Emop. o7. Cancer Vol. 4, pp. 27-31. Pergamon Press 1968. Printed in Great Britain

Progress in Treatment of

Cancer of Uterine Cervix* WILFRID MILLS

United Birmingham Hospitals

INTRODUCTION THE TREATMENT of carcinoma of the cervix is a twentieth century epic that is still incomplete. Over 13,000 women die of the disease annually in the U.S.A. and no race nor country is immune. The story begins at the turn of the century with the publication [1] of the first logical surgical attack, while at much the same time Pierre and Marie Curie had announced the result of their work on radioactivity. Both methods of treatment were adopted and have been used ever since.

Their rival merits were summarized 40 years later [2] by the statement that, "Medical opinion the world over appears to be more or less agreed that the Wertheim operation has been superceded by radium and deep X-rays". This was based upon reports from sixteen radiotherapy centres of a 27 per cent 5-year apparent cure rate of 7958 patients, represent- ing 88% of all cases seen in the areas concerned. For comparison Victor Bonney [3] had just published 5-year figures for his first 500 Wertheim operations with apparent cure of 40 and 63% operability, but a primary mortality of 15%. These comparable figures were achieved by a single surgeon of great skill and experience. The radical vaginal or Schauta operation (which makes no attempt remove pelvic lymphnodes) gave a similar cure rate with a lower primary mortality [4].

The end of the second world war brought great improvements in technique both for surgery and irradiation but it became less easy

*Presented at the Second International Symposium on the Biological Characterization of Human Turnouts, Rome, April 24-26, 1967.

to compare results. Surgical centres, especially in America, introduced more radical opera- tions and with the facilities of modern transport a high degree of selection of cases became inevitable. New diagnostic techniques revealed a hitherto untapped supply of early cases of doubtful invasion, and workers became in- creasingly dissatisfied with the classification of the disease into its four traditional stages prior to treatment. The picture to-day is one of transition with surgery and chemotherapy making inroads into the established position of radiotherapy.

EARLY DISEASE Modern diagnostic techniques of exfoliative

cytology, colpo-microscopy and serial section biopsy have increased the recognition of early disease, with the introduction of Stage 0 for apparently pre-invasive cancer. Furthermore the histological finding of early stromal invasion in biopsy specimens from patients free from clinical signs of invasive cancer has suggested that a modification of Stage I (Stage IA) be applied to these cases. Difficulties arise in interpretation of the histological picture by different pathologists (even granted adequate biopsy material) and a recent survey [5] has emphasised this and attempted to standardize the criteria for diagnosis of dysplasia, pre- invasion and micro-invasion.

The pre-invasive lesion appears to spread in three ways. It may flow off the cervix onto the vaginal fornix, pass up the endocervical canal even beyond the internal os, or creep up the ducts of the cervical racemose glands before invading the stroma. Wide surgical extirpation of most of the cervix would seem necessary to

27

28 Wilfrid Mills

ensure removal of sufficient tissue to establish the exact diagnosis, and this cone biopsy is now widely practised: rather than multiple punches or a superficial ring of squamo- columnar junction. The advantage of the large cone is that further treatment may be unnecessary, the procedure being curative as well as fully diagnostic [6]. Recent work [7] suggests that the pre-invasive lesion may in fact be cured by removal of lesser amounts of tissue insufficient to excise the entire lesion and that this may be followed by further pregnancy without undue risk.

The treatment of micro-invasion (Stage IA) has not yet been established and the difficulty of defining this condition adds to the uncer- tainty of the clinician. Most would treat it surgically, although individual preference may vary between a conservative attitude (when the cervix has already been amputated), a simple hysterectomy (abdominal or vaginal) and more radical operations of the Wertheim type. In this connection it should be emphasised that radiotherapy is potentially more radical than surgery as ovarian function is generally des- troyed. The surgeon operating for an early invasive growth in a young woman will often preserve an ovary.

ROUTINE TREATMENT "Radiotherapy is generally acknowledged to

be the preferred method of treatment: it has enjoyed this position from the time of the first world war to the present" [8]. The author of a standard American textbook justifies this claim by quoting apparent cure rates of 50% in long series of unselected cases, emphasising that no unselected surgical series is comparable. He points to the undoubted fact that almost all cases can receive this form of treatment with its low morbidity and mortality and he relegates surgery to the secondary role of treating irradiation failures.

This view however is not universally held. It is admitted that despite easy access to the cervix for irradiation some 25% of cases have an unhealed cervix at the end of treatment and the question ofradioresistance has received much attention. The grading of histological types of tumour regarding degree of cellular differentiation has some significance in this respect. The oxygenation of the tumour bed seems to be of importance, so that preliminary treatment of anaemia and use of high oxygen tension may be helpful. Medication with Vitamin K, testosterone and tocopherol have been suggested but the exact reason for radio-

resistance is unknown and its very existence is still in dispute.

The other theoretical disadvantage of radio- therapy is the decrease in effective dosage with increasing distance from a source of radium. Unfortunately cervical cancer will metastasize to pelvic lymphatic nodes in approximately 25% of all cases and the radiotherapist has no effective means of telling whether this has occurred. Thus his scheme for adequate dosage must include maximum irradiation of the centre of the pelvis with supplementary con- centration as necessary at the side walls. It has been disputed as to whether irradiation has the power to destroy cancer in these pelvic lymph- nodes but the work of Kottmeier in Stockholm is strongly suggestive that it can be done.

The failure of radiotherapy to cure all cases of apparently early disease has led to a re- evaluation of radical surgery. The tradition that this would have a high primary mortality was abolished when Meigs [9] published his series of 100 consecutive Wertheim operations without a death. The surgery of the Boston school used a more radical and elaborate technique than that traditionally employed in Britain and when this was combined with radio-therapy it produced a high rate of urinary fistulas. That this was not inevitable was shown by Schlink [10] who was the first to start a large series of selected cases treated by radical abdominal surgery after pre- operative treatment with radium. Two series from Britain have recently been published, treated in this way. Currie [11] reports 400 such operations with 5 deaths and 7 fistulas. His overall 5-year cure rate was 75% with figures as high as 84 per cent for Stage I (including 62 per cent for the 15% of Stage I cases with cancer in the excised pelvic lymph- nodes). Stallworthy [12] uses a higher initial dose of radium but takes exceptional care to preserve the blood supply to the ureter and bladder. His report on 285 cases (2 deaths and 7 fistulas) showed a 71% apparent cure rate with operability of 68% of all cases seen.

There are many other surgical techniques. The radical vaginal or Schauta operation is still performed and it is claimed that more parametric and paravaginal tissue can be removed by this approach. It is sometimes combined with an abdominal operation to dissect the pelvic lymphatic nodes. A syn- chronous combined approach has been used [13] which allows a complete vaginectomy to be included more easily with the abdominal operation, but these modifications do not affect the essential issue. Would overall results be

Progress in Treatment of Cancer of Uterine Cervix 29

improved if cases could be selected for either irradiation or surgery according as to degree of radio-resistance and lymphnode involvement? The answer to this question is still unknown but research continues in an at tempt to evaluate the patient more completely before treatment. Pelvic phlebography may show distortion and filling defects of the external iliac vein due to malignant lymphatic nodes. Pelvic lymphography [14] may show filling defects in hypogastric lymphnodes suggestive of malignant deposits. Serial biopsies from the cervix during treatment [15] may indicate the degree of radio-sensitivity. Vaginal exfoliative cytology techniques have indicated two further possible aids. The Sensitisation Response (S.R.), an index of some unusual cells in the pre-radiation smear was described by the Grahams [16], while the Radiation Response (R.R.) had been observed formerly [17]. These have been intensively studied as prog- nostic aids but the most recent evaluation [18] was unenthusiastic. It may well be that some cases can be cured with equal efficiency by either surgery or irradiation while others are inevitably incurable. Nevertheless, it would appear that combined therapy for selected operable cases carried out by surgeons and therapists of experience may well salvage some cases that would otherwise be lost.

THE A D V A N C E D CASE So long as the overall cure rate remains

at no better than 50% there will be many cases of advanced disease. They represent the sum of those presenting too late for hopeful t reatment and those whose therapy has proved to be inadequate. On rare occasions, especially in the elderly, the disease may seem to become spontaneously arrested, or some unconventional form of treatment, either physical or emotional, may lead to an apparent cure. Generally, however, progress is inexorable with the miseries of urinary and faecal fistulas, visceral and nerve root pain, and perpetual offensive discharge until merciful uraemia supervenes. Palliative procedures such as diversion of urine or faeces, neurosurgical injections or operations on the spinal theca and ligation of the main anterior trunk of the internal iliac arteries may be justified for the few. The terminal care may impose great physical and emotional demands upon those who nurse and care for these unhappy sufferers.

It was against this background of advanced lethal disease, frequently isolated in the pelvis, that Brunschwig [19] propounded the concept of surgical exenteration. The operation entailed

the removal of all the pelvic viscera with lymphnode dissection and transplanation of ureters into a terminal "wet" colostomy. Later modifications have preferred an isolated loop of ileum as a urinary conduit, while in some cases it has proved possible to save either rectum or bladder. The complete operation imposes a con- siderable strain upon both patient and surgeon and most clinics would advise it only in cases with a reasonable chance of permanent cure. It is most applicable when the disease is centrally placed, involving viscera rather than the pelvic wall and lymphnodes are not expected to be heavily involved. The selection of suitable cases poses great difficulty. I f used for terminal disease there will be little salvage, while in less advanced cases there will always be the feeling that a more conservative opera- tion might have sufficed.

The use of cytotoxic chemotherapy against cervical cancer gave little promise of success until Sullivan [20] suggested that intra-arterial therapy might surround the cancer cell with a locally lethal concentration of chemothera- peutic agent. The first report of apparent success was 2 years later when Trussell [21] reported from Uganda (where radiotherapy was not available) the use of intra-arterial methotrexate as primary treatment for 15 advanced cases. There was spectacular reduc- tion in the size of most tumours and one Stage I I I case might have been cured but was lost to follow up. Subsequent experience elsewhere has given mixed results and some authorities would not advise it after the blood supply to the tumour has been impaired by radiotherapy. Nevertheless, Hodgkinson [22] reports ex- perience of 19 cases and believes it to be a promising palliative measure that is temporarily effective, dangerous and not completely under- stood.

CONCLUSION Further progress may come about in a

number of ways. It is possible (though un- likely) that universal screening of women by vaginal cytology or other techniques will eliminate the problem of invasive cervical cancer, allowing cases to be treated early by local surgery. It may be that the three methods of t reatment currently available, surgery, radio- therapy and intra-arterial drug infusion, may be used in some new combination or sequence with results superior to those already recorded. Or maybe some new biochemical or immuno- logical technique will suddenly out date our present efforts and drive this female scourge from the face of the globe.

30 Wilfrid Mills

R E S U M E

Les rgsultats du traitement du cancer invasif du col ut&in ne produisaient jadis que des taux de gu&ison inf&ieurs ~ 25%, que l'on utilisdt la chirurgie ou la radioth&apie. Les progr~s les plus importants ont it~ obtenus par le diagnostic prgcoce, notammen: grdce au dgpistage. Une chirurgie limitge, dans des ces prg-invasifs, ou micro-invasifs, n' est pas mutilante et donne un haut pourcentage de gu#isons.

La radioth&apie est actuellement capable d'obtenir des gu&isons dans 40 ~ 50% des cas, mais les probl~mes de la radio-rgsistance et de l'invasion ganglionnaire demeurent. II serait utile de d&eler ces facteurs pgjoratifs avant le traitement. La chirurgie radicale peut produire des rgsultats remarquables dans les mains d'experts, surtout si elle est pr&gdle de radioth&apie, mais l'ingvitable sglection des cas rend une comparaison valable difficile.

La maladie ~ un stade avancg constitute un sgrieux problOme. Les interventions d'exent&ation pelvienne peuvent sauver quelques vies. Les agents cytostatiques aideront parfois des malades ayant des mgtastases ~ distance, et, administrgs par perfusions intra- art&idle continue, peuveni provoquer une rggression de la tumeur primitive. Les progrks de l'avenir viendront probablement de techniques biochimiques et immunologiques enti&e- ment nouvelles.

S U M M A R Y

Results for treatment of invasive cancer formerly showed apparent cure rates below 25% for all cases seen, whether irradiation or radical surgery was used. The most impor- tant progress has been in the technique of early diagnosis, including the screening of apparently healthy women. Limited surgery in cases of pre-invasion and micro-invasion may preserve function and give a high percentage of cures.

Radiotherapy to-day may give cure rates of 40-50% but the problems of radio- resistance and lymph node involvement remain. Diagnosis of these adverse factors prior to treatment would be beneficial. Radical surgery by experts will produce fine results especially i f preceded by radiotherapy, but the inevitable selection of cases makes valid comparison dubious.

Advanced disease presents a challenge. Exenteration procedures will save a few lives. Cytotoxic drugs will sometimes help the case with remote metastases, but when given by continuous intra-arterial perfusion they may produce regression of the primary tumour. Future progress should come from some entirely new biochemical or immunological procedure.

Z U S A M M E N F A S S U N G

Die Behandlung der invasiven Cervixkarzinome ergab friiher eine Heilungsrate von unter 25% fiir alle Fiille, gleichgiiltig ob mit Bestrahlung oder Radikaloperation behandelt. Der wichtigste Fortschritt wurde auf dem Gebiete der Friiherkennung und der Reihenuntersuchung symptomloser Frauen gemacht.

Mit Radiotherapie allein kann heute eine Heilungsrate von 40-50% erwartet werden. Ungelgst ist das Problem der Strahlenresistenz und der Lymphknotenmetastasierung. Die Abkliirung dieser Parameter vor der Therapie wiire wiinschenswert. Radikaloperation dutch einen Experten gibt sehr gute Resultate, besonders wenn kombiniert mit Vorbestrahlung. Die unvermeidliche Selektion der Fiille verunm6glicht aber eine statistische Auswertung der Resultate.

Die fortgeschrittenen Fiille sind immer noch ein groses Problem. Radikale Ausriiumung kann in einzelnen Fiillen helfen. Cyt~statica k6nn~n Fernmetastasen giinstig beeinflusen, und durch intraarterielle Perfusion kann der Prim&tumor direkt angegangen werden. Der weitere Fortschritt wird wahrscheinlich nur mgglich sein durch die Entwicklung von vollkommen neuen biochemischen und immunologischen Methoden.

Progress in Treatment of Cancer of Uterine Cervix 31

REFERENCES

1. A. WERTHEIM, A discussion on the diagnosis and treatment of cancer of the uterus. Brit. Med. J . ii, 689 (1905).

2. A. W. BOURNE and L. H. WILLIAMS, Recent Advances in Obstetrics and Gynaecology, 5th ed., p. 149, Churchill, London (1942).

3. V. BONNEY, The results of 500 cases of Wertheim's operation for carcinoma of the cervix. J. Obstet. Gynaee. Brit. Emp. 48, 421 (1941).

4. R. SCttRODER, Die Therapie des Carcinoma colli uteri. Zbl. Gyniik. 61, 546 (1937).

5. A. D. T. GOVAN, R. H. HAINES, et al., Changes in epithelium of the cervix uteri, o7. Obstet. Gynaec. Brit. Cwlth. 73, 883 (1966).

6. T. L. T. LEwis, Management of carcinoma-in-situ of the cervix. Proc. roy. Soc. Med. 59, 986 (1966).

7. G. H. GREF.N, Pregnancy following cervical carcinoma in situ. A review of 60 cases, o7. Obstet. Gynaec. Brit. Cwlth. 73, 897 (1966).

8. J .B . GRAHAM, L. S. J. SOTTO and F. P. PALOUCEK, Carcinoma of Cervix. p. 252. W. B. Saunders, Philadelphia (1962).

9. J .V . MEreS, Radical hysterectomy with bilateral pelvic lymph node dissections. Report of 100 patients operated on in 5 or more years ago. Amer. J . Obstet. Gynec. 62, 854 (1951).

10. H . H . SCHLINK, Cancer of the female pelvis. J. Obstet. Gynaec. Brit. Emp. 67, 402 (1960).

11. D. W. CURRIE, Figures of interest concerning the radical operation for car- cinoma of the cervix. Proc. roy. Soc. Med. 56, 878 (1963).

12. J. STALLWORTHY, Radical surgery following radiation treatment for cervical carcinoma. Ann. roy. Coll. Surg. Engl. 34, 161 (1964).

13. J. HOWKINS, Synchronous combined abdomino-vaginal hysterectomy. Lancet i, 872 (1951).

14. R . J . A, JACKSON, Lymphographic studies related to the problem of metastatic spread from carcinoma of the female genital tract. J. Obstet. Gynaec. Brit. Cwlth. 74, 339 (1967).

15. A. GLUCKSMANN and F. G. SPEAR, The qualitative and quantitative histo- logical examination of biopsy material from patients treated by radiation for carcinoma of the cervix of the uterus. Brit. 07. Radiol. 18, 313 (1945).

16. J. B. GRAHAM and R. M. GRAHAM, A cellular index of sensitivity to ionizing radiation. Cancer 6, 215 (1953).

17. R. M. GRAHAM, The effect of radiation of vaginal cells in cervical carcinoma. Surg. Gynec. and Obstet. 84, 153 (1947).

18. C.A. RHinO, et al., Sensitization and radiation response in cases with carcinoma of the uterine cervix. Investigations in 720 cases treated at Radiumhemmet 1954-1961. Acta Radiol. 3, 241 (1965).

19. A. BRUNSCHWm, Complete excision of pelvic viscera for advanced carcinoma. Cancer 1, 177 (1948).

20. R. D. SULLIVAN, et al., Antimetabolite-metabolite combination cancer chemo- therapy. Cancer 12, 1248 (1959).

21. R . R . TRUSSELL and G. MITFORD-BARBERTON, Carcinoma of the cervix treated with continuous intra-arterial methotrexate and intermittent intra-muscular leucovorin. Lancet i, 971 (1961).

22. C. P. HODOKINSON and C. R. BoYcE, Prolonged intra-arterial therapy for advanced pelvic malignancy. Cancer 18, 1536 (t965).