Clinical Oncology (1990) 2:168-172 © 1990 The Royal College of Radiologists
Clinical Oncology
Review Article Developments in Surgical Oncology: Induction (Neoadjuvant) Chemotherapy - The State of the Art F. O. Stephens Department of Surgery, The University of Sydney at The Royal Prince Alfred Hospital, Sydney, Australia
Abstract. The three established modalities for treat-
Keywords: Intra-arterial chemotherapy; Radio-
ment of cancer are operative surgery, radiotherapy and chemotherapy. In the past, patients have been referred to clinics where experts in the appropriate discipline have usually advised management by one or other of the three modalities. In recent years it has become apparent that for some cancers in which good results have not been forthcoming by one therapeutic modality alone, improvements may well be made by integrating management using two or three forms of treatment, in a planned approach. Management of localized cancers in which a surgical operation is likely to play a major part has traditionally been carried out by surgeons. However, operative surgery alone may not provide optimal care so that surgical oncology has developed as a discipline often embracing combined treatment with either chemotherapy or radiotherapy or both. In managing advanced but localized cancers for which a surgical operation alone is unlikely to produce tumour eradication (or for which tumour eradication can only be achieved with a mutilating operation such as amputation) it has become increasingly recognized that reduction of tumour size and viability by using chemotherapy first may render many tumours more susceptible to total eradication by subsequent radiotherapy and/or surgical operation. Such treatment is often referred to as 'induction' or 'neo-adjuvant' chemotherapy. This paper summarizes the principles of use of induction chemotherapy with integrated follow-up radiotherapy and/or surgical operation.
therapy, Radiation oncology; Regional chemotherapy; Induction; Neoadjuvant; Surgical oncology
Correspondence and offprint requests to: F. O. Stephens, Department of Surgery, The University of Sydney, Sydney NSW 2006, Australia.
INTRODUCTION
For centuries somewhat primitive operative surgery was the only effective method of eradicating cancers. It is less than 150 years, however, since modern surgery, as we understand it today, was made generally applicable for treatment of cancers. The impetus for development of modern surgery came from the discovery of general anaesthesia about 150 years ago followed by the work of Lister, Pasteur, Semmelweiss and Koch in which the principles of surgical asepsis were discovered. It is less than 100 years, following the work of the Curies, that radiotherapy was introduced as the second effective method of cancer treatment. It is about 50 years since Huggins and Hodges (1941) observed regression of certain tumours in response to hormone manipulation shortly followed by the accidental discovery in World War II that nitrogen mustard affected dividing cells. This introduced the era of modern chemotherapy against cancer. In 1950 after accidental injection of nitrogen mustard into an artery rather than a vein Klopp et al. (1950) observed a significant reaction in the skin in the distribution of the artery and suggested there could be an enhanced regional anticancer effect if anticancer agents were delivered directly into the artery supplying a tumour rather than indirectly into the systemic circulation. Thus in the 1950s and 1960s surgeons, who, traditionally managed patients with cancer, and who had the skills for exposing arteries and delivering intra-arterial agents, attempted to treat their
Developmentsin SurgicalOncology:Induction(Neoadjuvant)Chemotherapy most troublesome cancer problems with intra-arterial chemotherapy. This applied particularly in the head and neck for treatment of tumours which had recurred after previous attempts at surgical resection and/or radiotherapy. It became clear that the early attempts by surgeons at the use of intra-arterial chemotherapy in head and neck cancer were in general unsuccessful. The patients suffered consequences of side-effects of chemotherapy but gained little advantage by way of tumour response. Most surgeons thus lost interest in the use of anticancer agents prefering to rely on operative surgery alone or operative surgery with radiotherapy. Also in the 1950s and 1960s haematologists and some radiotherapists were becoming encouraged at the response of certain lymphomas and leukaemias to new anticancer drugs. They then used these agents in the management of some widespread solid tumours and were encouraged by some favourable responses. Thus there developed a group of haematologists and physicians with a specialized interest in the use of the new anticancer drugs in the treatment of widespread cancers - the medical oncologists. Thus in the 1960s and early 1970s there were three distinct groups of doctors primarily concerned with the management of cancers. Surgeons were mainly concerned with management of localized tumours which could be surgically removed. In cases of failure they referred patients to radiotherapists or medical oncologists. Radiotherapists were primarily interested in palliative care of advanced tumours, in management of lymphomas and management of some locally curable cancers. Medical oncologists were at first mainly concerned with management of neoplasms of the haemopoietic system and palliative care of widespread cancers. Later the value of adjuvant chemotherapy in management of patients with possible residual micrometastatic disease also fell mostly into the hands of medical oncologists. Some surgeons, however, encouraged by responses of some localized tumours continued to try to exploit the potential of combined modality management with anticancer agents in conjunction with operative surgery and possibly radiotherapy. It became apparent that localized tumours which best responded to anticancer agents were tumours which had not previously been treated with radiotherapy or surgical operation (von Essen et al., 1968). It seemed that for adequate perfusion of anticancer agents the tumour blood supply had to be intact and not damaged by previous radiotherapy or operative surgery. Even intra-arterial regional chemotherapy was relatively ineffective when used to treat tumours which had become partially devascularized by previous radiotherapy or surgical operation. It was much more likely to be effective in
169
previously untreated tumours, no matter how advanced, provided the blood supply was intact (Stephens, 1983a). Encouraging results were reported from a number of geographically scattered centres in managing advanced but previously untreated localized malignancies especially in the head and neck, limbs, breast and stomach. Best results were seen when chemotherapy was used first, followed by radiotherapy and/or surgical resection (Koyama et al., 1975; Jussawalla and Shetty, 1978; Stephens et al., 1980, 1986, 1987; Stephens, 1983b, 1988; Ensminger and Gyves, 1984; Jaffe et al., 1985; Kremetz, 1986; Noguchi et al., 1988). With the preliminary use of chemotherapy it became apparent that certain tumours which were unlikely to be eradicated by operative resection or radiotherapy alone, could be reduced to proportions more readily eradicated by a surgical operation or by radiotherapy or a combination of both. This application of chemotherapy as the first treatment modality in a combined therapeutic approach using the chemotherapy to induce changes which would make the tumour potentially more curable by standard means has been variously referred to as 'induction', 'neoadjuvant', 'reducing', 'primary', or 'basal' chemotherapy. There are good reasons for accepting that 'induction chemotherapy' is probably the most appropriate description whether the chemotherapeutic agents are given systemically or by regional infusion (Stephens, 1989). Although from historic comparison there is strong evidence that induction chemotherapy can be used effectively to reduce some advanced localized cancers to curable proportions, it has been difficult to organize well-randomized control studies to establish the point to the satisfaction of all. Numbers of matching patients in these categories are small. Another difficulty has been that differences in outcome have been so striking in some series that clinicians who have witnessed these responses have been reluctant not to treat first all their patients with advanced localized malignancies in this way (the induction chemotherapy being delivered either systematically or regionally). Some randomized studies have, however, recently become available indicating a significant beneficial effect of the use of induction chemotherapy in management of head and neck cancer (Shanta and Krishnamurthi, 1980; Arcangeli et al., 1983). Using historic controls a number of other studies have similarly indicated the value of induction chemotherapy especially when delivered by intra-arterial infusion in the management of advanced Stage III breast cancer, gastric cancer, and sarcomas and advanced cancers in limbs (Koyama et al., 1975; Jussawalla and Shetty, 1978; Stephens el al., 1980,
170 1986, 1987; Stephens, 1983b, 1988; Ensminger and Gyves, 1984; Jaffe et a l . , , 1985; Krementz, 1986). Seven principles of management using induction chemotherapy may now be described.
Principle 1 For some aggressive or advanced but localized malignant tumours, in which prospects of cure are not good by extirpative surgery alone, or by radiotherapy with or without surgery (or only by mutilating surgery such as limb amputation), chemotherapy can be effective in inducing changes which may render the tumours more curable by subsequent radiotherapy and/or surgical excision.
Principle 2 In such planned integrated tumour management it is important to use chemotherapy as the first modality of treatment whilst the tumour blood supply is intact and has not been compromised by previous surgical operation or radiotherapy.
Principle 3 In using chemotherapy as a first treatment modality it is the well-vascularized cells at the tumour periphery which are most affected by the chemotherapy. Less well-vascularized cells towards the centre of the tumour may be less affected. However, it is cells at the turnout periphery which are most likely to establish tumour recurrence after surgical excision so that it is most important that these be eliminated as completely as possible prior to surgery. The cells at the centre of the lesion are less affected by chemotherapy but are more certainly eradicated by surgical resection.
Principle 4 In combining chemotherapy with standard therapy in management of advanced and aggressive localized tumours it is important to eradicate as much tumour as possible by chemotherapy (within the patient's reasonable tolerance level) before embarking upon the next step in management. It is inappropriate to give a 'token' dose of chemotherapy in the hope of doing 'some good'. It is important to gain as much advantage from chemotherapy as possible in the induction treatment phase.
F.O. Stephens
Principle 5 Some tumours are supplied by an artery which can be cannulated so that the chemotherapy can be effectively administered at a higher concentration by intra-arterial delivery, thus offering a greater local antitumour potential than would be achieved if the same dose of the same agent were given systematically. The total dose of agent to which the tumour is exposed is also somewhat increased (Stephens, 1983a, 1988). The advantage in concentration and total dose will depend predominantly on the size of the artery being infused (the smaller the artery the greater the concentration and the greater the total dose exposure of the tumour cells to the agent infused).
Principle 6 1. When an antitumour agent is given by intraarterial infusion, in addition to a greater localized antitumour effect, there will also be greater regional toxicity, than after systemic administration of the same dose of the same agent over the same period. However, after passage through the regional tissues containing the turnout, except in the case of infusion of liver or kidney, most of the antitumour agent will then pass into the systemic circulation. Systemic toxicity will therefore be similar to systemic toxicity following systemic administration of the agent. 2. In the case of liver or kidney infusion, much of the agent may be detoxified or removed on first passage through the liver or kidney thus hopefully effecting a greater local antitumour response with significantly reduced risk of systemic toxicity. 3. After passing through the infused regional tissues, efflux of the chemotherapeutic agents into the systemic circulation will in fact initiate systemic 'adjuvant' chemotherapy from the first day of induction chemotherapy (unless liver or kidney is being infused). Additional systemic chemotherapy may or may not be required as adjuvant treatment subsequent to local tumour eradication.
Principle 7 No matter how effective induction chemotherapy appears to have been, it is almost inevitable that some tumour cells will have survived (especially towards the less-vascularized centre of the original tumour mass). These surviving cells will initiate recurrence of a more resistant tumour cell colony, unless follow-up radiotherapy or surgical excision, or both, are carried out.
Developments in Surgical Oncology:Induction (Neoadjuvant)Chemotherapy T H E P L A C E O F R A D I O T H E R A P Y IN INTEGRATED MANAGEMENT PROGRAMMES
The position of radiotherapy in integrated local tumour management is as yet uncertain. Radiotherapy used some months prior to chemotherapy will induce endarteritic changes which will reduce the effectiveness of subsequent chemotherapy by reduction of tumour blood flow. Radiotherapy given at the same time as chemotherapy may have an enhancing effect but risk of regional toxicity may also be considerably increased (Begg, 1986; Hopkins and Looney, 1988; Steel, 1989). Radiotherapy given after chemotherapy but before operative surgery may have advantages. Radiotherapy is also more effective when given to well-oxygenated tissues, so that it should be more effective given before operative surgery in which blood vessels will be damaged or ligated. Tumour in scar tissue is less sensitive to irradiation than tumour in well-vascularized tissue. Again, radiotherapy is more effective against the well-vascularized cells of the tumour periphery, than cells in the tumour centre. However, the central aspect of the tumour is that which can be most certainly eradicated by surgical resection if there is residual tumour after radiotherapy. Unfortunately, radiotherapy given prior to surgery may add difficulty to the operative dissection and risks impairing would healing following operation. For this reason many surgeons prefer that radiotherapy be given after and not before operative surgery. Thus it is clear that in using radiotherapy in a combined treatment regimen, it is best that it should not be given before chemotherapy. However, whether radiotherapy is best given during or immediately following chemotherapy or whether it should be reserved until after any operative surgery has been carried out is as yet uncertain and may well depend upon individual circumstances (both anatomical and geographical).
CONCLUSIONS
Much progress has been made in the treatment of advanced or locally aggressive regional malignancies but many questions remain to be answered. Some of these include: 1. The best combinations, administration of agents with least disturbance to 2. The most appropriate
doses and methods of to the greatest effect, the patient. timing of induction
3. 4.
5.
6.
171
chemotherapy in relation to following surgery or radiotherapy. The most appropriate timing of radiotherapy in relation to chemotherapy or surgery. The indications for or need for systemic adjuvant chemotherapy following apparently successful treatment of a primary cancer. The types of turnouts and situation of tumours which will best respond to combined management regimens. Possible integration of other forms of management such as immunotherapy, hyperthermia or laser treatment.
Surgeons involved in such studies (i.e. surgical oncologists) need to become skilled and informed in more aspects of cancer management than that normally required in management of the majority of patients with localized cancer and will do well with operative surgery alone. Questions like those above and many more need answers, but in establishing the rationale of combined modality management for cancers which do not have a good prognosis with one form of standard treatment alone and in establishing principles and rationale for induction chemotherapy then at least a good start has been made.
W H A T T H E N IS S U R G I C A L O N C O L O G Y ?
Surgical oncology is the study of malignant disease and the practice of caring for patients with malignant disease when a surgical operation may be required as a major component of treatment. Thus surgical oncology is mainly concerned with localized tumour problems. It aims at improving patient survival and quality of life by improved methods of tumour control and eradication. It requires not only the skills of an operating surgeon but embraces a thorough study of malignant disease and integration of all treatment modalities required in the care of these patients. Where necessary the surgical oncologist should cooperate with the medical oncologist and/or radiation oncologist in planning initial coordinated and integrated treatment likely to offer the best outcome for the patient.
References Arcangeli G, NerviC, Rihini R, Creton G, Mirri MA, Guerra A (1983). Combined radiation and drugs: the effect of intraarterial chemotherapyfollowedby radiotherapy in head and neck cancer. Radiotherapy and Oncology, 1,101-107.
172 Begg AC (1986). Additivity versus repair in fractionated treatment combining drugs and X-rays - a theoretical analysis. International Journal of Radiation Oncology Biology Physics, 9, 1667-1671. Ensminger WD, Gyves JW (1984). Regional cancer chemotherapy. Cancer Treatment Report, 68, 101-115. Hopkins HA, Looney WB (1988). Further experimental studies on alternating chemotherapy and radiotherapy. In Neo-adjuvant Chemotherapy - Second International Conference, ed. Jacquillat C, Weil M, Khayat D, John Libbey - Eurotext Publishers, London, Paris. Huggins C, Hodges CF (1941). Studies on prostatic cancer 1. The effect of castration, of oestrogen and androgen injection on serum phosphate in metastatic carcinoma of the prostate. Cancer Research, 1,293. Jaffe N, Robertson K, Takave Y, Cangir A, Wallace S, Carrasco H et al. (1985). Control of primary osteosarcoma with chemotherapy. Cancer, 56, 461-466. Jussawalla JD, Shetty PA (1978). Experiences with intra-arterial chemotherapy for head and neck cancer. Journal of Surgical Oncology, 10, 33-37. Klopp GT, Alford TC, Bateman J, Berry GN, Winship T (1950). Fractionated intra-arterial cancer chemotherapy. Annals of Surgery, 132, 811-832. Koyama H, Wada T, Takahashi Y, Iwanaga T, Aoki Y, Wada A et al. (1975). Intra-arterial infusion chemotherapy as a preoperative treatment of locally advanced breast cancer. Cancer, 36, 1603-1612. Krementz ET (1986). Regional perfusion. Cancer, 57,416-432. Noguchi S, Miyauchi K, Niahizawa Y, Koyama H, Terasawa T (1988). Management of inflammatory carcinoma of the breast with combined modality therapy including intra-arterial
F.O. Stephens infusion chemotherapy as an induction therapy. Cancer, 61, 1483-1491. Shanta V, Krishnamurthi S (1980). Combined bleomycin and radiotherapy in oral cancer. Clinical Radiology, 31,617-620. Steel G (1989). A letter. Radiotherapy and Oncology, 14, 315316. Stephens FO (1983a). Pharmacokinetics of intra-arterial chemotherapy. Recent Results in Cancer Research, 86, 1-12. Stephens FO (1983b). Clinical experience in the use of intraarterial infusion chemotherapy in the treatment of cancers in the head and neck, the extremities, the breast and stomach. Recent Results in Cancer Research, 86, 122-127. Stephens FO (1988). Why use regional chemotherapy - principles and pharmacokinetics. Regional Cancer Treatment, 1, 4-10. Stephens FO (1989). The case for a name change from neoadjuvant to induction chemotherapy. Cancer, 63, 1245. Stephens FO, Crea P, Harker GJS, Roberts B, Hambly CK (1980). Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer. Lancet, ii, 435-438. Stephens FO, Adams BG, Crea P (1986). Intra-arterial chemotherapy given preoperatively in management of gastric carcinoma. Surgery, Gynecology and Obstetrics, 162, 370-374. Stephens FO, TattersaU MHN, Marsden W, Waugh RC, Green D, McCarthy SW (1987). Regional chemotherapy using cisplatin and adriamycin as primary treatment for advanced sarcomas in shoulder, pelvis and thigh. Cancer, 60, 724-735. von Essen CF, Joseph LBM, Simon GT, Singh SP (1968). Sequential chemotherapy and radiation therapy of buccal mucosa carcinoma in South India: methods and preliminary results. American Journal of Roentgenology, 102, 530-540.
Clinical Oncology
Review Article Developments in Surgical Oncology: Induction (Neoadjuvant) Chemotherapy - The State of the Art F. O. Stephens Department of Surgery, The University of Sydney at The Royal Prince Alfred Hospital, Sydney, Australia
Abstract. The three established modalities for treat-
Keywords: Intra-arterial chemotherapy; Radio-
ment of cancer are operative surgery, radiotherapy and chemotherapy. In the past, patients have been referred to clinics where experts in the appropriate discipline have usually advised management by one or other of the three modalities. In recent years it has become apparent that for some cancers in which good results have not been forthcoming by one therapeutic modality alone, improvements may well be made by integrating management using two or three forms of treatment, in a planned approach. Management of localized cancers in which a surgical operation is likely to play a major part has traditionally been carried out by surgeons. However, operative surgery alone may not provide optimal care so that surgical oncology has developed as a discipline often embracing combined treatment with either chemotherapy or radiotherapy or both. In managing advanced but localized cancers for which a surgical operation alone is unlikely to produce tumour eradication (or for which tumour eradication can only be achieved with a mutilating operation such as amputation) it has become increasingly recognized that reduction of tumour size and viability by using chemotherapy first may render many tumours more susceptible to total eradication by subsequent radiotherapy and/or surgical operation. Such treatment is often referred to as 'induction' or 'neo-adjuvant' chemotherapy. This paper summarizes the principles of use of induction chemotherapy with integrated follow-up radiotherapy and/or surgical operation.
therapy, Radiation oncology; Regional chemotherapy; Induction; Neoadjuvant; Surgical oncology
Correspondence and offprint requests to: F. O. Stephens, Department of Surgery, The University of Sydney, Sydney NSW 2006, Australia.
INTRODUCTION
For centuries somewhat primitive operative surgery was the only effective method of eradicating cancers. It is less than 150 years, however, since modern surgery, as we understand it today, was made generally applicable for treatment of cancers. The impetus for development of modern surgery came from the discovery of general anaesthesia about 150 years ago followed by the work of Lister, Pasteur, Semmelweiss and Koch in which the principles of surgical asepsis were discovered. It is less than 100 years, following the work of the Curies, that radiotherapy was introduced as the second effective method of cancer treatment. It is about 50 years since Huggins and Hodges (1941) observed regression of certain tumours in response to hormone manipulation shortly followed by the accidental discovery in World War II that nitrogen mustard affected dividing cells. This introduced the era of modern chemotherapy against cancer. In 1950 after accidental injection of nitrogen mustard into an artery rather than a vein Klopp et al. (1950) observed a significant reaction in the skin in the distribution of the artery and suggested there could be an enhanced regional anticancer effect if anticancer agents were delivered directly into the artery supplying a tumour rather than indirectly into the systemic circulation. Thus in the 1950s and 1960s surgeons, who, traditionally managed patients with cancer, and who had the skills for exposing arteries and delivering intra-arterial agents, attempted to treat their
Developmentsin SurgicalOncology:Induction(Neoadjuvant)Chemotherapy most troublesome cancer problems with intra-arterial chemotherapy. This applied particularly in the head and neck for treatment of tumours which had recurred after previous attempts at surgical resection and/or radiotherapy. It became clear that the early attempts by surgeons at the use of intra-arterial chemotherapy in head and neck cancer were in general unsuccessful. The patients suffered consequences of side-effects of chemotherapy but gained little advantage by way of tumour response. Most surgeons thus lost interest in the use of anticancer agents prefering to rely on operative surgery alone or operative surgery with radiotherapy. Also in the 1950s and 1960s haematologists and some radiotherapists were becoming encouraged at the response of certain lymphomas and leukaemias to new anticancer drugs. They then used these agents in the management of some widespread solid tumours and were encouraged by some favourable responses. Thus there developed a group of haematologists and physicians with a specialized interest in the use of the new anticancer drugs in the treatment of widespread cancers - the medical oncologists. Thus in the 1960s and early 1970s there were three distinct groups of doctors primarily concerned with the management of cancers. Surgeons were mainly concerned with management of localized tumours which could be surgically removed. In cases of failure they referred patients to radiotherapists or medical oncologists. Radiotherapists were primarily interested in palliative care of advanced tumours, in management of lymphomas and management of some locally curable cancers. Medical oncologists were at first mainly concerned with management of neoplasms of the haemopoietic system and palliative care of widespread cancers. Later the value of adjuvant chemotherapy in management of patients with possible residual micrometastatic disease also fell mostly into the hands of medical oncologists. Some surgeons, however, encouraged by responses of some localized tumours continued to try to exploit the potential of combined modality management with anticancer agents in conjunction with operative surgery and possibly radiotherapy. It became apparent that localized tumours which best responded to anticancer agents were tumours which had not previously been treated with radiotherapy or surgical operation (von Essen et al., 1968). It seemed that for adequate perfusion of anticancer agents the tumour blood supply had to be intact and not damaged by previous radiotherapy or operative surgery. Even intra-arterial regional chemotherapy was relatively ineffective when used to treat tumours which had become partially devascularized by previous radiotherapy or surgical operation. It was much more likely to be effective in
169
previously untreated tumours, no matter how advanced, provided the blood supply was intact (Stephens, 1983a). Encouraging results were reported from a number of geographically scattered centres in managing advanced but previously untreated localized malignancies especially in the head and neck, limbs, breast and stomach. Best results were seen when chemotherapy was used first, followed by radiotherapy and/or surgical resection (Koyama et al., 1975; Jussawalla and Shetty, 1978; Stephens et al., 1980, 1986, 1987; Stephens, 1983b, 1988; Ensminger and Gyves, 1984; Jaffe et al., 1985; Kremetz, 1986; Noguchi et al., 1988). With the preliminary use of chemotherapy it became apparent that certain tumours which were unlikely to be eradicated by operative resection or radiotherapy alone, could be reduced to proportions more readily eradicated by a surgical operation or by radiotherapy or a combination of both. This application of chemotherapy as the first treatment modality in a combined therapeutic approach using the chemotherapy to induce changes which would make the tumour potentially more curable by standard means has been variously referred to as 'induction', 'neoadjuvant', 'reducing', 'primary', or 'basal' chemotherapy. There are good reasons for accepting that 'induction chemotherapy' is probably the most appropriate description whether the chemotherapeutic agents are given systemically or by regional infusion (Stephens, 1989). Although from historic comparison there is strong evidence that induction chemotherapy can be used effectively to reduce some advanced localized cancers to curable proportions, it has been difficult to organize well-randomized control studies to establish the point to the satisfaction of all. Numbers of matching patients in these categories are small. Another difficulty has been that differences in outcome have been so striking in some series that clinicians who have witnessed these responses have been reluctant not to treat first all their patients with advanced localized malignancies in this way (the induction chemotherapy being delivered either systematically or regionally). Some randomized studies have, however, recently become available indicating a significant beneficial effect of the use of induction chemotherapy in management of head and neck cancer (Shanta and Krishnamurthi, 1980; Arcangeli et al., 1983). Using historic controls a number of other studies have similarly indicated the value of induction chemotherapy especially when delivered by intra-arterial infusion in the management of advanced Stage III breast cancer, gastric cancer, and sarcomas and advanced cancers in limbs (Koyama et al., 1975; Jussawalla and Shetty, 1978; Stephens el al., 1980,
170 1986, 1987; Stephens, 1983b, 1988; Ensminger and Gyves, 1984; Jaffe et a l . , , 1985; Krementz, 1986). Seven principles of management using induction chemotherapy may now be described.
Principle 1 For some aggressive or advanced but localized malignant tumours, in which prospects of cure are not good by extirpative surgery alone, or by radiotherapy with or without surgery (or only by mutilating surgery such as limb amputation), chemotherapy can be effective in inducing changes which may render the tumours more curable by subsequent radiotherapy and/or surgical excision.
Principle 2 In such planned integrated tumour management it is important to use chemotherapy as the first modality of treatment whilst the tumour blood supply is intact and has not been compromised by previous surgical operation or radiotherapy.
Principle 3 In using chemotherapy as a first treatment modality it is the well-vascularized cells at the tumour periphery which are most affected by the chemotherapy. Less well-vascularized cells towards the centre of the tumour may be less affected. However, it is cells at the turnout periphery which are most likely to establish tumour recurrence after surgical excision so that it is most important that these be eliminated as completely as possible prior to surgery. The cells at the centre of the lesion are less affected by chemotherapy but are more certainly eradicated by surgical resection.
Principle 4 In combining chemotherapy with standard therapy in management of advanced and aggressive localized tumours it is important to eradicate as much tumour as possible by chemotherapy (within the patient's reasonable tolerance level) before embarking upon the next step in management. It is inappropriate to give a 'token' dose of chemotherapy in the hope of doing 'some good'. It is important to gain as much advantage from chemotherapy as possible in the induction treatment phase.
F.O. Stephens
Principle 5 Some tumours are supplied by an artery which can be cannulated so that the chemotherapy can be effectively administered at a higher concentration by intra-arterial delivery, thus offering a greater local antitumour potential than would be achieved if the same dose of the same agent were given systematically. The total dose of agent to which the tumour is exposed is also somewhat increased (Stephens, 1983a, 1988). The advantage in concentration and total dose will depend predominantly on the size of the artery being infused (the smaller the artery the greater the concentration and the greater the total dose exposure of the tumour cells to the agent infused).
Principle 6 1. When an antitumour agent is given by intraarterial infusion, in addition to a greater localized antitumour effect, there will also be greater regional toxicity, than after systemic administration of the same dose of the same agent over the same period. However, after passage through the regional tissues containing the turnout, except in the case of infusion of liver or kidney, most of the antitumour agent will then pass into the systemic circulation. Systemic toxicity will therefore be similar to systemic toxicity following systemic administration of the agent. 2. In the case of liver or kidney infusion, much of the agent may be detoxified or removed on first passage through the liver or kidney thus hopefully effecting a greater local antitumour response with significantly reduced risk of systemic toxicity. 3. After passing through the infused regional tissues, efflux of the chemotherapeutic agents into the systemic circulation will in fact initiate systemic 'adjuvant' chemotherapy from the first day of induction chemotherapy (unless liver or kidney is being infused). Additional systemic chemotherapy may or may not be required as adjuvant treatment subsequent to local tumour eradication.
Principle 7 No matter how effective induction chemotherapy appears to have been, it is almost inevitable that some tumour cells will have survived (especially towards the less-vascularized centre of the original tumour mass). These surviving cells will initiate recurrence of a more resistant tumour cell colony, unless follow-up radiotherapy or surgical excision, or both, are carried out.
Developments in Surgical Oncology:Induction (Neoadjuvant)Chemotherapy T H E P L A C E O F R A D I O T H E R A P Y IN INTEGRATED MANAGEMENT PROGRAMMES
The position of radiotherapy in integrated local tumour management is as yet uncertain. Radiotherapy used some months prior to chemotherapy will induce endarteritic changes which will reduce the effectiveness of subsequent chemotherapy by reduction of tumour blood flow. Radiotherapy given at the same time as chemotherapy may have an enhancing effect but risk of regional toxicity may also be considerably increased (Begg, 1986; Hopkins and Looney, 1988; Steel, 1989). Radiotherapy given after chemotherapy but before operative surgery may have advantages. Radiotherapy is also more effective when given to well-oxygenated tissues, so that it should be more effective given before operative surgery in which blood vessels will be damaged or ligated. Tumour in scar tissue is less sensitive to irradiation than tumour in well-vascularized tissue. Again, radiotherapy is more effective against the well-vascularized cells of the tumour periphery, than cells in the tumour centre. However, the central aspect of the tumour is that which can be most certainly eradicated by surgical resection if there is residual tumour after radiotherapy. Unfortunately, radiotherapy given prior to surgery may add difficulty to the operative dissection and risks impairing would healing following operation. For this reason many surgeons prefer that radiotherapy be given after and not before operative surgery. Thus it is clear that in using radiotherapy in a combined treatment regimen, it is best that it should not be given before chemotherapy. However, whether radiotherapy is best given during or immediately following chemotherapy or whether it should be reserved until after any operative surgery has been carried out is as yet uncertain and may well depend upon individual circumstances (both anatomical and geographical).
CONCLUSIONS
Much progress has been made in the treatment of advanced or locally aggressive regional malignancies but many questions remain to be answered. Some of these include: 1. The best combinations, administration of agents with least disturbance to 2. The most appropriate
doses and methods of to the greatest effect, the patient. timing of induction
3. 4.
5.
6.
171
chemotherapy in relation to following surgery or radiotherapy. The most appropriate timing of radiotherapy in relation to chemotherapy or surgery. The indications for or need for systemic adjuvant chemotherapy following apparently successful treatment of a primary cancer. The types of turnouts and situation of tumours which will best respond to combined management regimens. Possible integration of other forms of management such as immunotherapy, hyperthermia or laser treatment.
Surgeons involved in such studies (i.e. surgical oncologists) need to become skilled and informed in more aspects of cancer management than that normally required in management of the majority of patients with localized cancer and will do well with operative surgery alone. Questions like those above and many more need answers, but in establishing the rationale of combined modality management for cancers which do not have a good prognosis with one form of standard treatment alone and in establishing principles and rationale for induction chemotherapy then at least a good start has been made.
W H A T T H E N IS S U R G I C A L O N C O L O G Y ?
Surgical oncology is the study of malignant disease and the practice of caring for patients with malignant disease when a surgical operation may be required as a major component of treatment. Thus surgical oncology is mainly concerned with localized tumour problems. It aims at improving patient survival and quality of life by improved methods of tumour control and eradication. It requires not only the skills of an operating surgeon but embraces a thorough study of malignant disease and integration of all treatment modalities required in the care of these patients. Where necessary the surgical oncologist should cooperate with the medical oncologist and/or radiation oncologist in planning initial coordinated and integrated treatment likely to offer the best outcome for the patient.
References Arcangeli G, NerviC, Rihini R, Creton G, Mirri MA, Guerra A (1983). Combined radiation and drugs: the effect of intraarterial chemotherapyfollowedby radiotherapy in head and neck cancer. Radiotherapy and Oncology, 1,101-107.
172 Begg AC (1986). Additivity versus repair in fractionated treatment combining drugs and X-rays - a theoretical analysis. International Journal of Radiation Oncology Biology Physics, 9, 1667-1671. Ensminger WD, Gyves JW (1984). Regional cancer chemotherapy. Cancer Treatment Report, 68, 101-115. Hopkins HA, Looney WB (1988). Further experimental studies on alternating chemotherapy and radiotherapy. In Neo-adjuvant Chemotherapy - Second International Conference, ed. Jacquillat C, Weil M, Khayat D, John Libbey - Eurotext Publishers, London, Paris. Huggins C, Hodges CF (1941). Studies on prostatic cancer 1. The effect of castration, of oestrogen and androgen injection on serum phosphate in metastatic carcinoma of the prostate. Cancer Research, 1,293. Jaffe N, Robertson K, Takave Y, Cangir A, Wallace S, Carrasco H et al. (1985). Control of primary osteosarcoma with chemotherapy. Cancer, 56, 461-466. Jussawalla JD, Shetty PA (1978). Experiences with intra-arterial chemotherapy for head and neck cancer. Journal of Surgical Oncology, 10, 33-37. Klopp GT, Alford TC, Bateman J, Berry GN, Winship T (1950). Fractionated intra-arterial cancer chemotherapy. Annals of Surgery, 132, 811-832. Koyama H, Wada T, Takahashi Y, Iwanaga T, Aoki Y, Wada A et al. (1975). Intra-arterial infusion chemotherapy as a preoperative treatment of locally advanced breast cancer. Cancer, 36, 1603-1612. Krementz ET (1986). Regional perfusion. Cancer, 57,416-432. Noguchi S, Miyauchi K, Niahizawa Y, Koyama H, Terasawa T (1988). Management of inflammatory carcinoma of the breast with combined modality therapy including intra-arterial
F.O. Stephens infusion chemotherapy as an induction therapy. Cancer, 61, 1483-1491. Shanta V, Krishnamurthi S (1980). Combined bleomycin and radiotherapy in oral cancer. Clinical Radiology, 31,617-620. Steel G (1989). A letter. Radiotherapy and Oncology, 14, 315316. Stephens FO (1983a). Pharmacokinetics of intra-arterial chemotherapy. Recent Results in Cancer Research, 86, 1-12. Stephens FO (1983b). Clinical experience in the use of intraarterial infusion chemotherapy in the treatment of cancers in the head and neck, the extremities, the breast and stomach. Recent Results in Cancer Research, 86, 122-127. Stephens FO (1988). Why use regional chemotherapy - principles and pharmacokinetics. Regional Cancer Treatment, 1, 4-10. Stephens FO (1989). The case for a name change from neoadjuvant to induction chemotherapy. Cancer, 63, 1245. Stephens FO, Crea P, Harker GJS, Roberts B, Hambly CK (1980). Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer. Lancet, ii, 435-438. Stephens FO, Adams BG, Crea P (1986). Intra-arterial chemotherapy given preoperatively in management of gastric carcinoma. Surgery, Gynecology and Obstetrics, 162, 370-374. Stephens FO, TattersaU MHN, Marsden W, Waugh RC, Green D, McCarthy SW (1987). Regional chemotherapy using cisplatin and adriamycin as primary treatment for advanced sarcomas in shoulder, pelvis and thigh. Cancer, 60, 724-735. von Essen CF, Joseph LBM, Simon GT, Singh SP (1968). Sequential chemotherapy and radiation therapy of buccal mucosa carcinoma in South India: methods and preliminary results. American Journal of Roentgenology, 102, 530-540.
