurrence when less radical local treatments have been used. In treating locally advanced soft tissue sarcomas from 1976 to 1983 a regimen of continuous (about 5 weeks) induction chemotherapy with follow-up radical local tumour resection, with or without radiotherapy was used in 22 patients. In 19 of these 22 patients amputation was avoided without local tumour recurrence and 14 are long-term survivors, apparently free of disease. Since 1983 an intermittent regimen using Cisplatinurn and Adriamycin has been used in another 10 patients with soft tissue sarcomas. One of these required amputation, while the other nine had successful limb salvage procedures. To date six of these 10 have survived free of disease.3’ This intermittent regimen (which does not require prolonged hospitalization) has also been used in treating high grade sarcomas of bone, mostly as induction therapy before surgery, but on some occasions for palliative local control of advanced inoperable tumours of the pelvis and sacrum in conjunction with radiotherapy.” Of 41 patients with high-grade sarcomas of bone
who were treated between 1983 and 1991, three had advanced inoperable tumours with distant metastatic disease, five required amputation and the remaining 33 patients experienced successful limb salvage.34 Calculated actuarial survival of patients with osteosarcoma treated with a three phase programme of induction intra-arterial chemotherapy, surgical operation and adjuvant systemic chemotherapy was 58y0.~’The probability of survival in those patients with osteosarcoma who remained free of disease at the conclusion of this three phase programme has been estimated as 85% . 3 h MELANOMA
The most important principle of induction chemotherapy is that the treatment be given before a tumour and its blood supply have been disturbed by operative surgery or radiotherapy. This principle suggests that in patients presenting with locally advanced limb melanoma, isolated limb perfusion (ILP) with an appropriate cytotoxic agent is most likely to be effective if performed before standard operative surgery. This hypothesis is currently being tested in a large international multicentre trial conducted jointly by the European Organisation for the Research and Treatment of Cancer and the World Health Organization Melanoma Group. Patients with stage I but high risk melanoma in a limb (> 1.5 mm in thickness) are being randomized to receive either standard surgical treatment alone or standard surgical treatment after hyperthermic ILP with melphalan. This drug, administered in high dosage by ILP, has been shown to be very effective when used therapeutically to treat advanced or recurrent melanoma in a limb; complete remission is achieved under these circumstances in 40% of patients and partial remission in another 40% .37 No other drug or drug combination used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan.3x To date. over 700 patients from 17 centres have been entered into the EORTUWHO trial, 47 of them were contributed by the Sydney unit. Although the mean follow-up time is short (27 months), and no firm conclusions can yet be drawn, preliminary analysis of the data indicates a major prolongation of disease-free survival time in the group of patients who have received prophylactic regional perfusion chemotherapy by ILP with melphalan.
-
The future of surgical oncology The central theme of surgical oncology is that some patients with malignant disease are better managed by a combination of treatments rather than by operative surgery, radiotherapy or chemotherapy alone. The basic principles for such management have been described elsewhere.”
SURGICAL ONCOLOGY
It is clear that this is not the case for all malignant disease. The surgical oncologist will therefore be most involved in treating those patients who have malignant tumours with bad prognostic manifestations which even when advanced are due mainly to locoregional rather than systemically disseminated malignancy. A group of malignancies has already been identified for which the combination of regional chemotherapy and operative surgery appears to give results that are better than those for operative surgery alone. An important task for surgical oncologists is to conduct appropriately controlled trials to test the efficacy of this form of treatment in a more rigorous way. At the same time, new potentials for regional treatments are appearing which extend the role of the surgical oncologist. These include better delivery systems for intra-arterial drug administration and extrapolation of the concept of isolated perfusion to regions other than the limbs (e.g. isolated pelvic perfusion, isolated liver perfusion). These methods will require a period of evaluation before they reach a stage where formal trials are appropriate. The role of the surgical oncologist will be mainly as consultant, stimulator, organizer and teacher. It is not easy to convince surgeons that their patient’s interest may be better served by delaying operation, possibly for several weeks, to allow induction chemotherapy to be applied first. Nor is it easy to convince medical oncologists that a drug which they regard as their own may perhaps have a better effect if given regionally and as an integrated preoperative measure. Although the surgical oncologist should be trained in a very wide range of cancer surgery. it is likely that in most institutions there will be other surgeons who are better qualified to perform some radical procedures. When this is so, their expertise should be used. It is likely that in one particular field the surgical oncologist will be the best trained surgeon available and that area plus the more advanced techniques of providing regional drug delivery should provide sufficient operative surgery to sustain enthusiasm and maintain and develop surgical skills. All in all the concept of combining treatment modalities to convert locally advanced malignant tumours normally associated with a poor prognosis (or possibly only curable by mutilating operative surgery such as amputation) into tumours with an overall improved prognosis (and without the need for such mutilating operative procedures) is exciting for all involved, patients and practitioners alike.
References I . KLOPPC. T., BATEMAN J., ALFOKDC. & WINSHIP T. (1950) Fractionated regional cancer chemotherapy. Ann. Surg. 132, 811-32. P. & B ~ N N E TM. T B. (1968) Intra arterial 2. HELMAN
695 cytotoxic therapy and X-ray therapy for cancer of the breast. Br. J . Surg. 55. 419-23. 3 . NEKVIC . , AKCANGLLI G . , C A S A LC. ~ e f a / . (1970) A reappraisal of intra arterial chemotherapy. Cmcer 26, 577-82. S., AKAOT. ITOH B. et a / . (1976) A study of 4 . FUJIMOTO survival in patients with stomach cancer treated by a combination of preoperative intra arterial infusion therapy and surgery. Cuncer 37, 1648-53. D. L . , E l L B t K F. R., T O W N S t N D c. M . J . 5. MOKION et u / . (1976) Limb salvage from multidisciplinary treatment approach for skeletal and soft tissue sarcomas of the extremity. Ann. Surg. 184, 268-78. 6. CKtECH 0 . & KKtMhNIZ E. T . ( 1958) Chemotherapy of cancer: Regional perfusion utilizing an extra corporeal circuit. Ann. Surg. 148, 616-32. 7. SrwHENs F. 0 . (1972) Modern trends in the surgical management of malignant disease. Med. J. Aust. 1, 591-6. 8. STEPHENS F. 0. (1973) Combined therapy in the treatment of advanced localised malignancy. In: Papers of the 4th GSM Royal Australasian College of Surgeons (Ed. S. S. Ratman). pp. 746-54. Eurasia Press, Singapore. 9. S T E P H ~ NF. S 0. (1973) Bleomycin -a new approach in cancer chemotherapy. Med. J. Ausr. 1, 1277-83. 10. SiwHtNs F. 0 . (1974) Combined chemotherapy. radiotherapy and surgery in the treatment of advanced but localised solid malignancy turnours. Ausr. N . Z . J . Surg. 44, 343-53. I I . S T ~ P HF. ~N 0.S(1978) CRAB chemotherapy. ,4171. J . Surg. 135, 375-8. G . J. S . , DICKINSON R. T. J . 12. Sl~LPlltNSF. O., HAKKEK & R0BtKI.s B. A. (1979) Pre-operative basal cheniotherapy in the management of cancer in the stomach: a preliminary report. A m . N.Z. J. Surx. 49, 331-5. 13. STLPHtNS F. o., CKth P., HAKtitK G . J . s., ROHt-KTS B. A . & h h 4 B L Y C. K . (1980) Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer. Laircc,r. 30, 43SSX. 14. S r w H t N s F. 0. (1983) Clinical experience in the use of intra-arterial infusion chemotherapy in the treatment of cancers in the head and neck, the extremities, the breast and stomach. Recent Resu/t.s Cailwr Re.$. 86, 122-7. 15. SrEPtwNs F. 0. (1992) Advances in integrated regional cancer treatment - the past. the present and future trend\. Region. Cuncer Treur. 5 . 16. Vth International Conference o n Advances in Regional Cancer Treatment - Conference Abstracts ( 1991). Region. Caiicer Trecir. 4 , 3-52. 17. TAGUCHI T. (Ed.) (1991) Proceediiigs of rhe filternatronnl Coiferenee on Regiorlul Chemorherrrp?.,fiw Liver Cancer. Churchill Press, Osaka. 18. ST~PHENS F. 0. (1989) The case for a name change from neoadjuvant chemotherapy to induction cheniotherapy. Caricer 63, 1245-6. G. J . S . & S T E P H b N S F. 0. (1991) The use of 19. HARKEK sheep epidermal squamous cell carcinoma to evaluate intra-arterial bleomycin infusion chemotherapy. Region. Caiicer Treat. 4 , I2 1-6. 20. WAUGHR. c. & S r E P H E N S F. 0 . (1990) Indications for surgical or radiological placement of cannulas for intra-arterial induction chemotherapy. Aust. Radiol. 34, 196-9.
696
STEPHENS ET A L .
2 I . STtPHENs F. 0. (1990) Intra-arterial induction chemotherapy in locally advanced stage 111 breast cancer. Cancer 66, 645-50. F., WEILM. et ul. (1988) 22. JACQUiLLAr C . , BAILLET Results of conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy and external interstitial irradiation in 98 patients with locally advanced breast cancer. Cancer 61, 1977-82. 23. HORNBACK N. B. & SHIDNIA H. (1978) Carcinoma of the lower lip: Treatment results at Indiana University Hospitals. Cancer 41, 352-7. 24. FLETCHER G. H. & Jesst, R. H. (1980) The place of irradiation in the management of primary lesions in head and neck cancers. Cancer 39, 862-7. RlGHlNl R. et al. (1983) 25. AKCANCtLl G . , NERVl Combined radiation and drugs. The effect of intraarterial chemotherapy followed by radiotherapy in head and neck cancer. Rndiother. Oncol. 1, 101-7. 26. Leading Article (1980) Management of advanced gastric cancer: a more promising future. Med. J . Aust. 1, 402-3. 27. FIELIIING J. W . L. (1988) The value of multidisciplinary approach in management of gastric cancer. Recent Results Cancer Res. 110, 57-64. 28. BoDI)IE A . W . , McBRwt C. M. & BALCIIC. M. (1989) Gastric Cancer. Am. J . Surg. 157, 595-606. 29. HAKTLEY L. c., EVANSE. & WlNPSoK C . J . (1987) Factors influencing prognosis in gastric cancer. Aust. N.Z. J . Surg. 57, 59. 30. STEPHENS F. 0. (1988) Management of gastric cancer with regional chemotherapy preceding gastrectomy: 5 year survival results. Re&. Cancer Treat. 1, 80-2. 3 I , STEPII~NS F. 0. (1991) Gastric cancer - induction chemotherapy using intra-arterial infusion. In: Marlugernerit qf Gastric Cancer (Ed. P. Sugarbaker), pp. 161-70. Kluwer Academic Publishers, Boston.
32.
33.
34.
c.,
35.
36. 37.
F. o., MARSDtN F. W. & TAITEKSALL M. H. N . (1990) Regional induction chemotherapy followed by radiotherapy and/or surgery in management of large and aggressive sarcomas in shoulder, pelvis and limbs. In: ‘Progress in Regional Cancer Therapy’ (Eds. R. Jakasz and H. Rainer), pp. 160-7. Springer-Verlag. Berlin. MARSDENF. W . , S l t P I i E N S F. O . , T A - ~ E R S A L L M. H. N., MCCARTHY S . W . & WAUGH R. (1989)The influence of intra-arterial chemotherapy on local control of bone sarcoma. In: Nett, Developments f o r Limb Salvage in Musculoskeletal Tumours (Ed. T. Yamamoro), pp. 193-8. Springer-Verlag, Tokyo. MARSIIEN F. W.,STEPHENS F. o., WAUC~H R. & MCCARrtw S. W. (1991) Soft tissue complications of intra-arterial chemotherapy. Definition, prevention and treatment. In: Comp/ications of Limb Scilvafr: Prevention, Managemetit uncl Outcome (Ed. K. L. B. Brown), pp. 313-18. ISOLS, Montreal. STEPHENS F. o.,MCCAR7llY S . W. & MARSDEN F. W., FEKKARI A. (1991) IIb Osteosarcoma. Current management, local control and survival statistics experience in Australia. Clin. Orthop. 270, 113-19. MAKSDEN F. W. & SHARLAND M. (1992) Osteosarcoma: then and now. A fifty year review at Royal Prince Alfred Hospital. Aust. N.Z. J . Surg. 62,45-5 I . KROON B. B. R. (1988) Regional isolation perfusion in melanoma of the limbs; accomplishments, unsolved problems, future. Eur. J . Surg. Oncol. 14, STEPHENS
101-10.
38. THOMPSON J. F. & GIANoU-rSOS M. P. (1992) Isolated limb perfusion for melanoma: Effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J . Surg. 16, 227-33. 39. STtPHENs F. 0. (1990) Developments in surgical oncology - the state of the art. C/iti. Oticol. 2, 168-72.
69 1
PERSONAL VIEW SURGICAL ONCOLOGY AND THE ROLE OF REGIONAL CHEMOTHERAPY F. 0. STEPHENS,* D. W. STOREY,.' J . F. THOMPSON" A N D F. W. MARSDEN' *Department of Surgery, The University of Sydney and 'Department of Surgical Oncology, South ' Wules, Australia The Royal Prince Aljired Hospital, Sydney, N ~ M
Introduction The discipline of surgical oncology has been struggling for the past 20 years to establish its proper place in the management of malignant disease and the role of the surgical oncologist in the treatment of cancer has been unclear. Surgeons have tended to feel. often correctly, that the person best equipped to undertake modern surgical care is a surgeon with specialized regional operative expertise and interest, and that it is beyond the capacity of one surgeon to cover all anatomical regions and systems. Medical oncologists have often regarded any surgeon who professed an interest in chemotherapy as an interloper. Radiotherapists have tended to be surprised and have sometimes become suspicious when a surgeon appeared to understand anything more than the most fundamental elements of radiobiology. The place of the surgical oncologist is in the process of becoming more clearly defined. There is no doubt that many cancers are well treated by operation or radiotherapy alone. There is also no doubt that the management of patients with widely disseminated malignant disease has been transformed by the increasingly sophisticated application of systemic chemotherapy. In either of these settings, the surgical oncologist has little to offer over and above that which can be provided by an appropriately trained regional surgeon and/or a medical oncologist or radiotherapist. There remains, however, a group of malignant diseases for which currently accepted radical operative surgery or radiotherapy give poor results and in which the pattern of failure is essentially locoregional. Examples are: advanced cancer of the head and neck; and some malignancies arising in the gastrointestinal tract.
Correspondence: Professor F.O. Stephens, Department of Surgical Oncology. Royal Prince Alfred Hospital, Misscnden Road. Camperdown. NSW 2050, Australia. Accepted for publication 9 April 1992.
There are other malignant diseases that have i propensity for widespread dissemination, but which in certain patients also show a consistent tendency to locoregional patterns of recurrence. Examples of these are melanomas in a limb, soft tissue or bone sarcomas and locally advanced breast cancers. Still other malignancies have patterns of spread, such as to the liver or peritoneal cavity. which tend to be associated with terminal illness yet are frequently seen without more widespread dissemination. Examples are colorectal, gastric, pancreatico-biliary and ovarian cancers and ocular melanomas. These diseases as a group are usually only partially sensitive to radiotherapy or chemotherapy. They present some of the most difficult problems in oncology. It is the regional nature of these diseases which makes it desirable for their management to be carried out by practitioners whose training allows them to plan and initiate appropriate multimodal regional therapy. This is the role of surgical oncologists. Thus surgical oncologists arc far from being merely surgeons who operate on cancer patients, although their possession of surgical skills and experience is extremely important and clearly differentiates them from their colleagues, the medical oncologists. They are in essence surgeons who provide fully integrated regional cancer management for conditions in which this is likely to be more effective than single modality treatment.
Regional chemotherapy An important concept in surgical oncology is the application of regional chemotherapy. This started with the observation by Klopp in 1950 that after accidental injection of nitrogen mustard into an artery rather than a vein there was a much increased tissue reaction in the distribution of the artery.' Klopp therefore postulated that intra-arterial delivery of an effective anti-cancer agent had the potential for a greater local effect than could be achieved by its systemic administration. After the development of effective systemic anticancer agents in the 1950s and 1960s, there was an
602
initial wave of enthusiasm for regional chemotherapy. Surgeons familiar with exposure and cannulation of arteries used these agents intra-arterially as suggested by Klopp. The results were poor and most surgeons abandoned the idea, even though improved results were being achieved by their medical colleagues who were using the same agents to treat patients with disseminated disease. In retrospect one reason for these initial disappointments is apparent; intra-arterial chemotherapy was mostly tried on tumours which were recurrent after operative treatment and/or radiotherapy had failed. The resulting impairment of blood supply defeated the very basis of intra-arterial therapy - that is achievement of a high local concentration of cytotoxic agents. The next logical step, the use of regional chemotherapy as the firstline treatment, was only taken up by a small number of determined individuals. Helman and Bennett in South Africa used this approach in advanced breast cancer in the 1960s.* Nervi ef a / . in Italy reported the application of such principles in head and neck cancers in 1970.3 Fujimoto in Japan first reported the use of regional chemotherapy in gastric cancer in 1976.4 Also in 1976 Morton in the USA reported the use of pre-operative intraarterial chemotherapy as the first treatment modality in the management of patients with limb sarcoma.5 Meanwhile, Creech and Krementz in the USA had established a similar concept for the treatment of locally recurrent limb melanoma by using a cardiopulmonary bypass pump to perfuse the isolated limb with melphalan.6 The University of Sydney Surgical Oncology Unit started similar treatments at about the same time for locally advanced breast cancer, locally advanced head and neck cancer, gastric cancer and locally advanced malignant neoplasms in limb^.^-'^ There was little appreciation by each of these surgical groups of the developments in other centres until 1982, when Karl Aigner in Germany arranged a meeting of many of those involved." From his efforts has arisen The International Society for Regional Cancer Treatment, which is now well established, with biennial conferences and an internationally recognized journal. At the most recent meeting of this Society, in June 1991, it was clear that important advances in regional cancer treatment continue to be made by surgical oncologists around the world. Contributions included discussions of advances in limb perfusion for melanoma, management of intraperitoneal malignancy by various forms of intracavity chemotherapy, hyperthermic cytotoxic perfusion of the isolated pelvis for pelvic recurrence, management of stage I11 breast cancer, management of limb sarcoma and management of hepatic metastases. There were reports of continuing developments in methods to further enhancing the regional to systemic drug
STEPHENS ET A L .
concentration advantage; these included drug delivery on albumin and starch microspheres, manipulation of the local circulation with pharmacological agents, and systemic haemofiltration to extract the agents from the general circulation and thus reduce systemic toxicity. Delivery of cytotoxic agents to hepatic malignancies using lipiodol as a locally concentrating agent or gelfoam as a locally embolizing agent seems to hold particular promise. The isolated perfusion technique has even been extended to the liver, where the vascular isolation techniques learnt in liver transplantation have allowed development of this daunting but nonetheless practicable procedure. 1 6 , " The surgical oncologist must draw on his or her skills as a surgeon in employing all of these techniques. First, establishing a regional intra-arterial delivery system often involves operative placement of a catheter or a portal device, and the more adventurous methods of isolated regional perfusion require vascular surgical skills of a high order. Second, in most of the applications the essence of the method is that the regional cytotoxic therapy is not the definitive treatment; rather it is given with the aim of destroying as many malignant cells as possible but particularly those cells at the periphery of the field which will be encompassed by subsequent radical surgery or radiotherapy. Ix
Induction chemotherapy In the past, most systemic chemotherapy has been applied as postoperative adjuvant therapy after local resection of solid tumours. The recognition that intra-arterial chemotherapy should be given before operation led to the concept of using adjuvant therapies in general before rather than after operative surgery. This approach has been referred to as neoadjuvant or preferably induction chemotherapy. The obvious question to be asked is whether systemic rather than regional chemotherapy could be used as induction treatment? This would obviate the need for the more complex techniques required for intra-arterial delivery. With the exception of stage Ill cancer of the breast, there has been little study of this important question. However, there now is enough understanding of the pharmacokinetics of drug delivery to suggest that intra-arterial induction therapy will prove to have a local advantage in those malignancies that are known to be poorly responsive to systemic agents at tolerable dosage. Investigation of this question, central to the role of intra-arterial chemotherapy, has been hampered by the lack of animal models that closely mimic the relevant human disease states. One successful model has been the Australian sheep, which develops squamous cell carcinoma on the exposed skin of nose and ears and thus lends itself to direct observation of the regional effects of intra-arterial therapy.
SURGICAL ONCOLOGY
This is an excellent model, but it is difficult to obtain affected sheep and although early studies have confirmed the superiority of regional over systemic treatment for some agents," progress in elucidating the details of the pharmacokinetics has necessarily been slow.
Local experience with regional chemotherapy The principle of using intra-arterial induction chemotherapy before any other treatment has been applied in the Department of Surgical Oncology at the University of Sydney since 1970.'-'O During the years when the department was essentially alone in Australia in offering this type of therapy, the pattern of patients treated was dictated by the level of acceptance or otherwise by the referring doctors, especially surgeons and general practitioners. Therefore in each group of patients there has been a mixture of moderately advanced lesions that would have been treated more conventionally in other centres, along with patients with very advanced lesions who had already been rejected by appropriately skilled regional surgeons. The patient mix was further varied when the senior author (FOS) moved, in 1984, from Sydney Hospital to the Royal Prince Alfred Hospital causing the disruption of established referral channels and reinforcing the already apparent predominance of very advanced lesions. There has been no possibility of controlled studies in this setting, but many lessons have been learnt (Table I). In each group of patients, the results have been better than would have been expected for the degree of advancement of the tumours and there were dramatic responses in some patients who were clearly beyond other modes of treatment. The delivery methods have vaned over time, with gradual replacement of operative cannula placeTable 1. Some of the lessons learned over 20 years experience in the use of induction regional chemotherapy 1 The intra-arterial cannula needs to be held securely in
place. 2 The position of the catheter, establishing that the flow through it is directed to the tumour site, must he checked (with Patent Blue dye and/or a radionuclide study) before each drug infusion. 3 The rate of infusion must be carefully monitored. Too rapid flow of some agents (e.g. Adriamycin) may result in excessive local tissue damage. 4 There must he appropriate and adequate monitoring of both therapeutic effects and side effects o f treatment, with adjustment of doses and timing of agents used if necessary. 5 An appropriate course of chemotherapy must be completed before subsequent radiotherapy and/or surgical resection, which will he required even when there is apparently total tumour response to chemotherapy.
693
ment by radiological techniques where possible.20 The chemotherapy regimens used have been based on three principles. ( I ) When more than one type of anti-cancer agent is known to be effective against the tumour being treated, then a regimen of multiple compatible agents is generally preferred to a single agent regimen. (2) The multiple agents selected usually do not have the same major side effects, thus avoiding compounding chemotherapy side effects. (3) The agents used act at different stages in the cell division process, thus achieving a 'broadside' action against dividing tumour cells.x-'" BREAST CANCER
Twenty-two patients with breast cancer were treated and all had advanced stage 111 lesions. Although there have been dramatic effects on gross advanced disease and local control was achieved in 17 of the patients," the fact remains that good results are also possible with systemic induction chemotherapy,'2 and patients tend to die of widespread metastatic disease. This condition is thus a good example of the potential value of induction chemotherapy in achieving local tumour control but possibly a poor example of the role of regional cytotoxic treatment, as systemic induction chemotherapy may have achieved similar results. HEAD AND NECK CANCER
Twelve patients with advanced squamous cell carcinoma of the lower lip were treated. All had lesions that were larger than 2 cm and that penetrated underlying muscle. Conventional management of these patients would have involved operative surgery and/or radiotherapy, with expected tumour eradication in about two-thirds of the case^.^^.^^ Cure was achieved in 11 of 12, which is an encouraging result. The one patient who was not cured had extensive involvement of the mandible and widespread involvement of skin and nodes on both sides of the neck. Total tumour eradication was also achieved in over 50% of 37 patients treated for locally advanced cancers of the tongue, floor of mouth, oropharynx and salivary glands. This is clearly better than would have been anticipated from standard therapy, even though randomized studies with matched controls were not performed. The difficulty of arranging appropriately randomized studies to show a significant difference in results using preoperative induction chemotherapy by intra-arterial or intravenous delivery is widely recognized, although a randomized study by Arcangeli et a / . appeared to show an advantage in using intra-arterial induction chemotherapy before radiotherapy. 2s
694
STEPHENS E T A L . GASTRIC CANCkR
For all adenocarcinomas of the gastrointestinal tract, from the oesophagus to the rectum, conventional treatment results are generally poor (with 5 year survival ranging from 45% for colon cancer to 2Y0 for cancer of the pancreas). Recurrent disease tends to be predominantly a locoregional problem. However, only gastric and hepatic cancers lend themselves readily to regional induction chemotherapy because only the stomach and liver have a single infusable artery of supply. the coeliac axis. With the exception of some Japanese experience, reported 5 year survival for patients who have been subjected to a radical gastrectomy with curative intent is rarely better than 30Y0.’~-~’The 35 patients treated with induction intra-arterial chemotherapy followed by radical gastrectomy included a few patients with disease that may have been confined to the submucosa, but most had advanced disease extending to the serosa, and more than half had local lymph node involvement. The 5 year survival of those with nodes free of cancer in the operative specimen was 72%, and for those with involved nodes it was 3 1 ‘/o. For the whole group the 5 year survival was 47%.’”.’’ As with the rest of the experience, many patients were referred because they were felt to have a poor prognosis. These results are therefore considered to be encouraging and a multicentre controlled study using a simplified delivery resimen is planned. LIMB SARCOMA
Osteosarcomas and advanced soft tissue sarcomas in limbs have, in the past, been treated by amputation because of the high risk of local recurrence when less radical local treatments have been used. In treating locally advanced soft tissue sarcomas from 1976 to 1983 a regimen of continuous (about 5 weeks) induction chemotherapy with follow-up radical local tumour resection, with or without radiotherapy was used in 22 patients. In 19 of these 22 patients amputation was avoided without local tumour recurrence and 14 are long-term survivors, apparently free of disease. Since 1983 an intermittent regimen using Cisplatinurn and Adriamycin has been used in another 10 patients with soft tissue sarcomas. One of these required amputation, while the other nine had successful limb salvage procedures. To date six of these 10 have survived free of disease.3’ This intermittent regimen (which does not require prolonged hospitalization) has also been used in treating high grade sarcomas of bone, mostly as induction therapy before surgery, but on some occasions for palliative local control of advanced inoperable tumours of the pelvis and sacrum in conjunction with radiotherapy.” Of 41 patients with high-grade sarcomas of bone
who were treated between 1983 and 1991, three had advanced inoperable tumours with distant metastatic disease, five required amputation and the remaining 33 patients experienced successful limb salvage.34 Calculated actuarial survival of patients with osteosarcoma treated with a three phase programme of induction intra-arterial chemotherapy, surgical operation and adjuvant systemic chemotherapy was 58y0.~’The probability of survival in those patients with osteosarcoma who remained free of disease at the conclusion of this three phase programme has been estimated as 85% . 3 h MELANOMA
The most important principle of induction chemotherapy is that the treatment be given before a tumour and its blood supply have been disturbed by operative surgery or radiotherapy. This principle suggests that in patients presenting with locally advanced limb melanoma, isolated limb perfusion (ILP) with an appropriate cytotoxic agent is most likely to be effective if performed before standard operative surgery. This hypothesis is currently being tested in a large international multicentre trial conducted jointly by the European Organisation for the Research and Treatment of Cancer and the World Health Organization Melanoma Group. Patients with stage I but high risk melanoma in a limb (> 1.5 mm in thickness) are being randomized to receive either standard surgical treatment alone or standard surgical treatment after hyperthermic ILP with melphalan. This drug, administered in high dosage by ILP, has been shown to be very effective when used therapeutically to treat advanced or recurrent melanoma in a limb; complete remission is achieved under these circumstances in 40% of patients and partial remission in another 40% .37 No other drug or drug combination used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan.3x To date. over 700 patients from 17 centres have been entered into the EORTUWHO trial, 47 of them were contributed by the Sydney unit. Although the mean follow-up time is short (27 months), and no firm conclusions can yet be drawn, preliminary analysis of the data indicates a major prolongation of disease-free survival time in the group of patients who have received prophylactic regional perfusion chemotherapy by ILP with melphalan.
-
The future of surgical oncology The central theme of surgical oncology is that some patients with malignant disease are better managed by a combination of treatments rather than by operative surgery, radiotherapy or chemotherapy alone. The basic principles for such management have been described elsewhere.”
SURGICAL ONCOLOGY
It is clear that this is not the case for all malignant disease. The surgical oncologist will therefore be most involved in treating those patients who have malignant tumours with bad prognostic manifestations which even when advanced are due mainly to locoregional rather than systemically disseminated malignancy. A group of malignancies has already been identified for which the combination of regional chemotherapy and operative surgery appears to give results that are better than those for operative surgery alone. An important task for surgical oncologists is to conduct appropriately controlled trials to test the efficacy of this form of treatment in a more rigorous way. At the same time, new potentials for regional treatments are appearing which extend the role of the surgical oncologist. These include better delivery systems for intra-arterial drug administration and extrapolation of the concept of isolated perfusion to regions other than the limbs (e.g. isolated pelvic perfusion, isolated liver perfusion). These methods will require a period of evaluation before they reach a stage where formal trials are appropriate. The role of the surgical oncologist will be mainly as consultant, stimulator, organizer and teacher. It is not easy to convince surgeons that their patient’s interest may be better served by delaying operation, possibly for several weeks, to allow induction chemotherapy to be applied first. Nor is it easy to convince medical oncologists that a drug which they regard as their own may perhaps have a better effect if given regionally and as an integrated preoperative measure. Although the surgical oncologist should be trained in a very wide range of cancer surgery. it is likely that in most institutions there will be other surgeons who are better qualified to perform some radical procedures. When this is so, their expertise should be used. It is likely that in one particular field the surgical oncologist will be the best trained surgeon available and that area plus the more advanced techniques of providing regional drug delivery should provide sufficient operative surgery to sustain enthusiasm and maintain and develop surgical skills. All in all the concept of combining treatment modalities to convert locally advanced malignant tumours normally associated with a poor prognosis (or possibly only curable by mutilating operative surgery such as amputation) into tumours with an overall improved prognosis (and without the need for such mutilating operative procedures) is exciting for all involved, patients and practitioners alike.
References I . KLOPPC. T., BATEMAN J., ALFOKDC. & WINSHIP T. (1950) Fractionated regional cancer chemotherapy. Ann. Surg. 132, 811-32. P. & B ~ N N E TM. T B. (1968) Intra arterial 2. HELMAN
695 cytotoxic therapy and X-ray therapy for cancer of the breast. Br. J . Surg. 55. 419-23. 3 . NEKVIC . , AKCANGLLI G . , C A S A LC. ~ e f a / . (1970) A reappraisal of intra arterial chemotherapy. Cmcer 26, 577-82. S., AKAOT. ITOH B. et a / . (1976) A study of 4 . FUJIMOTO survival in patients with stomach cancer treated by a combination of preoperative intra arterial infusion therapy and surgery. Cuncer 37, 1648-53. D. L . , E l L B t K F. R., T O W N S t N D c. M . J . 5. MOKION et u / . (1976) Limb salvage from multidisciplinary treatment approach for skeletal and soft tissue sarcomas of the extremity. Ann. Surg. 184, 268-78. 6. CKtECH 0 . & KKtMhNIZ E. T . ( 1958) Chemotherapy of cancer: Regional perfusion utilizing an extra corporeal circuit. Ann. Surg. 148, 616-32. 7. SrwHENs F. 0 . (1972) Modern trends in the surgical management of malignant disease. Med. J. Aust. 1, 591-6. 8. STEPHENS F. 0. (1973) Combined therapy in the treatment of advanced localised malignancy. In: Papers of the 4th GSM Royal Australasian College of Surgeons (Ed. S. S. Ratman). pp. 746-54. Eurasia Press, Singapore. 9. S T E P H ~ NF. S 0. (1973) Bleomycin -a new approach in cancer chemotherapy. Med. J. Ausr. 1, 1277-83. 10. SiwHtNs F. 0 . (1974) Combined chemotherapy. radiotherapy and surgery in the treatment of advanced but localised solid malignancy turnours. Ausr. N . Z . J . Surg. 44, 343-53. I I . S T ~ P HF. ~N 0.S(1978) CRAB chemotherapy. ,4171. J . Surg. 135, 375-8. G . J. S . , DICKINSON R. T. J . 12. Sl~LPlltNSF. O., HAKKEK & R0BtKI.s B. A. (1979) Pre-operative basal cheniotherapy in the management of cancer in the stomach: a preliminary report. A m . N.Z. J. Surx. 49, 331-5. 13. STLPHtNS F. o., CKth P., HAKtitK G . J . s., ROHt-KTS B. A . & h h 4 B L Y C. K . (1980) Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer. Laircc,r. 30, 43SSX. 14. S r w H t N s F. 0. (1983) Clinical experience in the use of intra-arterial infusion chemotherapy in the treatment of cancers in the head and neck, the extremities, the breast and stomach. Recent Resu/t.s Cailwr Re.$. 86, 122-7. 15. SrEPtwNs F. 0. (1992) Advances in integrated regional cancer treatment - the past. the present and future trend\. Region. Cuncer Treur. 5 . 16. Vth International Conference o n Advances in Regional Cancer Treatment - Conference Abstracts ( 1991). Region. Caiicer Trecir. 4 , 3-52. 17. TAGUCHI T. (Ed.) (1991) Proceediiigs of rhe filternatronnl Coiferenee on Regiorlul Chemorherrrp?.,fiw Liver Cancer. Churchill Press, Osaka. 18. ST~PHENS F. 0. (1989) The case for a name change from neoadjuvant chemotherapy to induction cheniotherapy. Caricer 63, 1245-6. G. J . S . & S T E P H b N S F. 0. (1991) The use of 19. HARKEK sheep epidermal squamous cell carcinoma to evaluate intra-arterial bleomycin infusion chemotherapy. Region. Caiicer Treat. 4 , I2 1-6. 20. WAUGHR. c. & S r E P H E N S F. 0 . (1990) Indications for surgical or radiological placement of cannulas for intra-arterial induction chemotherapy. Aust. Radiol. 34, 196-9.
696
STEPHENS ET A L .
2 I . STtPHENs F. 0. (1990) Intra-arterial induction chemotherapy in locally advanced stage 111 breast cancer. Cancer 66, 645-50. F., WEILM. et ul. (1988) 22. JACQUiLLAr C . , BAILLET Results of conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy and external interstitial irradiation in 98 patients with locally advanced breast cancer. Cancer 61, 1977-82. 23. HORNBACK N. B. & SHIDNIA H. (1978) Carcinoma of the lower lip: Treatment results at Indiana University Hospitals. Cancer 41, 352-7. 24. FLETCHER G. H. & Jesst, R. H. (1980) The place of irradiation in the management of primary lesions in head and neck cancers. Cancer 39, 862-7. RlGHlNl R. et al. (1983) 25. AKCANCtLl G . , NERVl Combined radiation and drugs. The effect of intraarterial chemotherapy followed by radiotherapy in head and neck cancer. Rndiother. Oncol. 1, 101-7. 26. Leading Article (1980) Management of advanced gastric cancer: a more promising future. Med. J . Aust. 1, 402-3. 27. FIELIIING J. W . L. (1988) The value of multidisciplinary approach in management of gastric cancer. Recent Results Cancer Res. 110, 57-64. 28. BoDI)IE A . W . , McBRwt C. M. & BALCIIC. M. (1989) Gastric Cancer. Am. J . Surg. 157, 595-606. 29. HAKTLEY L. c., EVANSE. & WlNPSoK C . J . (1987) Factors influencing prognosis in gastric cancer. Aust. N.Z. J . Surg. 57, 59. 30. STEPHENS F. 0. (1988) Management of gastric cancer with regional chemotherapy preceding gastrectomy: 5 year survival results. Re&. Cancer Treat. 1, 80-2. 3 I , STEPII~NS F. 0. (1991) Gastric cancer - induction chemotherapy using intra-arterial infusion. In: Marlugernerit qf Gastric Cancer (Ed. P. Sugarbaker), pp. 161-70. Kluwer Academic Publishers, Boston.
32.
33.
34.
c.,
35.
36. 37.
F. o., MARSDtN F. W. & TAITEKSALL M. H. N . (1990) Regional induction chemotherapy followed by radiotherapy and/or surgery in management of large and aggressive sarcomas in shoulder, pelvis and limbs. In: ‘Progress in Regional Cancer Therapy’ (Eds. R. Jakasz and H. Rainer), pp. 160-7. Springer-Verlag. Berlin. MARSDENF. W . , S l t P I i E N S F. O . , T A - ~ E R S A L L M. H. N., MCCARTHY S . W . & WAUGH R. (1989)The influence of intra-arterial chemotherapy on local control of bone sarcoma. In: Nett, Developments f o r Limb Salvage in Musculoskeletal Tumours (Ed. T. Yamamoro), pp. 193-8. Springer-Verlag, Tokyo. MARSIIEN F. W.,STEPHENS F. o., WAUC~H R. & MCCARrtw S. W. (1991) Soft tissue complications of intra-arterial chemotherapy. Definition, prevention and treatment. In: Comp/ications of Limb Scilvafr: Prevention, Managemetit uncl Outcome (Ed. K. L. B. Brown), pp. 313-18. ISOLS, Montreal. STEPHENS F. o.,MCCAR7llY S . W. & MARSDEN F. W., FEKKARI A. (1991) IIb Osteosarcoma. Current management, local control and survival statistics experience in Australia. Clin. Orthop. 270, 113-19. MAKSDEN F. W. & SHARLAND M. (1992) Osteosarcoma: then and now. A fifty year review at Royal Prince Alfred Hospital. Aust. N.Z. J . Surg. 62,45-5 I . KROON B. B. R. (1988) Regional isolation perfusion in melanoma of the limbs; accomplishments, unsolved problems, future. Eur. J . Surg. Oncol. 14, STEPHENS
101-10.
38. THOMPSON J. F. & GIANoU-rSOS M. P. (1992) Isolated limb perfusion for melanoma: Effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J . Surg. 16, 227-33. 39. STtPHENs F. 0. (1990) Developments in surgical oncology - the state of the art. C/iti. Oticol. 2, 168-72.
