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Gynecologic oncology: Present status and future aspects
Gynecologic oncology: Present status and future aspects PER
KOLSTAD,
M.D.
Oslo, Norway
gynecologic cancer should be made by an individual physician with one main interest, whether he be surgeon, radiotherapist, or chemotherapist. This implies that every such patient should be referred to a hospital where this facility for interdisciplinary consultation exists. Gynecologic oncology is in fact an old specialty, and many of the achievements within the general field of cancer diagnosis and treatment have evolved from clinical and experimental researches on female pelvic cancer. Techniques for both radical operation and radiotherapy of gynecologic cancer were developed very early. Ernst Wertheim began his series of radical hysterectomies for cancer of the cervix in 1898, using an operation which had been described by Kies in 1895. Taussig and Nathanson in the early 1930’s introduced pelvic lymphadenectomy after radium therapy without removal of the uterus. Lymphadenectomy was used sporadically by Wertheim in conjunction with his operation. Meigs began to do routine lymphadenectomy with the radical hysterectomy in 1939. Pelvic exenteration for gynecologic cancer was first performed by Brunschwig in 1946 and by Parsons in 1947. The first use of radium in the treatment of cancer of the cervix was in New York in 1903 by Margaret Cleaves. Abbe was able to report an eight-year cure in 1913. The Stockholm method of intracavitary radium application was developed by Forsseli in 19101914. The Paris method was established in 1919 and the Manchester system in 1938. Miiller in 1949 introduced intraperitoneal
I N T H E L A s T three decades, in all fields of medicine we have seen what almost amounts to an explosion of knowledge. The effect has been that, even in the comparatively limited area of one specialty, no longer can an individual physician master all the different techniques of investigation and treatment that have developed. The old saying that a specialist is one who knows more and more about less and less is no longer strictly true-he cannot keep on learning more and more, there are limits to human capability. Specialization within a specialty is therefor accepted as a necessity. This has happened in obstetrics and gynecology, where one finds departments of gynecologic endocrinology, fertility, reproductive biology, and perinatal medicine already in existence in several institutions. To this list can now justifiably be added gynecologic oncology. I do not need to remind you of the results of inadequate initial therapy in a woman with early gynecologic cancer when they lead to persistent disease, a miserable existence, and often a painful death. They put a heavy responsibility on the shoulders of any physician who will nowadays treat a cancer patient, for specialized oncology units in several different countries have shown that cooperation between disciplines produces greatly improved results. Ideally, nowadays, no decision about the initial treatment of a patient with From the Department of Gynecology, The Norwegian Radium Hospital. The Joseph Price Oration Presented at the Eighty-third Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, September 7-9, 1972.
597
598
March 1. 19i3 Am. J. Ohstrt. Cynecol.
Kolstod
instillation of radioactive colloidal gold in the treatment of ovarian cancer. The female reproductive system cbntinues to be a fertile field for research in and development of new methods in cancer therapy. One gynecologic neoplasm, choriocarcinoma, was the first malignancy known to be cured by chemotherapy. The first report of successful methotrexate treatment of this very malignant tumor was published by Li, Hertz, and Spencer1 in 1956. Within the field of cancer detection, the profession may certainly be proud that the possibilities for the early detection of gynecologic cancer today are so varied, and that the methods are so well developed. One thinks especially of Papanicolaou’s contribution of exfoliative cytology and of Hinselmann’s pioneer work on colposcopy. These are only a few examples to show that gynecologic oncology through the years has been a fertile field for research and the development of new techniques. There is still, however, no universal agreement upon a definition of the specialty or upon the qualifications needed for a physician to become certified as a gynecologic oncologist. In most places the setup is based on what is called “tradition’‘-this is really the indelible imprint of the powerful personalities of one or two pioneers. Gynecologic
oncology
units
In many if not most countries in the world the majority of patients with gynecologic cancer are treated in hospitals remote from and without any connection with a medical school or a cancer treatment center. Too often choice of therapy will depend upon the interests and beliefs of the individual to whom the woman is referred. Both radiation and operation have an acknowledged and proved place in the therapy of female genital cancer, They may be utilized alone or in combination. Chemotherapy and hormone therapy have also come into regular use the last two decades. In the near future it is possible that improved knowledge about cellular immunolo
ation and treatment of certain tumor types. But in spite of this, adequate radiotherapy and skilled surgery are still the means by which most permanent cures are reached. For many years now, there has been constant debate between surgeons and radiotherapists as to which form of therapy gave better results for a given type of genital cancer. This is now out of date. It must be obvious that an adequate work-up of the cancer patient is not possible without access to advanced equipment and methods and the combined expertise of individuals from several disciplines. To make a proper selection of therapy it is necessary not only to know the histologic type and the primary site of the tumor, but also the growth pattern and the exact extent of the disease. Furthermore, we must with a high degree of precision know what we can achieve by, for example, intracavitary radioisotope treatment, high voltage external irradiation, radical operation, chemotherapy, or a combination of two or more of these treatment modalities. Perhaps most important is an exact knowledge about the limitations and complications of each method. All this takes the skill and experience of several different experts-both the surgeon and the radiotherapist must each play their part in cooperation with othersall together with one object in view, the best possible treatment of the individual patient. Scandinavia is often referred to as an example of good organization of health services and this includes the field of cancer therapy. In Denmark, Finland, Norway, and Sweden regional cancer treatment centers cover specified geographic areas (Table I). There are, however, some differences in the organization of gynecologic oncology between the four countries which may exemplify the situation in many parts of the Western world. In Sweden, gynecologic oncology has for many years been synonymous with gynecologic radiotherapy. This specialty has ever since the days of GGsta Forssell had a prominent position in Swedish medicine. The outstanding work of his successors at the Radiumhemmet, Heyman and Kottmeier, is well known. To acquire the certificate of gyne-
Volume Number
115 5
Table I. Regional in Scandinavia Country Denmark Finland Norway Sweden Total
Gynecologic
cancer
Population (million)
treatment
599
centers
No. of regional centers
5.0 4.8
3 3
3.9 8.0 21.7
oncology
: z
cologic radiotherapy, it is necessary first to become a specialist in gynecology and obstetrics. In addition, half a year’s training in general radiotherapy and one and a half years’ training in gynecologic radiotherapy is required. The gynecologic radiotherapist in Sweden is responsible both for the intracavitary and the external radiotherapy. In Finland there also exists an advanced certificate for gynecologic radiotherapy. The main responsibility of the gynecologic radiotherapist there is intracavitary treatment with radium or other radioisotopes. Both in Finland and Sweden a variable amount of surgery is carried out in the departments of gynecologic radiotherapy. In some clinics, the operative part of the work is minimal, in others the spectrum of pelvic operations performed is broader. In general, however, surgery for female pelvic cancer in both Finland and Sweden is mainly concentrated in the gynecologic departments of the larger county or regional hospitals. The regional hospitals in Scandinavia usually serve as teaching hospitals for the universities. In contrast to Sweden and Finland, there are no specialized units for gynecologic cancer in the radiotherapy centers in Denmark. Treatment is determined by the radiotherapist, and it is not required that he should be trained in the discipline of gynecology and obstetrics. Surgery for pelvic cancer is performed both in surgical and gynecologic departments and in different types of hospitals around in the country. There is, however, a tendency toward concentration of the most advanced radical pelvic operation in the larger regional hospitals. It is in Norway that one finds centraliza-
BERGEN
Fig. 1. The
only fully equipped cancer treatment center in Norway today is located at Oslo. Two other centers are under development at the Universities of Bergen and Trondheim. Probably one center will also be built at the University of Tromse.
tion of gynecologic cancer treatment fully developed. There is only one large cancer treatment center, The Norwegian Radium Hospital, which is located in Oslo. To this hospital about 90 per cent of all new cases of invasive carcinoma of the cervix and the vulva, and about 60 per cent of all cases of carcinoma of the corpus and the ovary are referred. The cost of travel to and from Oslo and of the period in hospital is completely covered by the National Health Service. Two other cancer treatment centers are now under development, one at the University of Bergen to cater for the Western part of Norway, and one at the new University of Trondheim, to deal with patients from the Northern and Central part of the country (Fig. 1). The chief of the Gynecologic Department
600
Kolstad
of The Norwegian Radium Hospital has traditionally always been a person trained in gynecology and obstetrics with some additional training in gynecologic radiotherapy. No board of gynecologic radiotherapy exists. Recruitment of the permanent staff and residents comes from the discipline of gynecology and obstetrics. The Department is responsible not only for intracavitary radioisotope treatment, but also for external radiotherapy, all operations, and hormone and cytostatic therapy. It must be emphasized, however, that there is a continuous close cooperation with the Radiotherapy Department, the Surgery Department, especially the Urologic Section, the Chemotherapy Section, and with the staffs of the service units, the Radiodiagnostic Department, the Radioisotope and Histopathological Laboratories. The daily supervision of external radiotherapy is carried out by the radiotherapists and the radiophysicists. In spite of these organizational differences in the gynecologic oncology services within the cancer treatment centers in Scandinavia, there is general agreement amongst the medical profession that certain types of cancer should always be referred to these centers. For instance, it is very exceptional for invasive carcinoma of the cervix to be treated in a community or county hospital. It should also be stressed that close collaboration exists between the general practitioner, the specialist in private practice, the local hospital and the cancer treatment center. Adequate diagnosis, treatment and follow-up are considered absolutely dependent upon an intimate teamwork in which all these links in the health service system must take part. There certainly is no general model for the establishment of sections of gynecologic oncology which will fit in with both medical tradition and the health care system in all places. There should, however, be no difference of opinion about the necessity of concentration of patients, equipment and knowhow in special units. These units may be part of larger cancer treatment centers or independent sections of departments of gynecology and obstetrics. They would preferably be affiliated to a medical school. Ideally each
March 1. 1973 Am. J. Obstet. Cynecol.
unit should serve a region with a population of not less than one million people in order that it may receive enough patients. It is of the utmost importance that, when these gynecologic oncology units are established, there shall be no doubt that the responsibility for the treatment of the woman with genital cancer rests primarily with the obstetrician and gynecologist. The necessity for cooperation with experts from several fields must be accepted, but in my opinion, the initial work-up of the patient and the final responsibility for care should always lie with the gynecologic oncologist. What has been called “treatment by committee” never works out for the best+ne clinician must be in final charge of the patient for optimum results, but of course he must have special training and experience. If this view is accepted, then the next step is to define the qualifications needed for this advanced specialty. Advanced
certification
Two years ago, Thornton2 in his Presidential Address to this assembly, suggested the following education for the physician especially trained in all phases of the treatment of gynecologic malignancy. After having passed the Board of Obstetrics and Gynecology, three additional years of training in gynecologic oncology would be required. The program should include adequate operative experience for the independent performance of radical operative procedures. The gynecologic oncologist should also possess knowledge of the principles of radiobiology and radiation physics and skill in the techniques of radiation therapy, but not the training to qualify as a radiotherapist. He would be expected to possess knowledge of the modes of action and experience in the use of the various chemotherapeutic agents. Finally, he should have formal training and experience in gross and microscopic pathology. I agree completely with these recommendations, but I would like to add that the gynecologic oncologist should receive some extra training in general abdominal surgery and urology, and he should also have taken a course in
Volume Number
115 5
Gynecologic
cancer epidemiology and statistics in order to be able to conduct and evaluate clinical trials and follow-up studies. Since this Presidential Address was given, the United States has to the best of my knowledge been the first country in the world to establish an advanced Board for Gynecologic Oncology. This certainly will have great influence on the future development both of educational programs and of gynecologic oncology units, and this will ultimately show itself by improved care of the individual patient. It probably will take a long time before other countries are able to follow the American Board of Obstetrics and Gynecology in this matter. In Scandinavia discussions about the establishment of gynecologic oncology as a separate specialty have been going on for some years, but the organizational differences in the four countries which I have described previously have made it difficult to reach agreement. One special criticism is that there will be too few permanent positions to attract residents to a 2 to 3 year advanced education. In the meantime, the already established gynecologic oncology departments serve as teaching units for residents aiming at the certificate in obstetrics and gynecology. For example, in Sweden it is required that the Chief and the Assistant Chiefs of a Department of Gynecology and Obstetrics must have at least half a year’s education in gynecologic radiotherapy. In Norway almost every specialist in obstetrics and gynecology whether he works in private practice or in a hospital has had a minimum of half a year’s training at The Norwegian Radium Hospital. This of course makes cooperation between the doctor at the local level and the cancer treatment center much more easy. Registration
and
follow-up
A complete picture of the cancer situation in a given population cannot be achieved without compulsory notification of all new cases and all deaths from cancer. Cancer registration and epidemiological investigations are today well recognized tools in the fight against cancer. Gynecologic oncology units should preferably always collaborate
STAGE
IV
STAGE
III
STAGE
II
STAGE
oncology
601
I
-40
1932 Total
number
-so treated:
-60
1970
8652
Fig. 2. Stage distribution for carcinoma of the cervix at The Norwegian Radium Hospital, 19321970. with a cancer registry covering the population which the unit aims at serving. This situation is already established in Scandinavia and in some other countries or areas within larger countries. In Scandinavia there is the ideal situation that the population of each country is not too big and is relatively stable. In addition, every person is liable to report every change of address even if he is only moving from one place to another within the same city. This makes it easy for the Cancer Registries to trace every patient once she is reported to have cancer. The introduction of personal identification numbers and automated data processing has made this type of follow-up even more complete and simpler. For instance, in Norway the Cancer Registry now at regular intervals matches the information stored in the computer with information received from the Central Statistical Bureau about all deaths in the country. For every deceased person where cancer has been diagnosed during life or when cancer is mentioned on the death certificate, additional information can if necessary easily be obtained from the physician who signed the death certificate. The Scandinavian Cancer Registries have been in operation since the early 1950’s and already several interesting epidemiological studies have been published. For example, to the gynecologist it is very surprising that in spite of increasing and widespread use of exfoliative cytology with resulting detection and eradication of a large
602 Kolstad
t
March 1. 1973 Am. J. Obstet. Cynecol.
t
CERVIX
conduct his own follow-up investigations. Treatment protocols for the different types, sites and stages of cancer should at regular intervals be evaluated and re-evaluated. When clinical trials are planned, it should be done in collaboration with experts in statistics. It is not always realized that it takes a substantial number of patients to prove or disprove that, for example, one special treatment modality will give let us say 10 per cent more five-year survivors than another method. And one needs at least a 10 per cent difference to be certain that one method is to be preferred. The actual number will be around 400 patients in the trial group and 400 in the control group. A 20 per cent increase in survival will need at least 200 in each group. This is one more advantage of concentrating patients in special oncology units. Although it is possible to conduct cooperative clinical trials by combining results from several hospitals, it is of course much more likely that one will obtain identical treatment conditions in one single or a few large units. Both regular follow-up studies and clinical trials are dependent upon good record keeping and a follow-up system that makes it possible to register all relevant details on a prospective basis. That is to say, the information that will be required at the end of the investigation must be known at the beginning and arrangements made for its collection in each individual patient’s notesone can never go back and collect it afterward. In this computerized age it seems reasonable to adjust medical records to the computer so that all clinical data of importance can easily be stored and retrieved. In the design of records for a gynecologic oncology unit, however, it should be kept in mind that they serve many functions. They are not only scientific documents suitable for a computer, but also working documents which the physician must be able to use continuously during the patient’s stay in the hospital. The medical records may also be referred to under legal circumstances. And an even more “down-to-earth” warningcomputerized record systems are all very fine for the large unit working in hundreds of
dOVARY
0 L
I
1953
-55
-60
-65
-70
YEAR
Fig. 3. Total number of cases of carcinoma of the cervix, ovary, and corpus reported to the Cancer Registry of Norway 1953-1970. number of in situ lesions, there has been no decrease in the incidence rates of invasive cervical carcinoma.3 It has since been observed that the high risk group of women tend to avoid mass screening and that screening of a population at intervals does not pick up the rapidly growing tumor.’ Personally I feel, however, that it is too early to draw any conclusions about the effect of the screening programs which started only eight to ten years ago. One very definite observation is that the stage distribution of carcinoma of the cervix has shown a shift. Today almost 60 per cent of all cases are in clinical Stage I when first detected and only 15 per cent are in the late Stages III and IV (Fig. 2). The statistics from the Cancer Registries show clearly that carcinoma of the corpus and carcinoma of the ovary are becoming more frequent (Fig. 3) . The ratio between the incidence rates for carcinoma of the cervix and carcinoma of the corpus now varies between 1.5 : 1 and 2.2 : 1, and the absolute number of ovarian carcinomas detected is close to the number of invasive cervical carcinomas so that the ratio between them approaches 1: 1 .5 Side by side with these large-scale epidemiological studies emanating from the Cancer Registries, the gynecologic oncologist must
Volume Number
115 5
patients they are ache. It effective,
Gynecologic
every year, but for the smaller unit liable to be an unnecessary headis better to use the simpler, just as good old manual card index system.
While we have been thinking about plans for gynecologic oncology units, no doubt some of your thoughts have wandered to the more distant future. Is it possible to foresee future developments? Compared with malignant tumors at other sites the treatment results in gynecologic cancer must be characterized as good. But there are still innumerable problems to be solved. The magic word which is used under so many circumstances today in connection with unsettled problems is “research.” Undoubtedly basic research at the molecular and cellular level, immunologic investigations, and research aimed at the development of new chemotherapeutic agents may lead us to the ultimate goal, precise knowledge about the cause or causes of cancer. What has been achieved in the first 70 years of the twentieth century is remarkable. Perhaps the next 30 years will produce even more astonishing results. But until it is possible to prevent cancer, the clinician in his daily work with the patient must never forget that his part is as vital as that played by the basic scientist. There are lots of loose ends that must be tidied up by properly designed clinical research. The gynecologic oncology unit must in the years to come take on this great responsibility. Let me illustrate my view by a few practical examples. The frequency of Stage I carcinoma of the cervix has increased considerably the last two decades. A relatively large proportion of these lesions are found in the younger age groups. Both adequate radiotherapy and skilled operation may give a cure rate of more than 80 per cent. At our Clinic during the years 1960-1966 537 Stage IB carcinomas of the cervix were treated by combined preoperative radium and radical hysterectomy with pelvic lymphadenectomy. The over-all five-year survival was
603
Table II. Results
of combined treatment of the cervix, Stage IB6
carcinoma
in
5 year surHistologic
Horizons
oncology
type
Total
Epidermoid Adenocarcinoma Undifferentiated Total
vival (%I
No.
474 34 29 537
89.2 85.4 79.3 88.3
Table III.
Lymph node metastases in carcinoma of the cervix, Stage IB, before the use of peroperative lymphographic control” Positive Histologic
type
Epidermoid Adenocarcinoma Undifferentiated Total
Total No.
474 34 29 53t
nodes
No.
Per cent
73 3 5 81
15.4 8.8 17.2 757
Table IV. Lymph node metastases in carcinoma of the cervix Stage IB after the use of peroperative lymphographic control* Positive Total
No.
221
No.
nodes Per cent
26
57
*In eight patients cancer-involved left behind if peroperative lymphograms
nodes would had not
have been been used.
88.3 per cent (Table II). It was found that the most significant prognostic factor was positive nodes, for only 62.9 per cent survived 5 years as compared with 92.9 per cent in those without node involvement. The frequency of positive nodes was found to be 15.1 per cent (Table III). In order to improve the technique of dissection of the pelvic lymph nodes and thereby possibly achieve still better results, we have since 1970 used peroperative lymphographic control during the extended Wertheim operations. It was soon realized that our earlier lymphadenectomies must often have been incomplete. Even with the aid of peroperative lymphography it is difficult to find all
604
Kolsrad
Fig. 4. Lymph section; c and
March 1, 1973 Am. J. Obstet. Gynecol.
nodes in the pelvis before d, complete dissection.
and after
the 1ymph nodes draining the uterine cervix (Fig. 4). Tc P date 251 patients have been operated upon L with this technique, and the frequency of p’ ositive nodes in Stage IB has been 26 per (:ent (Table IV), which is 11 per cent more than in the earlier series. The increase
lymphadenectomy:
a and
b, incomplete
dis-
is probably due not only to more complete dissection but also to improved histopathologic examination. In 8 patients positive nodes would have been left behind if lymphographic control had not been used. Will this more meticulous procedure really give a higher cure rate? This question can only be
Volume Number
115 5
answered after a careful and complete follow-up of a large number of patients. Another pertinent question in the treatment of carcinoma of the cervix is intimately connected with radiobiologic studies in the laboratory. It is a well established fact that hypoxic and near-anoxic tumor cells are more resistant to ionizing irradiation than are well-oxygenated cells7 Furthermore, it has conclusively been shown that the proportion of cervical cancers with reduced vascularization and anoxic foci increases with advancing stage of the disease.8 The question is whether the poor results of radiotherapy in the more advanced stages are to a large extent dependent upon the oxygen factor. Basic research in the laboratories indicates that this may be true, but laboratory studies cannot give us the final answer. Only clinical studies can solve this problem. At our clinic a trial in which patients breathed atmospheric oxygen during radiotherapy of carcinoma of the cervix Stage II was carried out during the years 1967-1968. After a follow-up period of 3 to 5 years, 36.9 per cent with pelvic recurrence was found in the control series as compared with 23.3 per cent in the oxygen series, and the difference in survival was 10 per cent.” There are indications that to achieve optimal results, it is not sufficient to give the patient oxygen at atmospheric pressure. Hyperbaric oxygen radiotherapy there-
Gynecologic
oncology
605
fore has come into use in several institutions for different tumor types.l” Carcinoma of the cervix seems well suited to this type of therapy. However, only controlled clinical trials will show if hyperbaric oxygen radiotherapy is better than conventional methods. The trials reported up to date indicate an affirmative answer.ll This has been a brief review of a theme that hopefully is of interest to all those who wish to improve the provision of health care to women with gynecologic cancer. I have not shown any remarkable results or intricate studies, nor indulged in dreams about the future. The aim of this address has been to discuss some very simple basic problems. Some possible lines for the future organization of
REFERENCES
1.
2. 3.
4.
5.
Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Sot. Exp. Biol. (N. Y.) 93: 361, 1956. Thornton, W. N.: AM. J. OBSTET. GYNECOL. 109: 671, 1971. The Cancer Registry of Norway: Trends in Cancer Incidence in Norway 1955-67, Oslo, 1972, Universitetsforlaget. Pedersen, E., Hoeg, K., and Kolstad, P.: Acta Obstet. Gynecol. Stand. 50 (Suppl. 1 l), 1971. Ringertz, N.,, editor: Cancer incidence in Finland, Iceland, Norway and Sweden. Acta Path. Microbial. Stand., Sect. A, Suppl. 224, 1971.
6. 7. 8.
9. 10.
Rampone, J. F., Klem, V., and Kolstad, P.: Obstet. Gynecol. In press. Gray, L. H.: Am. J. Roentgenol. 85: 803, 196i. Kolstad, P.: Vascularization, oxygen tension and radiocurabilitv in cancer of the cervix. Oslo, 1963, Univektetsforlaget. Bergsje, P., and Kolstad, P.: Stand. J. Clin. Lab. Invest. 22 (Suppl. 106): 167, 1968. Churchill-Davidson, -I., Sanger, C., and Thomlinson. R. H.: Br. 1. Radio]. 30: 406. 1957. ’ Pizey, N. C. D., and Bullimore, J. A.: J. Obstet. Gynaecol. Br. Commonw. 75: 1275, 1968. ”
11.
KOLSTAD,
M.D.
Oslo, Norway
gynecologic cancer should be made by an individual physician with one main interest, whether he be surgeon, radiotherapist, or chemotherapist. This implies that every such patient should be referred to a hospital where this facility for interdisciplinary consultation exists. Gynecologic oncology is in fact an old specialty, and many of the achievements within the general field of cancer diagnosis and treatment have evolved from clinical and experimental researches on female pelvic cancer. Techniques for both radical operation and radiotherapy of gynecologic cancer were developed very early. Ernst Wertheim began his series of radical hysterectomies for cancer of the cervix in 1898, using an operation which had been described by Kies in 1895. Taussig and Nathanson in the early 1930’s introduced pelvic lymphadenectomy after radium therapy without removal of the uterus. Lymphadenectomy was used sporadically by Wertheim in conjunction with his operation. Meigs began to do routine lymphadenectomy with the radical hysterectomy in 1939. Pelvic exenteration for gynecologic cancer was first performed by Brunschwig in 1946 and by Parsons in 1947. The first use of radium in the treatment of cancer of the cervix was in New York in 1903 by Margaret Cleaves. Abbe was able to report an eight-year cure in 1913. The Stockholm method of intracavitary radium application was developed by Forsseli in 19101914. The Paris method was established in 1919 and the Manchester system in 1938. Miiller in 1949 introduced intraperitoneal
I N T H E L A s T three decades, in all fields of medicine we have seen what almost amounts to an explosion of knowledge. The effect has been that, even in the comparatively limited area of one specialty, no longer can an individual physician master all the different techniques of investigation and treatment that have developed. The old saying that a specialist is one who knows more and more about less and less is no longer strictly true-he cannot keep on learning more and more, there are limits to human capability. Specialization within a specialty is therefor accepted as a necessity. This has happened in obstetrics and gynecology, where one finds departments of gynecologic endocrinology, fertility, reproductive biology, and perinatal medicine already in existence in several institutions. To this list can now justifiably be added gynecologic oncology. I do not need to remind you of the results of inadequate initial therapy in a woman with early gynecologic cancer when they lead to persistent disease, a miserable existence, and often a painful death. They put a heavy responsibility on the shoulders of any physician who will nowadays treat a cancer patient, for specialized oncology units in several different countries have shown that cooperation between disciplines produces greatly improved results. Ideally, nowadays, no decision about the initial treatment of a patient with From the Department of Gynecology, The Norwegian Radium Hospital. The Joseph Price Oration Presented at the Eighty-third Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, September 7-9, 1972.
597
598
March 1. 19i3 Am. J. Ohstrt. Cynecol.
Kolstod
instillation of radioactive colloidal gold in the treatment of ovarian cancer. The female reproductive system cbntinues to be a fertile field for research in and development of new methods in cancer therapy. One gynecologic neoplasm, choriocarcinoma, was the first malignancy known to be cured by chemotherapy. The first report of successful methotrexate treatment of this very malignant tumor was published by Li, Hertz, and Spencer1 in 1956. Within the field of cancer detection, the profession may certainly be proud that the possibilities for the early detection of gynecologic cancer today are so varied, and that the methods are so well developed. One thinks especially of Papanicolaou’s contribution of exfoliative cytology and of Hinselmann’s pioneer work on colposcopy. These are only a few examples to show that gynecologic oncology through the years has been a fertile field for research and the development of new techniques. There is still, however, no universal agreement upon a definition of the specialty or upon the qualifications needed for a physician to become certified as a gynecologic oncologist. In most places the setup is based on what is called “tradition’‘-this is really the indelible imprint of the powerful personalities of one or two pioneers. Gynecologic
oncology
units
In many if not most countries in the world the majority of patients with gynecologic cancer are treated in hospitals remote from and without any connection with a medical school or a cancer treatment center. Too often choice of therapy will depend upon the interests and beliefs of the individual to whom the woman is referred. Both radiation and operation have an acknowledged and proved place in the therapy of female genital cancer, They may be utilized alone or in combination. Chemotherapy and hormone therapy have also come into regular use the last two decades. In the near future it is possible that improved knowledge about cellular immunolo
ation and treatment of certain tumor types. But in spite of this, adequate radiotherapy and skilled surgery are still the means by which most permanent cures are reached. For many years now, there has been constant debate between surgeons and radiotherapists as to which form of therapy gave better results for a given type of genital cancer. This is now out of date. It must be obvious that an adequate work-up of the cancer patient is not possible without access to advanced equipment and methods and the combined expertise of individuals from several disciplines. To make a proper selection of therapy it is necessary not only to know the histologic type and the primary site of the tumor, but also the growth pattern and the exact extent of the disease. Furthermore, we must with a high degree of precision know what we can achieve by, for example, intracavitary radioisotope treatment, high voltage external irradiation, radical operation, chemotherapy, or a combination of two or more of these treatment modalities. Perhaps most important is an exact knowledge about the limitations and complications of each method. All this takes the skill and experience of several different experts-both the surgeon and the radiotherapist must each play their part in cooperation with othersall together with one object in view, the best possible treatment of the individual patient. Scandinavia is often referred to as an example of good organization of health services and this includes the field of cancer therapy. In Denmark, Finland, Norway, and Sweden regional cancer treatment centers cover specified geographic areas (Table I). There are, however, some differences in the organization of gynecologic oncology between the four countries which may exemplify the situation in many parts of the Western world. In Sweden, gynecologic oncology has for many years been synonymous with gynecologic radiotherapy. This specialty has ever since the days of GGsta Forssell had a prominent position in Swedish medicine. The outstanding work of his successors at the Radiumhemmet, Heyman and Kottmeier, is well known. To acquire the certificate of gyne-
Volume Number
115 5
Table I. Regional in Scandinavia Country Denmark Finland Norway Sweden Total
Gynecologic
cancer
Population (million)
treatment
599
centers
No. of regional centers
5.0 4.8
3 3
3.9 8.0 21.7
oncology
: z
cologic radiotherapy, it is necessary first to become a specialist in gynecology and obstetrics. In addition, half a year’s training in general radiotherapy and one and a half years’ training in gynecologic radiotherapy is required. The gynecologic radiotherapist in Sweden is responsible both for the intracavitary and the external radiotherapy. In Finland there also exists an advanced certificate for gynecologic radiotherapy. The main responsibility of the gynecologic radiotherapist there is intracavitary treatment with radium or other radioisotopes. Both in Finland and Sweden a variable amount of surgery is carried out in the departments of gynecologic radiotherapy. In some clinics, the operative part of the work is minimal, in others the spectrum of pelvic operations performed is broader. In general, however, surgery for female pelvic cancer in both Finland and Sweden is mainly concentrated in the gynecologic departments of the larger county or regional hospitals. The regional hospitals in Scandinavia usually serve as teaching hospitals for the universities. In contrast to Sweden and Finland, there are no specialized units for gynecologic cancer in the radiotherapy centers in Denmark. Treatment is determined by the radiotherapist, and it is not required that he should be trained in the discipline of gynecology and obstetrics. Surgery for pelvic cancer is performed both in surgical and gynecologic departments and in different types of hospitals around in the country. There is, however, a tendency toward concentration of the most advanced radical pelvic operation in the larger regional hospitals. It is in Norway that one finds centraliza-
BERGEN
Fig. 1. The
only fully equipped cancer treatment center in Norway today is located at Oslo. Two other centers are under development at the Universities of Bergen and Trondheim. Probably one center will also be built at the University of Tromse.
tion of gynecologic cancer treatment fully developed. There is only one large cancer treatment center, The Norwegian Radium Hospital, which is located in Oslo. To this hospital about 90 per cent of all new cases of invasive carcinoma of the cervix and the vulva, and about 60 per cent of all cases of carcinoma of the corpus and the ovary are referred. The cost of travel to and from Oslo and of the period in hospital is completely covered by the National Health Service. Two other cancer treatment centers are now under development, one at the University of Bergen to cater for the Western part of Norway, and one at the new University of Trondheim, to deal with patients from the Northern and Central part of the country (Fig. 1). The chief of the Gynecologic Department
600
Kolstad
of The Norwegian Radium Hospital has traditionally always been a person trained in gynecology and obstetrics with some additional training in gynecologic radiotherapy. No board of gynecologic radiotherapy exists. Recruitment of the permanent staff and residents comes from the discipline of gynecology and obstetrics. The Department is responsible not only for intracavitary radioisotope treatment, but also for external radiotherapy, all operations, and hormone and cytostatic therapy. It must be emphasized, however, that there is a continuous close cooperation with the Radiotherapy Department, the Surgery Department, especially the Urologic Section, the Chemotherapy Section, and with the staffs of the service units, the Radiodiagnostic Department, the Radioisotope and Histopathological Laboratories. The daily supervision of external radiotherapy is carried out by the radiotherapists and the radiophysicists. In spite of these organizational differences in the gynecologic oncology services within the cancer treatment centers in Scandinavia, there is general agreement amongst the medical profession that certain types of cancer should always be referred to these centers. For instance, it is very exceptional for invasive carcinoma of the cervix to be treated in a community or county hospital. It should also be stressed that close collaboration exists between the general practitioner, the specialist in private practice, the local hospital and the cancer treatment center. Adequate diagnosis, treatment and follow-up are considered absolutely dependent upon an intimate teamwork in which all these links in the health service system must take part. There certainly is no general model for the establishment of sections of gynecologic oncology which will fit in with both medical tradition and the health care system in all places. There should, however, be no difference of opinion about the necessity of concentration of patients, equipment and knowhow in special units. These units may be part of larger cancer treatment centers or independent sections of departments of gynecology and obstetrics. They would preferably be affiliated to a medical school. Ideally each
March 1. 1973 Am. J. Obstet. Cynecol.
unit should serve a region with a population of not less than one million people in order that it may receive enough patients. It is of the utmost importance that, when these gynecologic oncology units are established, there shall be no doubt that the responsibility for the treatment of the woman with genital cancer rests primarily with the obstetrician and gynecologist. The necessity for cooperation with experts from several fields must be accepted, but in my opinion, the initial work-up of the patient and the final responsibility for care should always lie with the gynecologic oncologist. What has been called “treatment by committee” never works out for the best+ne clinician must be in final charge of the patient for optimum results, but of course he must have special training and experience. If this view is accepted, then the next step is to define the qualifications needed for this advanced specialty. Advanced
certification
Two years ago, Thornton2 in his Presidential Address to this assembly, suggested the following education for the physician especially trained in all phases of the treatment of gynecologic malignancy. After having passed the Board of Obstetrics and Gynecology, three additional years of training in gynecologic oncology would be required. The program should include adequate operative experience for the independent performance of radical operative procedures. The gynecologic oncologist should also possess knowledge of the principles of radiobiology and radiation physics and skill in the techniques of radiation therapy, but not the training to qualify as a radiotherapist. He would be expected to possess knowledge of the modes of action and experience in the use of the various chemotherapeutic agents. Finally, he should have formal training and experience in gross and microscopic pathology. I agree completely with these recommendations, but I would like to add that the gynecologic oncologist should receive some extra training in general abdominal surgery and urology, and he should also have taken a course in
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Gynecologic
cancer epidemiology and statistics in order to be able to conduct and evaluate clinical trials and follow-up studies. Since this Presidential Address was given, the United States has to the best of my knowledge been the first country in the world to establish an advanced Board for Gynecologic Oncology. This certainly will have great influence on the future development both of educational programs and of gynecologic oncology units, and this will ultimately show itself by improved care of the individual patient. It probably will take a long time before other countries are able to follow the American Board of Obstetrics and Gynecology in this matter. In Scandinavia discussions about the establishment of gynecologic oncology as a separate specialty have been going on for some years, but the organizational differences in the four countries which I have described previously have made it difficult to reach agreement. One special criticism is that there will be too few permanent positions to attract residents to a 2 to 3 year advanced education. In the meantime, the already established gynecologic oncology departments serve as teaching units for residents aiming at the certificate in obstetrics and gynecology. For example, in Sweden it is required that the Chief and the Assistant Chiefs of a Department of Gynecology and Obstetrics must have at least half a year’s education in gynecologic radiotherapy. In Norway almost every specialist in obstetrics and gynecology whether he works in private practice or in a hospital has had a minimum of half a year’s training at The Norwegian Radium Hospital. This of course makes cooperation between the doctor at the local level and the cancer treatment center much more easy. Registration
and
follow-up
A complete picture of the cancer situation in a given population cannot be achieved without compulsory notification of all new cases and all deaths from cancer. Cancer registration and epidemiological investigations are today well recognized tools in the fight against cancer. Gynecologic oncology units should preferably always collaborate
STAGE
IV
STAGE
III
STAGE
II
STAGE
oncology
601
I
-40
1932 Total
number
-so treated:
-60
1970
8652
Fig. 2. Stage distribution for carcinoma of the cervix at The Norwegian Radium Hospital, 19321970. with a cancer registry covering the population which the unit aims at serving. This situation is already established in Scandinavia and in some other countries or areas within larger countries. In Scandinavia there is the ideal situation that the population of each country is not too big and is relatively stable. In addition, every person is liable to report every change of address even if he is only moving from one place to another within the same city. This makes it easy for the Cancer Registries to trace every patient once she is reported to have cancer. The introduction of personal identification numbers and automated data processing has made this type of follow-up even more complete and simpler. For instance, in Norway the Cancer Registry now at regular intervals matches the information stored in the computer with information received from the Central Statistical Bureau about all deaths in the country. For every deceased person where cancer has been diagnosed during life or when cancer is mentioned on the death certificate, additional information can if necessary easily be obtained from the physician who signed the death certificate. The Scandinavian Cancer Registries have been in operation since the early 1950’s and already several interesting epidemiological studies have been published. For example, to the gynecologist it is very surprising that in spite of increasing and widespread use of exfoliative cytology with resulting detection and eradication of a large
602 Kolstad
t
March 1. 1973 Am. J. Obstet. Cynecol.
t
CERVIX
conduct his own follow-up investigations. Treatment protocols for the different types, sites and stages of cancer should at regular intervals be evaluated and re-evaluated. When clinical trials are planned, it should be done in collaboration with experts in statistics. It is not always realized that it takes a substantial number of patients to prove or disprove that, for example, one special treatment modality will give let us say 10 per cent more five-year survivors than another method. And one needs at least a 10 per cent difference to be certain that one method is to be preferred. The actual number will be around 400 patients in the trial group and 400 in the control group. A 20 per cent increase in survival will need at least 200 in each group. This is one more advantage of concentrating patients in special oncology units. Although it is possible to conduct cooperative clinical trials by combining results from several hospitals, it is of course much more likely that one will obtain identical treatment conditions in one single or a few large units. Both regular follow-up studies and clinical trials are dependent upon good record keeping and a follow-up system that makes it possible to register all relevant details on a prospective basis. That is to say, the information that will be required at the end of the investigation must be known at the beginning and arrangements made for its collection in each individual patient’s notesone can never go back and collect it afterward. In this computerized age it seems reasonable to adjust medical records to the computer so that all clinical data of importance can easily be stored and retrieved. In the design of records for a gynecologic oncology unit, however, it should be kept in mind that they serve many functions. They are not only scientific documents suitable for a computer, but also working documents which the physician must be able to use continuously during the patient’s stay in the hospital. The medical records may also be referred to under legal circumstances. And an even more “down-to-earth” warningcomputerized record systems are all very fine for the large unit working in hundreds of
dOVARY
0 L
I
1953
-55
-60
-65
-70
YEAR
Fig. 3. Total number of cases of carcinoma of the cervix, ovary, and corpus reported to the Cancer Registry of Norway 1953-1970. number of in situ lesions, there has been no decrease in the incidence rates of invasive cervical carcinoma.3 It has since been observed that the high risk group of women tend to avoid mass screening and that screening of a population at intervals does not pick up the rapidly growing tumor.’ Personally I feel, however, that it is too early to draw any conclusions about the effect of the screening programs which started only eight to ten years ago. One very definite observation is that the stage distribution of carcinoma of the cervix has shown a shift. Today almost 60 per cent of all cases are in clinical Stage I when first detected and only 15 per cent are in the late Stages III and IV (Fig. 2). The statistics from the Cancer Registries show clearly that carcinoma of the corpus and carcinoma of the ovary are becoming more frequent (Fig. 3) . The ratio between the incidence rates for carcinoma of the cervix and carcinoma of the corpus now varies between 1.5 : 1 and 2.2 : 1, and the absolute number of ovarian carcinomas detected is close to the number of invasive cervical carcinomas so that the ratio between them approaches 1: 1 .5 Side by side with these large-scale epidemiological studies emanating from the Cancer Registries, the gynecologic oncologist must
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patients they are ache. It effective,
Gynecologic
every year, but for the smaller unit liable to be an unnecessary headis better to use the simpler, just as good old manual card index system.
While we have been thinking about plans for gynecologic oncology units, no doubt some of your thoughts have wandered to the more distant future. Is it possible to foresee future developments? Compared with malignant tumors at other sites the treatment results in gynecologic cancer must be characterized as good. But there are still innumerable problems to be solved. The magic word which is used under so many circumstances today in connection with unsettled problems is “research.” Undoubtedly basic research at the molecular and cellular level, immunologic investigations, and research aimed at the development of new chemotherapeutic agents may lead us to the ultimate goal, precise knowledge about the cause or causes of cancer. What has been achieved in the first 70 years of the twentieth century is remarkable. Perhaps the next 30 years will produce even more astonishing results. But until it is possible to prevent cancer, the clinician in his daily work with the patient must never forget that his part is as vital as that played by the basic scientist. There are lots of loose ends that must be tidied up by properly designed clinical research. The gynecologic oncology unit must in the years to come take on this great responsibility. Let me illustrate my view by a few practical examples. The frequency of Stage I carcinoma of the cervix has increased considerably the last two decades. A relatively large proportion of these lesions are found in the younger age groups. Both adequate radiotherapy and skilled operation may give a cure rate of more than 80 per cent. At our Clinic during the years 1960-1966 537 Stage IB carcinomas of the cervix were treated by combined preoperative radium and radical hysterectomy with pelvic lymphadenectomy. The over-all five-year survival was
603
Table II. Results
of combined treatment of the cervix, Stage IB6
carcinoma
in
5 year surHistologic
Horizons
oncology
type
Total
Epidermoid Adenocarcinoma Undifferentiated Total
vival (%I
No.
474 34 29 537
89.2 85.4 79.3 88.3
Table III.
Lymph node metastases in carcinoma of the cervix, Stage IB, before the use of peroperative lymphographic control” Positive Histologic
type
Epidermoid Adenocarcinoma Undifferentiated Total
Total No.
474 34 29 53t
nodes
No.
Per cent
73 3 5 81
15.4 8.8 17.2 757
Table IV. Lymph node metastases in carcinoma of the cervix Stage IB after the use of peroperative lymphographic control* Positive Total
No.
221
No.
nodes Per cent
26
57
*In eight patients cancer-involved left behind if peroperative lymphograms
nodes would had not
have been been used.
88.3 per cent (Table II). It was found that the most significant prognostic factor was positive nodes, for only 62.9 per cent survived 5 years as compared with 92.9 per cent in those without node involvement. The frequency of positive nodes was found to be 15.1 per cent (Table III). In order to improve the technique of dissection of the pelvic lymph nodes and thereby possibly achieve still better results, we have since 1970 used peroperative lymphographic control during the extended Wertheim operations. It was soon realized that our earlier lymphadenectomies must often have been incomplete. Even with the aid of peroperative lymphography it is difficult to find all
604
Kolsrad
Fig. 4. Lymph section; c and
March 1, 1973 Am. J. Obstet. Gynecol.
nodes in the pelvis before d, complete dissection.
and after
the 1ymph nodes draining the uterine cervix (Fig. 4). Tc P date 251 patients have been operated upon L with this technique, and the frequency of p’ ositive nodes in Stage IB has been 26 per (:ent (Table IV), which is 11 per cent more than in the earlier series. The increase
lymphadenectomy:
a and
b, incomplete
dis-
is probably due not only to more complete dissection but also to improved histopathologic examination. In 8 patients positive nodes would have been left behind if lymphographic control had not been used. Will this more meticulous procedure really give a higher cure rate? This question can only be
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answered after a careful and complete follow-up of a large number of patients. Another pertinent question in the treatment of carcinoma of the cervix is intimately connected with radiobiologic studies in the laboratory. It is a well established fact that hypoxic and near-anoxic tumor cells are more resistant to ionizing irradiation than are well-oxygenated cells7 Furthermore, it has conclusively been shown that the proportion of cervical cancers with reduced vascularization and anoxic foci increases with advancing stage of the disease.8 The question is whether the poor results of radiotherapy in the more advanced stages are to a large extent dependent upon the oxygen factor. Basic research in the laboratories indicates that this may be true, but laboratory studies cannot give us the final answer. Only clinical studies can solve this problem. At our clinic a trial in which patients breathed atmospheric oxygen during radiotherapy of carcinoma of the cervix Stage II was carried out during the years 1967-1968. After a follow-up period of 3 to 5 years, 36.9 per cent with pelvic recurrence was found in the control series as compared with 23.3 per cent in the oxygen series, and the difference in survival was 10 per cent.” There are indications that to achieve optimal results, it is not sufficient to give the patient oxygen at atmospheric pressure. Hyperbaric oxygen radiotherapy there-
Gynecologic
oncology
605
fore has come into use in several institutions for different tumor types.l” Carcinoma of the cervix seems well suited to this type of therapy. However, only controlled clinical trials will show if hyperbaric oxygen radiotherapy is better than conventional methods. The trials reported up to date indicate an affirmative answer.ll This has been a brief review of a theme that hopefully is of interest to all those who wish to improve the provision of health care to women with gynecologic cancer. I have not shown any remarkable results or intricate studies, nor indulged in dreams about the future. The aim of this address has been to discuss some very simple basic problems. Some possible lines for the future organization of
REFERENCES
1.
2. 3.
4.
5.
Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Sot. Exp. Biol. (N. Y.) 93: 361, 1956. Thornton, W. N.: AM. J. OBSTET. GYNECOL. 109: 671, 1971. The Cancer Registry of Norway: Trends in Cancer Incidence in Norway 1955-67, Oslo, 1972, Universitetsforlaget. Pedersen, E., Hoeg, K., and Kolstad, P.: Acta Obstet. Gynecol. Stand. 50 (Suppl. 1 l), 1971. Ringertz, N.,, editor: Cancer incidence in Finland, Iceland, Norway and Sweden. Acta Path. Microbial. Stand., Sect. A, Suppl. 224, 1971.
6. 7. 8.
9. 10.
Rampone, J. F., Klem, V., and Kolstad, P.: Obstet. Gynecol. In press. Gray, L. H.: Am. J. Roentgenol. 85: 803, 196i. Kolstad, P.: Vascularization, oxygen tension and radiocurabilitv in cancer of the cervix. Oslo, 1963, Univektetsforlaget. Bergsje, P., and Kolstad, P.: Stand. J. Clin. Lab. Invest. 22 (Suppl. 106): 167, 1968. Churchill-Davidson, -I., Sanger, C., and Thomlinson. R. H.: Br. 1. Radio]. 30: 406. 1957. ’ Pizey, N. C. D., and Bullimore, J. A.: J. Obstet. Gynaecol. Br. Commonw. 75: 1275, 1968. ”
11.