GYNECOLOGIC
ONCOLOGY
47, 210-215
(1992)
Proposal of a Modified (FIG0 1985) Classification of Stages I and II Cancer of the Uterine Cervix MARIJAN ILIJAS, M.D. Gynecological
Department,
Central
Institute
for
Tumors
and Allied
Diseases,
Zagreb,
Croatia
Received June 27, 1991 A modified FIG0 (1985) classification of cancer of the uterine cerviz has been suggested. The changes refer to stages I and II of the disease. The already accepted system of cervical cancer staging has been used. Stages Ib, IIa, and IIb have been subdivided, similar to stage Ia. The criterion used in staging is the size of the tumor up to, or more than 2 cm (Ib 1 and Ib 2) and, for stage II, the extent of penetration into adjacent tissue. The condition of lymph nodes should be noted by LN( +) or LN( - ) along with the stage of the disease. Such staging should demonstrate an objective evaluation of treatment results obtained by different methods and their combinations. o 1~ Academic PM, I~C. INTRODUCTION
The first classification of gynecological cancer, which is in routine use up to the present, was established in Geneva in 1925 [l]. The original classification involved four basic groups, which were subsequently-depending upon the extent of the disease and site of tumor proliferationsubdivided into smaller groups. The Cancer Committee of the International Federation of Gynecologists and Obstetricians (FIGO) divided, in 1961, the first stage of cervical cancer into two subgroups: Ia or preclinical cancer, and Ib, covering all other tumors limited to the uterine cervix [2]. Ever since, i.e., for 30 years, discussion has been going on, opinions have been contrasted, and arguments in favour of new divisions have been put forward. The acceptance of the fifth modified FIG0 Classification in 1970 [3] marked a qualitative step forward in this effort. At the time, subclinical stage Ia cancer was divided as follows: Ia (l), early invasion of the stroma to the depth of 5 mm; Ia (2), occult cancer with more extensive invasion. However, even this division did not satisfy all gynecologists, and new proposals ensued. The Nomenclature Committee of the Society of Gynecological Oncologists (SGO) defined, in 1974, microinvasive cancer as a lesion which penetrates, at one or several sites, the 210 0090-8258/92 $4.00 Copyright0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
stroma to the depth of 3 mm from the base of the epithelium without involving lymph or blood vessels [4]. The same definition of stage Ia was accepted in 1978 by the Cancer Committee of the Japanese Society of Obstetricians and Gynecologists. An invasion to the depth greater than 3 mm, with the involvement of blood and lymph vessels and confluent growth, was classified into stage Ib of the disease [5]. This gave rise to two definitions of microinvasive cancer-the FIG0 definition with a depth of invasion up to 5 mm, and the SGO definition with a depth of invasion up to 3 mm. All the other tumors limited to the uterine cervix were classified, irrespectively of their size, into stage Ib of the disease. Finally, at the 1985 Berlin Congress, the precise definition of stage Ia and its division into subgroups was accepted [6]. Stage Ia (1) involves early invasion of the stroma to the depth of 1 mm from the basal membrane, connected continuously with CIS. Stage Ia (2) includes tumors measurable in two dimensions-to the depth of 5 mm and to the diameter of 7 mm. This has to be reported, and so does blood vessel invasion, but it does not affect the stage of the disease. This seemed to have taken care of the microcancer problem first defined by Mestwerdt in 1947 [7]. However, a new problem appeared. Every lesion of greater dimension that stage Ia (2) limited to the uterine cervix, enters stage Ib of the disease. This has created just one big group of patients with microscopically verified tumors larger than 5 x 7 mm and with bulky exophytic cervical tumors. Such a division is completely illogical. It only introduces confusion and enhances the differences between treatment results, as reported by different authors, although these reports cover patients with the “same” stage of the disease, treated by the same method. In view of the incidence of cervical cancer [8], a detailed, simple (for the clinician), exact, and acceptable division would be required. The changes introduced in the FIG0 Classifications of cancer of the vulva, corpus uteri, and
MODIFIED
CLASSIFICATION
TABLE 1 FIG0 (1985) Classificationof Cancer of the Uterine Cervix Stage 0 Stage I Stage Ia Stage Ia 1 Stage Ia 2
Stage Ib Stage II Stage IIa Stage IIb Stage III
Stage IIIa Stage IIIb Stage IV Stage IVa Stage IVb
Intraepithelial cancer, CIS. Cancer strictly limited to the cervix (proliferation to the corpus uteri is neglected). Preclinical cervical cancer diagnosed only microscopically. Minimal, microscopically evident invasion of the stroma. Microscopically detected measurable lesion; the top limit of the depth of invasion is 5 mm from the base of the epithelium and the other, horizontal dimension, up to 7 mm; larger lesions have to be classed in stage Ib. Lesion of larger dimensions than stage Ia 2, whether clinically established or not. The cancer proliferates from the cervix, but does not involve the pelvic wall; the cancer involves the vagina, but not the caudal third. Without infiltration of the parametrium. Infiltration of the parametrium. Cancer proliferation to the pelvic wall; rectal examination shows no free space between the tumor and the pelvic wall; the tumor involves the caudal third of the vagina; all cases include hydronephrosis or renal affunction. Involvement of the caudal third of the vagina, without proliferation to the pelvic wall. Proliferation to the pelvic wall, or hydronephrosis and renal affunction. Cancer proliferation beyond the pelvis, or involvement of the bladder or rectal mucosa. Proliferation to the bladder or rectum with involvement of mucosa. Dissemination to distant organs.
OF CERVICAL
SUGGESTED MODIFIED
CLASSIFICATION
Table 1 reviews the valid FIG0 (1985) staging [9] and Table 2 reviews the suggested modified classification. DISCUSSION
TABLE 2 SuggestedModified FIG0 (1985)Classificationof Cancer of the Uterine Cervix Stage 0 Stage I
Stage Ia (1) Stage Ia Stage Ib (1) Stage Ib
(4
Stage II
Stage IIa 0) Stage IIa
(2)
Stage IIb (1) Stage IIb
(2)
The FIG0 Classification of cervical cancer is a clinical one, and it is based on findings obtained by inspection, palpation, biopsy, laboratory tests, endoscopic examination (cysto- and rectoscopy), X ray (intravenous urography), ultrasound, and depending upon requirements and available facilities, by CT and NMR. In terms of the current classification, stage 0 remains unaltered. In stage I of the disease, the tumor is limited to the
211
uterine cervix (proliferation to the corpus is neglected). Logically, a subdivision into preclinical (Ia) and clinically evident cancer (Ib) would be correct. However, the current classification of 1985 has created a large group involving a varying extent of the disease, which belongs to stage Ib. It includes subclinical, microscopically verified tumors with a penetration to the depth of 5 mm plus, as well as large tumors involving the entire uterine cervix or growing exophytically from it. Thus, subclinical tumors, which are larger by only 1 mm than Ia (2) tumors, have been classified into the same group with tumors measuring, in a single dimension, 5, 6, or more cm! This produces substantially different treatment results because-although stage Ib of the disease is reported-the heterogenity of the group makes any realistic comparison of results impossible. The same holds true for stage Ia,
(4
ovaries (Berlin 198.5, and Rio de Janeiro 1988) [6,9] support and further demonstrate the rationale of this proposal.
CANCER
Stage III Stage IIIa Stage IIIb Stage IV Stage IVa Stage IVb
Intraepithelial neoplasia (CIN III, CIS). Cancer limited to the uterine cervix (proliferation to the corpus uteri, type of invasion, penetration of blood and lymph vessels, and the degree of tumor maturity do not affect the stage of the disease). Penetration through the basal membrane to the depth of up to 3 mm (microcancer). Occult cancer with penetration to a depth greater than 3 mm. Clinically evident cancer with a diameter of up to 2 cm. Cancer with a diameter greater than 2 cm. Proliferation of cancer to the cranial and middle third of the vagina and into the parametrium (not to the pelvic wall); the involvement of the parametrium is dominant. Initial proliferation to the fornix vaginae. Proliferation to the cranial and middle third of the vagina. Initial involvement of the parametrium. Involvement of the middle and distal third of the parametrium, but not to the pelvic wall. Cancer proliferation to the caudal third of the vagina, or infiltration of parametrium to the pelvic wall. Proliferation to the vagina. Proliferation to the parametrium. Cancer infiltration into the bladder or rectal mucosa, or proliferation beyond the pelvis. Penetration into the bladder or rectum. Distant metastases.
Note. The condition of the lymph nodes should be noted along with the stage of the disease, e.g., Ib (2), LN (+), or LN (-).
212
MARIJAN
in view of the current FIG0 Classifications (with the measurement of two dimensions and a maximum volume of 350 mm”) [lo] and of the SGO definition of microinvasive cancer (penetration of up to 3 mm without blood or lymph vessel invasion) [4]. The suggested modified subdivision of stage I of the disease (see Table 2) finds considerable justification in the work and results reported by a variety of authors [lo141. Stage Ia (1)-penetration through the basal membrane to the depth of up to 3 mm, regardless of blood vessel invasion-would represent microcancer. This is a compromise between the FIG0 and SGO definitions of microcancer. FIG0 allows for a penetration of 1 mm in depth and SGO for 3 mm without blood or lymph vessel invasion. In terms of such current classifications, initial invasive cancer is distinguished from stage 0 of the disease (CIS), but in terms of diagnostics, therapy, treatment results, and survival rates it is actually put on the same level with that stage. This is confirmed by analyses produced by a number of investigators. In his retrospective study, Kolstad [ 1l] reports on 643 patients with microinvasive, squamous cell carcinoma of the uterine cervix. Depending upon the depth of invasion, the patients have been divided into three groups: (1) up to 1 mm (232); (2) l-3 mm (224); and (3) 3-5 mm (187 patients). Only 1 patient (out of 456) with a penetration of up to 3 mm died of cancer (0.22%). As established on review, this was a case of anaplastic carcinoma with blood vessel invasion, treated by hysterectomy. In the same group, blood vessel invasion was verified in 35 patients (7.6%). In the remaining 187 patients with a depth of invasion of 3-5 mm, blood vessel invasion was detected in 36 (19.3%). Also in this group, 3 patients (1.6%) died of cancer; they were also treated by hysterectomy. The difference between these two groups of patients was evident and statistically significant (P < 0.01). Tsukamoto et al. [12] analyzed 118 patients with stage Ia of the disease. In 103 the depth of invasion was up to 3 mm (87%). In 74 pelvic lymphadenectomy was performed. One patient only presented lymph node metastases. Out of 68 Wertheim-Meigs operations in stage Ia (2) of the disease, Kolstad [ll] reports only 2 cases with single lymph metastases. The results of these two authors obviously coincide; the same coincidence is to be found in the prevailing penetration, up to 3 mm, in stage Ia of the disease: in Kolstad [ll] 71% and in Tsukamoto et al. [12] 87% of patients present with a depth of up to 3 mm. Burghardt et al. [lo] reports on 101 patients with microinvasive cancer, out of which 85 have a penetration of up to 3 mm. However, in this case vascular invasion defies expectations--40% vs 25% at the penetration of 3-5 mm. In 309 patients with stage Ia (1) of the disease with an early invasion of the stroma followed up for 5
ILIJAS
years or more, there was no relapse regardless of performed therapy. The result of treatment would therefore be identical to that in CIS, which justifies the questioning of such staging. Out of 89 patients with Ia (2) microcancer, 5 (5.6%) relapsed 1 to 4 years after primary therapy (conization or hysterectomy). These were inadequately treated, poorly differentiated cancers with confluent growth and vascular invasion. In the same paper Burghardt reports on 38 patients, who were transferred, by using the new classification (FIG0 1985), from stage Ia (2) to stage Ib of the disease (tumors larger than 5 x 7 mm). Out of 36 operated patients, 15 (41.6%) presented with vascular invasion. Irrespectively of treatment, none of the 38 patients relapsed after a follow-up of 5 years or more. Analysis of 154 patients with a depth of penetration of up to 3 mm and 362 patients with a depth of up to 5 mm disclosed no differences in terms of mortality and number of relapses between the two groups [lo]. Therefore, although he advocates the current classification, Burghardt has demonstrated that the depth of invasion up to 5 mm is not essential for relapse. However, as the rate of blood and lymph vessel involvement increases with the depth of invasion, I believe that it would be justified to accept the SGO suggestion and the pathologists’ criteria for scoring stage Ia of the disease [15] and to distinguish between the depth of invasion of up to 3 mm and of more than 3 mm. In other words, stage Ia (1) would involve penetration of up to 3 mm, and stage Ia (2) penetration of more than 3 mm. The type of invasion, tumor differentiation, and blood vessel invasion do not affect the stage of the disease. Clinically evident Ib cancer is divided into two subgroups: Ib (l), including tumors up to 2 cm in diameter; and Ib (2), including tumors with a 2-cm-plus diameter (see Table 2). The same principle has been accepted for cancer of the vulva and ovaries. It is well known that the percentage of lymph node metastases increases with tumor size. Thus, Kolstad [ll] reports in Ia (2) tumors 3.2% of metastases into pelvic lymph nodes. For the same disease stage, Tsukamoto et al. [12] reports 1.4% of metastases. According to Lee et ul.‘s studies [16] on 954 patients, the incidence of positive lymph nodes in stage Ib of the disease is 12.9%. Depending upon tumor size, it may vary from 11% (for tumors up to 1 cm) to 59% (Ccm-plus tumors) [17]. Differences in treatment results have forced investigators to divide Ib tumors in terms of size [17-201. Thus, well-meaning divisions have been developed into tumors having a diameter of up to 1 cm, l-3 cm, and 3 cm plus [17] up to and above 2 cm [20,21], or up to or above 3 cm [18]. As the FIG0 Classification of vulvar and ovarian cancer already allows for tumors sizes up to, and more than, 2 cm, it would be
MODIFIED
CLASSIFICATION
TABLE 3 Correlation of Tumor Size, S-Year Survival, and Lymph Node Metastases
Disease stage Microcarcinoma Ib tumor less than 2 cm Ib tumor more than 2 cm
5-Year survival (%I
Lymph node metastases (%I
96.6 89.4 70.5
0 8 24.6
quite normal to apply such a division to cervical cancer as well. The volume of the tumor, when the disease is limited to the cervix, is a real boundary between early and advanced stages of the disease. An accurate diagnosis is extremely important in the selection of adequate treatment. According to Onnis et al. [19], the tumor diameter is in strict correlation with the 5-year survival rate and the incidence of lymph metastases (Table 3). If the lymph nodes are positive, the 5-year survival rate is 57.1% for stage I of the disease [19]. Similar results have been reported by Fuller et al. [21] and Delgado et al. [18]; the latter has divided stage Ib cancer into tumors up to and larger than 3 cm. In the first group there were 15.1% and in the second 33.6% of relapses. Although they did not divide tumors in terms of size, Lee et al. [16] obtained a 5-year survival rate in stage Ib of 87.7% in cases with negative lymph nodes (LN - ) and of 73.1% in those with positive lymph nodes (LN + ). This matches fully the results reported by Onnis et al. [19], reviewed in Table 3, and confirms the connection between tumor size on the one hand and dissemination into lymph nodes and patient survival on the other. In consideration of the low percentage of lymph metastases, a high 5-year survival rate, and the already accepted (vulva, ovaries) tumor size limit of 2 cm, I believe that the suggested division is justified. The results presented above demonstrate the success of surgery in the early stages of the disease, but in advanced cases planned and combined treatment by different methods is required. Adjuvant chemo- and/or radiotherapy in patients with positive lymph nodes and Ib (1) tumors will reduce the number of relapses and prolong survival. The improvement of treatment results by exact classification is the main target and the basic underlying motive of this paper. Stage II of the current FIG0 Classification (Table 1) refers to cancer proliferation to the cranial and middle third of the vagina (IIa) and to the parametrium, but not to the pelvic wall (IIb). Such a division has created two large groups of patients. Stage IIa of the disease includes patients with the initial cancer proliferation from the cervix to the fornix vaginae, as well as patients with tumor infiltration of the middle third of the vagina. Similarly,
OF CERVICAL
CANCER
213
cases of initial infiltration of the parametrium or involvement almost to the pelvic wall are classified into stage IIb. Within the subgroups there are major differences in terms of therapeutic approach, number of relapses, and survival rates. The incidence of positive lymph nodes correlates with the stage of disease and tumor size. Lee et al. [16] reports 26.8% lymph node metastases (LN+) for stage IIa and 35.2% for stage IIb. The 5-year survival rate is 79.8% for IIa (LN-) and 40.9% for IIa (LN+) patients. This shows that the extent of the disease within the same group is a decisive prognostic factor. Fuller et al. [21] reports, for stage IIa, 22% of lymph node metastases and a 5-year survival rate of 72%. The similarity of these results affords the conclusion that both groups included cases with smaller tumors, initial involvement of the vagina, and negative lymph nodes. This justifies the suggested modified division (Table 2) of stage IIa into: IIa (l), initial proliferation to the fornix vaginae; IIa (2), proliferation to the cranial and middle third of the vagina. In IIa (1) tumors, the 5-year survival rate after the Wertheim-Meigs operation will be similar to that in Ib (LN + ) tumors [16]. A more extensive involvement of the vagina, IIa (2), requires more radical surgery (exenteration), irradiation, or chemotherapy. The combinations of these methods will improve treatment results and bring them at least somewhat closer to those achieved in stage IIa (1). The situation is similar with the current stage IIb of the disease. The assessment of parametrium involvement is purely subjective. If the infiltrate is not very pronounced, the probability of errors in assessment is about 60% [22]. It is therefore important, when circumstances permit, to use CT and NMR in the determination of tumor extent in such cases [17]. By establishing the extent of the disease, we shall be able to select the most adequate treatment mode and to obtain better results. At present the 5-year survival rate is about 60%, although it may vary, depending upon lymph node involvement, from 40.6% (LN+) to 71.4% (LN-) [16]. If no surgery is performed, the rate is 47% after radiotherapy and 35.3% after radio and chemotherapy [ 191. The poorer results in nonsurgically treated patients are also due to other factors (age, intercurrent disease, and general patient condition). The progress attained in diagnosis by noninvasive methods (CT, NMR) allows for a modification of the current stage IIb of the disease as follows: IIb (l), initial involvement of the parametrium; IIb (2), infiltration of the middle and distal third of the parametrium, but not to the pelvic wall. This division correlates with positive lymph nodes [16] and survival and will contribute to the design of new therapeutic approaches. It will also permit an objective
214
MARIJAN
comparison of results obtained by different methods and thereby advance therapy. Stages III and IV of the current FIG0 Classification remain unaltered. The incidence of lymph metastases exceeds 60%. Depending upon therapy, the 5-year survival rate for stage III varies from 28.5 to 37.5% and for stage IV, in a small number of patients, it is up to 20% [19]. Because these stages involve very extensive and advanced tumors, treatment requires all available methods and knowledge. Cisplatin-based chemotherapy produces encouraging results in the treatment of recurrent and advanced squamous cell carcinoma of the uterine cervix [2325]. The combination of irradiation and chemotherapy is more efficient than the use of either method [26-281. Unfortunately, because of the advanced disease in stages III and IV, and because of the need to apply all possible treatments for the time being, a more detailed division would not produce any therapeutic progress. The introduction of new methods and drugs may suggest the need for changing the classification in these stages as well. At present, the patients will benefit most if the disease is detected at an early stage.
CONCLUSION The suggested modification of the FIG0 (1985) Classification of cancer of the uterine cervix has derived from the need to objectively compare one’s own observations with the work of other authors. This simple and logical clinical division, based on already generally accepted principles, will improve treatment results by promoting the introduction of new therapeutic approaches. The studies quoted above clearly show that most investigators face the same problem in analyzing their results. This led to the introduction of subgroups for individual stages of the disease, but has not resulted in uniformity, and only uniformity can guarantee objectivity. Such staging allows the comparison of the efficiency of different drugs, methods, and their combinations in the (truly) same stage of the disease. The introduction of invasion type, blood and lymph vessel involvement, and tumor maturity into classification is not justified. These are prognostic factors which force us to careful planning and administration of adequate therapy. Their combination with the clinical stage of the disease would produce an unmanageable division and many minor subgroups. I hope that the outlined suggestion, and the comment on the division of cervical cancer, will produce a response. Several different and argumented attitudes concerning the same problem will bring about a classification which will please most gynecologists, at least for a time.
ILIJAS
REFERENCES 1. Grgurevic, M. Classification of malignant tumors in females genitalia, Libri Oncol. 1, 193-200 (1972). 2. Kottmeier, H. L. Annual report on the results of treatment in gynecological cancer, (Dr. Kottmeir, Ed.), Vol. 13, Stockholm (1961). 3. Kottmeier, H. L. Annual report on the results of treatment in carcinoma of the uterus, vagina and ovary, (Dr. Kottmeir, Ed.), Vol. 15, Stockholm (1973). 4. Seski, J. C., Murray, R. A., and Morley, G. Microinvasive squamous carcinoma of the cervix: Definition, histologic analysis, late results of treatment, Obstet. Gynecol. 50, 410-414 (1977). 5. Noda, K., Taki, I., Takeuchi, S., and Kashimura, Y. A new proposal regarding criteria for stage Ia cancer in the uterine cervix, Gynecol. Oncol. 8, 353-369 (1979). 6. Pettersson, F. Annual report on results of treatment in carcinoma of the uterus, vagina, vulva, ovary and trophoblastic disease, (Dr. Pettersson, Ed.), Vol. 20, Stockholm (1988). 7. Mestwerdt, G. Die Friihdiagnose des Kollumkarzinoms, Zentralbl. Gyniikol. 69, 198-202 (1947). 8. American Cancer Society. Cancer facts andfigures-1989, American Cancer Society, Atlanta (1989). 9. Shepherd, J. H. Revised FIG0 staging for gynaecological cancer, Br. J. Obstet. Gynecol. %, 889-892 (1989). 10. Burghardt, E., Girardi, F., Lahousen, M., Pickel, H., and Tamussino, K. Microinvasive carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage Ia), Cancer 67, 1037-1045 (1991). 11. Kolstad, P. Follow-up study of 232 patients with stage Ia 1 and 411 patients with stage Ia 2 squamous cell carcinoma of the cervix (microinvasive carcinoma), Gynecol. Oncol. 33, 256-272 (1989). 12. Tsukamoto, N., Kaku, T., Matsukuma, K., Matsuyama, T., Kamura, T., Saito, T., and Suenaga, T. The problem of stage Ia (FIGO, 1985) carcinoma of the uterine cervix, Gynecol. Oncol. 34, 1-6 (1989). 13. Simon, N. L., Gore, H., Shingleton, H. M. Soong, S. J., Orr, J. W., and Hatch, K. D. Study of superficially invasive carcinoma of the cervix, Obstet. Gynecol. 68, 19-24 (1986). 14. Creasman, W. T., Fetter, B. F., Clarke-Pearson, D. L., Kaufman, L., and Parker, R. T. Management of stage Ia carcinoma of the cervix, Am. J. Obstet. Gynecol. 153, 164-172 (1985). 15. Pot&en, H. E., Tyler, C. W., and Sobin, L. H. International histological classification of tumors, 1975, Vol. 13, Histological typing of female genital tract tumors. World Health Organization, Geneva (1975). 16. Lee, Y. N., Wang, K. L., Lin, M. H., Liu, C. H., Wang, K. G., Lan, C. C., Chuang, J. T., Chen, A. C., and Wu, C. C. Radical hysterectomy with pelvic lymph node dissection for treatment of cervical cancer: A clinical review of 954 cases, Gynecol. Oncol. 32, 135-142 (1989). 17. Hricak, H. Carcinoma of the female reproductive organs, Cancer Suppl. 67, 1209-1218 (1991). 18. Delgado, D., Bundy, B., Zaino, R., Sevin, B. U., Creasman, W. T., and Major, F. Prospective surgical-pathological study of disease-free interval in patients with stage Ib squamous cell carcinoma of the cervix: A gynecologic oncology group study, Gynecol. Oncol. 38, 352-3.57 (1990). 19. Onnis, A., Marchetti, M., Maggino, T., de Toffoli, J., and Piazza,
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20.
21.
22. 23.
24. 25.
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M. Clinical experience in gynecological cancer management, Eur. .I. Gynaecol. Oncol. 12, 11-26 (1991). Onnis, A., and Marchetti, M. Adequate staging for an adequate management in uterine cancers, Eur. J. Gynecol. Oncol. 12, 99102 (1991). Fuller, A. F., Elliot, N., Kosloff, C., Hoskins, W., and Lewis J. L., Jr. Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage Ib and IIa carcinoma of the cervix, Gynecof. Oncol. 33, 34-39 (1989). Averette, H. E., Ford J. H., Jr, and Dudan, R. C. Staging of cervical cancer, Cfin. Obstet. Gynecol. 18, 215-219 (1975). Rotmensch, J., Senekjian, E., Javaheri, G., and Herbst, A. Evaluation of bolus c&platinum and continuous 5fluorouracil infusion for metastatic and recurrent squamous cell carcinoma of the cervix, Gynecol. Oncol. 29, 76-81 (1988). Kumar, L., and Bhargava, V. L. Chemotherapy in recurrent and advanced cervical cancer, Gynecol. Oncol. 40, 107-111 (1991). Weis, G. R., Green, S., Hannigan, E. V., Boutselis, J. G., Surwit,
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E. A., Wallace, D. L., and Alberts, D. S. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A southwest oncology group study, Gynecol. Oncol. 39, 332-336 (1990). 26. Soeters, R., Bloch, B., Levin, W., Dehaeck, C. M. D., and Goldberg, G. Combined chemotherapy and radiotherapy in patients with advanced squamous carcinoma of the cervix (cis-platinum-bleomycin-vinblastine), Gynecol. Oncol. 33, 44-45 (1989). 27. John, M., Flam, M., SikiC, B., Rotman, M., Cooper, J., Malec, M., Hannigan, J., and Phillips, T. Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: A phase I-II prospective intergroup NCOG-RTOG study, Gynecol. Oncol. 37, l-5 (1990). 28. Heaton, D., Yordan, E., Reddy, S., Bonomi, P., Lee, M. S., Lincoln, S., Graham, J., Dolan, T., Miller, A., Phillips, A., Kirschner, C., Bergen, S., and Wilbanks, G. Treatment of 29 patients with bulky squamous cell carcinoma of the cervix with simultaneous cisplatin, 5-fluorouracil, and split-course hyperfractionated radiation therapy, Gynecol. Oncol. 38, 323-327 (1990).
ONCOLOGY
47, 210-215
(1992)
Proposal of a Modified (FIG0 1985) Classification of Stages I and II Cancer of the Uterine Cervix MARIJAN ILIJAS, M.D. Gynecological
Department,
Central
Institute
for
Tumors
and Allied
Diseases,
Zagreb,
Croatia
Received June 27, 1991 A modified FIG0 (1985) classification of cancer of the uterine cerviz has been suggested. The changes refer to stages I and II of the disease. The already accepted system of cervical cancer staging has been used. Stages Ib, IIa, and IIb have been subdivided, similar to stage Ia. The criterion used in staging is the size of the tumor up to, or more than 2 cm (Ib 1 and Ib 2) and, for stage II, the extent of penetration into adjacent tissue. The condition of lymph nodes should be noted by LN( +) or LN( - ) along with the stage of the disease. Such staging should demonstrate an objective evaluation of treatment results obtained by different methods and their combinations. o 1~ Academic PM, I~C. INTRODUCTION
The first classification of gynecological cancer, which is in routine use up to the present, was established in Geneva in 1925 [l]. The original classification involved four basic groups, which were subsequently-depending upon the extent of the disease and site of tumor proliferationsubdivided into smaller groups. The Cancer Committee of the International Federation of Gynecologists and Obstetricians (FIGO) divided, in 1961, the first stage of cervical cancer into two subgroups: Ia or preclinical cancer, and Ib, covering all other tumors limited to the uterine cervix [2]. Ever since, i.e., for 30 years, discussion has been going on, opinions have been contrasted, and arguments in favour of new divisions have been put forward. The acceptance of the fifth modified FIG0 Classification in 1970 [3] marked a qualitative step forward in this effort. At the time, subclinical stage Ia cancer was divided as follows: Ia (l), early invasion of the stroma to the depth of 5 mm; Ia (2), occult cancer with more extensive invasion. However, even this division did not satisfy all gynecologists, and new proposals ensued. The Nomenclature Committee of the Society of Gynecological Oncologists (SGO) defined, in 1974, microinvasive cancer as a lesion which penetrates, at one or several sites, the 210 0090-8258/92 $4.00 Copyright0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
stroma to the depth of 3 mm from the base of the epithelium without involving lymph or blood vessels [4]. The same definition of stage Ia was accepted in 1978 by the Cancer Committee of the Japanese Society of Obstetricians and Gynecologists. An invasion to the depth greater than 3 mm, with the involvement of blood and lymph vessels and confluent growth, was classified into stage Ib of the disease [5]. This gave rise to two definitions of microinvasive cancer-the FIG0 definition with a depth of invasion up to 5 mm, and the SGO definition with a depth of invasion up to 3 mm. All the other tumors limited to the uterine cervix were classified, irrespectively of their size, into stage Ib of the disease. Finally, at the 1985 Berlin Congress, the precise definition of stage Ia and its division into subgroups was accepted [6]. Stage Ia (1) involves early invasion of the stroma to the depth of 1 mm from the basal membrane, connected continuously with CIS. Stage Ia (2) includes tumors measurable in two dimensions-to the depth of 5 mm and to the diameter of 7 mm. This has to be reported, and so does blood vessel invasion, but it does not affect the stage of the disease. This seemed to have taken care of the microcancer problem first defined by Mestwerdt in 1947 [7]. However, a new problem appeared. Every lesion of greater dimension that stage Ia (2) limited to the uterine cervix, enters stage Ib of the disease. This has created just one big group of patients with microscopically verified tumors larger than 5 x 7 mm and with bulky exophytic cervical tumors. Such a division is completely illogical. It only introduces confusion and enhances the differences between treatment results, as reported by different authors, although these reports cover patients with the “same” stage of the disease, treated by the same method. In view of the incidence of cervical cancer [8], a detailed, simple (for the clinician), exact, and acceptable division would be required. The changes introduced in the FIG0 Classifications of cancer of the vulva, corpus uteri, and
MODIFIED
CLASSIFICATION
TABLE 1 FIG0 (1985) Classificationof Cancer of the Uterine Cervix Stage 0 Stage I Stage Ia Stage Ia 1 Stage Ia 2
Stage Ib Stage II Stage IIa Stage IIb Stage III
Stage IIIa Stage IIIb Stage IV Stage IVa Stage IVb
Intraepithelial cancer, CIS. Cancer strictly limited to the cervix (proliferation to the corpus uteri is neglected). Preclinical cervical cancer diagnosed only microscopically. Minimal, microscopically evident invasion of the stroma. Microscopically detected measurable lesion; the top limit of the depth of invasion is 5 mm from the base of the epithelium and the other, horizontal dimension, up to 7 mm; larger lesions have to be classed in stage Ib. Lesion of larger dimensions than stage Ia 2, whether clinically established or not. The cancer proliferates from the cervix, but does not involve the pelvic wall; the cancer involves the vagina, but not the caudal third. Without infiltration of the parametrium. Infiltration of the parametrium. Cancer proliferation to the pelvic wall; rectal examination shows no free space between the tumor and the pelvic wall; the tumor involves the caudal third of the vagina; all cases include hydronephrosis or renal affunction. Involvement of the caudal third of the vagina, without proliferation to the pelvic wall. Proliferation to the pelvic wall, or hydronephrosis and renal affunction. Cancer proliferation beyond the pelvis, or involvement of the bladder or rectal mucosa. Proliferation to the bladder or rectum with involvement of mucosa. Dissemination to distant organs.
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SUGGESTED MODIFIED
CLASSIFICATION
Table 1 reviews the valid FIG0 (1985) staging [9] and Table 2 reviews the suggested modified classification. DISCUSSION
TABLE 2 SuggestedModified FIG0 (1985)Classificationof Cancer of the Uterine Cervix Stage 0 Stage I
Stage Ia (1) Stage Ia Stage Ib (1) Stage Ib
(4
Stage II
Stage IIa 0) Stage IIa
(2)
Stage IIb (1) Stage IIb
(2)
The FIG0 Classification of cervical cancer is a clinical one, and it is based on findings obtained by inspection, palpation, biopsy, laboratory tests, endoscopic examination (cysto- and rectoscopy), X ray (intravenous urography), ultrasound, and depending upon requirements and available facilities, by CT and NMR. In terms of the current classification, stage 0 remains unaltered. In stage I of the disease, the tumor is limited to the
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uterine cervix (proliferation to the corpus is neglected). Logically, a subdivision into preclinical (Ia) and clinically evident cancer (Ib) would be correct. However, the current classification of 1985 has created a large group involving a varying extent of the disease, which belongs to stage Ib. It includes subclinical, microscopically verified tumors with a penetration to the depth of 5 mm plus, as well as large tumors involving the entire uterine cervix or growing exophytically from it. Thus, subclinical tumors, which are larger by only 1 mm than Ia (2) tumors, have been classified into the same group with tumors measuring, in a single dimension, 5, 6, or more cm! This produces substantially different treatment results because-although stage Ib of the disease is reported-the heterogenity of the group makes any realistic comparison of results impossible. The same holds true for stage Ia,
(4
ovaries (Berlin 198.5, and Rio de Janeiro 1988) [6,9] support and further demonstrate the rationale of this proposal.
CANCER
Stage III Stage IIIa Stage IIIb Stage IV Stage IVa Stage IVb
Intraepithelial neoplasia (CIN III, CIS). Cancer limited to the uterine cervix (proliferation to the corpus uteri, type of invasion, penetration of blood and lymph vessels, and the degree of tumor maturity do not affect the stage of the disease). Penetration through the basal membrane to the depth of up to 3 mm (microcancer). Occult cancer with penetration to a depth greater than 3 mm. Clinically evident cancer with a diameter of up to 2 cm. Cancer with a diameter greater than 2 cm. Proliferation of cancer to the cranial and middle third of the vagina and into the parametrium (not to the pelvic wall); the involvement of the parametrium is dominant. Initial proliferation to the fornix vaginae. Proliferation to the cranial and middle third of the vagina. Initial involvement of the parametrium. Involvement of the middle and distal third of the parametrium, but not to the pelvic wall. Cancer proliferation to the caudal third of the vagina, or infiltration of parametrium to the pelvic wall. Proliferation to the vagina. Proliferation to the parametrium. Cancer infiltration into the bladder or rectal mucosa, or proliferation beyond the pelvis. Penetration into the bladder or rectum. Distant metastases.
Note. The condition of the lymph nodes should be noted along with the stage of the disease, e.g., Ib (2), LN (+), or LN (-).
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in view of the current FIG0 Classifications (with the measurement of two dimensions and a maximum volume of 350 mm”) [lo] and of the SGO definition of microinvasive cancer (penetration of up to 3 mm without blood or lymph vessel invasion) [4]. The suggested modified subdivision of stage I of the disease (see Table 2) finds considerable justification in the work and results reported by a variety of authors [lo141. Stage Ia (1)-penetration through the basal membrane to the depth of up to 3 mm, regardless of blood vessel invasion-would represent microcancer. This is a compromise between the FIG0 and SGO definitions of microcancer. FIG0 allows for a penetration of 1 mm in depth and SGO for 3 mm without blood or lymph vessel invasion. In terms of such current classifications, initial invasive cancer is distinguished from stage 0 of the disease (CIS), but in terms of diagnostics, therapy, treatment results, and survival rates it is actually put on the same level with that stage. This is confirmed by analyses produced by a number of investigators. In his retrospective study, Kolstad [ 1l] reports on 643 patients with microinvasive, squamous cell carcinoma of the uterine cervix. Depending upon the depth of invasion, the patients have been divided into three groups: (1) up to 1 mm (232); (2) l-3 mm (224); and (3) 3-5 mm (187 patients). Only 1 patient (out of 456) with a penetration of up to 3 mm died of cancer (0.22%). As established on review, this was a case of anaplastic carcinoma with blood vessel invasion, treated by hysterectomy. In the same group, blood vessel invasion was verified in 35 patients (7.6%). In the remaining 187 patients with a depth of invasion of 3-5 mm, blood vessel invasion was detected in 36 (19.3%). Also in this group, 3 patients (1.6%) died of cancer; they were also treated by hysterectomy. The difference between these two groups of patients was evident and statistically significant (P < 0.01). Tsukamoto et al. [12] analyzed 118 patients with stage Ia of the disease. In 103 the depth of invasion was up to 3 mm (87%). In 74 pelvic lymphadenectomy was performed. One patient only presented lymph node metastases. Out of 68 Wertheim-Meigs operations in stage Ia (2) of the disease, Kolstad [ll] reports only 2 cases with single lymph metastases. The results of these two authors obviously coincide; the same coincidence is to be found in the prevailing penetration, up to 3 mm, in stage Ia of the disease: in Kolstad [ll] 71% and in Tsukamoto et al. [12] 87% of patients present with a depth of up to 3 mm. Burghardt et al. [lo] reports on 101 patients with microinvasive cancer, out of which 85 have a penetration of up to 3 mm. However, in this case vascular invasion defies expectations--40% vs 25% at the penetration of 3-5 mm. In 309 patients with stage Ia (1) of the disease with an early invasion of the stroma followed up for 5
ILIJAS
years or more, there was no relapse regardless of performed therapy. The result of treatment would therefore be identical to that in CIS, which justifies the questioning of such staging. Out of 89 patients with Ia (2) microcancer, 5 (5.6%) relapsed 1 to 4 years after primary therapy (conization or hysterectomy). These were inadequately treated, poorly differentiated cancers with confluent growth and vascular invasion. In the same paper Burghardt reports on 38 patients, who were transferred, by using the new classification (FIG0 1985), from stage Ia (2) to stage Ib of the disease (tumors larger than 5 x 7 mm). Out of 36 operated patients, 15 (41.6%) presented with vascular invasion. Irrespectively of treatment, none of the 38 patients relapsed after a follow-up of 5 years or more. Analysis of 154 patients with a depth of penetration of up to 3 mm and 362 patients with a depth of up to 5 mm disclosed no differences in terms of mortality and number of relapses between the two groups [lo]. Therefore, although he advocates the current classification, Burghardt has demonstrated that the depth of invasion up to 5 mm is not essential for relapse. However, as the rate of blood and lymph vessel involvement increases with the depth of invasion, I believe that it would be justified to accept the SGO suggestion and the pathologists’ criteria for scoring stage Ia of the disease [15] and to distinguish between the depth of invasion of up to 3 mm and of more than 3 mm. In other words, stage Ia (1) would involve penetration of up to 3 mm, and stage Ia (2) penetration of more than 3 mm. The type of invasion, tumor differentiation, and blood vessel invasion do not affect the stage of the disease. Clinically evident Ib cancer is divided into two subgroups: Ib (l), including tumors up to 2 cm in diameter; and Ib (2), including tumors with a 2-cm-plus diameter (see Table 2). The same principle has been accepted for cancer of the vulva and ovaries. It is well known that the percentage of lymph node metastases increases with tumor size. Thus, Kolstad [ll] reports in Ia (2) tumors 3.2% of metastases into pelvic lymph nodes. For the same disease stage, Tsukamoto et al. [12] reports 1.4% of metastases. According to Lee et ul.‘s studies [16] on 954 patients, the incidence of positive lymph nodes in stage Ib of the disease is 12.9%. Depending upon tumor size, it may vary from 11% (for tumors up to 1 cm) to 59% (Ccm-plus tumors) [17]. Differences in treatment results have forced investigators to divide Ib tumors in terms of size [17-201. Thus, well-meaning divisions have been developed into tumors having a diameter of up to 1 cm, l-3 cm, and 3 cm plus [17] up to and above 2 cm [20,21], or up to or above 3 cm [18]. As the FIG0 Classification of vulvar and ovarian cancer already allows for tumors sizes up to, and more than, 2 cm, it would be
MODIFIED
CLASSIFICATION
TABLE 3 Correlation of Tumor Size, S-Year Survival, and Lymph Node Metastases
Disease stage Microcarcinoma Ib tumor less than 2 cm Ib tumor more than 2 cm
5-Year survival (%I
Lymph node metastases (%I
96.6 89.4 70.5
0 8 24.6
quite normal to apply such a division to cervical cancer as well. The volume of the tumor, when the disease is limited to the cervix, is a real boundary between early and advanced stages of the disease. An accurate diagnosis is extremely important in the selection of adequate treatment. According to Onnis et al. [19], the tumor diameter is in strict correlation with the 5-year survival rate and the incidence of lymph metastases (Table 3). If the lymph nodes are positive, the 5-year survival rate is 57.1% for stage I of the disease [19]. Similar results have been reported by Fuller et al. [21] and Delgado et al. [18]; the latter has divided stage Ib cancer into tumors up to and larger than 3 cm. In the first group there were 15.1% and in the second 33.6% of relapses. Although they did not divide tumors in terms of size, Lee et al. [16] obtained a 5-year survival rate in stage Ib of 87.7% in cases with negative lymph nodes (LN - ) and of 73.1% in those with positive lymph nodes (LN + ). This matches fully the results reported by Onnis et al. [19], reviewed in Table 3, and confirms the connection between tumor size on the one hand and dissemination into lymph nodes and patient survival on the other. In consideration of the low percentage of lymph metastases, a high 5-year survival rate, and the already accepted (vulva, ovaries) tumor size limit of 2 cm, I believe that the suggested division is justified. The results presented above demonstrate the success of surgery in the early stages of the disease, but in advanced cases planned and combined treatment by different methods is required. Adjuvant chemo- and/or radiotherapy in patients with positive lymph nodes and Ib (1) tumors will reduce the number of relapses and prolong survival. The improvement of treatment results by exact classification is the main target and the basic underlying motive of this paper. Stage II of the current FIG0 Classification (Table 1) refers to cancer proliferation to the cranial and middle third of the vagina (IIa) and to the parametrium, but not to the pelvic wall (IIb). Such a division has created two large groups of patients. Stage IIa of the disease includes patients with the initial cancer proliferation from the cervix to the fornix vaginae, as well as patients with tumor infiltration of the middle third of the vagina. Similarly,
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CANCER
213
cases of initial infiltration of the parametrium or involvement almost to the pelvic wall are classified into stage IIb. Within the subgroups there are major differences in terms of therapeutic approach, number of relapses, and survival rates. The incidence of positive lymph nodes correlates with the stage of disease and tumor size. Lee et al. [16] reports 26.8% lymph node metastases (LN+) for stage IIa and 35.2% for stage IIb. The 5-year survival rate is 79.8% for IIa (LN-) and 40.9% for IIa (LN+) patients. This shows that the extent of the disease within the same group is a decisive prognostic factor. Fuller et al. [21] reports, for stage IIa, 22% of lymph node metastases and a 5-year survival rate of 72%. The similarity of these results affords the conclusion that both groups included cases with smaller tumors, initial involvement of the vagina, and negative lymph nodes. This justifies the suggested modified division (Table 2) of stage IIa into: IIa (l), initial proliferation to the fornix vaginae; IIa (2), proliferation to the cranial and middle third of the vagina. In IIa (1) tumors, the 5-year survival rate after the Wertheim-Meigs operation will be similar to that in Ib (LN + ) tumors [16]. A more extensive involvement of the vagina, IIa (2), requires more radical surgery (exenteration), irradiation, or chemotherapy. The combinations of these methods will improve treatment results and bring them at least somewhat closer to those achieved in stage IIa (1). The situation is similar with the current stage IIb of the disease. The assessment of parametrium involvement is purely subjective. If the infiltrate is not very pronounced, the probability of errors in assessment is about 60% [22]. It is therefore important, when circumstances permit, to use CT and NMR in the determination of tumor extent in such cases [17]. By establishing the extent of the disease, we shall be able to select the most adequate treatment mode and to obtain better results. At present the 5-year survival rate is about 60%, although it may vary, depending upon lymph node involvement, from 40.6% (LN+) to 71.4% (LN-) [16]. If no surgery is performed, the rate is 47% after radiotherapy and 35.3% after radio and chemotherapy [ 191. The poorer results in nonsurgically treated patients are also due to other factors (age, intercurrent disease, and general patient condition). The progress attained in diagnosis by noninvasive methods (CT, NMR) allows for a modification of the current stage IIb of the disease as follows: IIb (l), initial involvement of the parametrium; IIb (2), infiltration of the middle and distal third of the parametrium, but not to the pelvic wall. This division correlates with positive lymph nodes [16] and survival and will contribute to the design of new therapeutic approaches. It will also permit an objective
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comparison of results obtained by different methods and thereby advance therapy. Stages III and IV of the current FIG0 Classification remain unaltered. The incidence of lymph metastases exceeds 60%. Depending upon therapy, the 5-year survival rate for stage III varies from 28.5 to 37.5% and for stage IV, in a small number of patients, it is up to 20% [19]. Because these stages involve very extensive and advanced tumors, treatment requires all available methods and knowledge. Cisplatin-based chemotherapy produces encouraging results in the treatment of recurrent and advanced squamous cell carcinoma of the uterine cervix [2325]. The combination of irradiation and chemotherapy is more efficient than the use of either method [26-281. Unfortunately, because of the advanced disease in stages III and IV, and because of the need to apply all possible treatments for the time being, a more detailed division would not produce any therapeutic progress. The introduction of new methods and drugs may suggest the need for changing the classification in these stages as well. At present, the patients will benefit most if the disease is detected at an early stage.
CONCLUSION The suggested modification of the FIG0 (1985) Classification of cancer of the uterine cervix has derived from the need to objectively compare one’s own observations with the work of other authors. This simple and logical clinical division, based on already generally accepted principles, will improve treatment results by promoting the introduction of new therapeutic approaches. The studies quoted above clearly show that most investigators face the same problem in analyzing their results. This led to the introduction of subgroups for individual stages of the disease, but has not resulted in uniformity, and only uniformity can guarantee objectivity. Such staging allows the comparison of the efficiency of different drugs, methods, and their combinations in the (truly) same stage of the disease. The introduction of invasion type, blood and lymph vessel involvement, and tumor maturity into classification is not justified. These are prognostic factors which force us to careful planning and administration of adequate therapy. Their combination with the clinical stage of the disease would produce an unmanageable division and many minor subgroups. I hope that the outlined suggestion, and the comment on the division of cervical cancer, will produce a response. Several different and argumented attitudes concerning the same problem will bring about a classification which will please most gynecologists, at least for a time.
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REFERENCES 1. Grgurevic, M. Classification of malignant tumors in females genitalia, Libri Oncol. 1, 193-200 (1972). 2. Kottmeier, H. L. Annual report on the results of treatment in gynecological cancer, (Dr. Kottmeir, Ed.), Vol. 13, Stockholm (1961). 3. Kottmeier, H. L. Annual report on the results of treatment in carcinoma of the uterus, vagina and ovary, (Dr. Kottmeir, Ed.), Vol. 15, Stockholm (1973). 4. Seski, J. C., Murray, R. A., and Morley, G. Microinvasive squamous carcinoma of the cervix: Definition, histologic analysis, late results of treatment, Obstet. Gynecol. 50, 410-414 (1977). 5. Noda, K., Taki, I., Takeuchi, S., and Kashimura, Y. A new proposal regarding criteria for stage Ia cancer in the uterine cervix, Gynecol. Oncol. 8, 353-369 (1979). 6. Pettersson, F. Annual report on results of treatment in carcinoma of the uterus, vagina, vulva, ovary and trophoblastic disease, (Dr. Pettersson, Ed.), Vol. 20, Stockholm (1988). 7. Mestwerdt, G. Die Friihdiagnose des Kollumkarzinoms, Zentralbl. Gyniikol. 69, 198-202 (1947). 8. American Cancer Society. Cancer facts andfigures-1989, American Cancer Society, Atlanta (1989). 9. Shepherd, J. H. Revised FIG0 staging for gynaecological cancer, Br. J. Obstet. Gynecol. %, 889-892 (1989). 10. Burghardt, E., Girardi, F., Lahousen, M., Pickel, H., and Tamussino, K. Microinvasive carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage Ia), Cancer 67, 1037-1045 (1991). 11. Kolstad, P. Follow-up study of 232 patients with stage Ia 1 and 411 patients with stage Ia 2 squamous cell carcinoma of the cervix (microinvasive carcinoma), Gynecol. Oncol. 33, 256-272 (1989). 12. Tsukamoto, N., Kaku, T., Matsukuma, K., Matsuyama, T., Kamura, T., Saito, T., and Suenaga, T. The problem of stage Ia (FIGO, 1985) carcinoma of the uterine cervix, Gynecol. Oncol. 34, 1-6 (1989). 13. Simon, N. L., Gore, H., Shingleton, H. M. Soong, S. J., Orr, J. W., and Hatch, K. D. Study of superficially invasive carcinoma of the cervix, Obstet. Gynecol. 68, 19-24 (1986). 14. Creasman, W. T., Fetter, B. F., Clarke-Pearson, D. L., Kaufman, L., and Parker, R. T. Management of stage Ia carcinoma of the cervix, Am. J. Obstet. Gynecol. 153, 164-172 (1985). 15. Pot&en, H. E., Tyler, C. W., and Sobin, L. H. International histological classification of tumors, 1975, Vol. 13, Histological typing of female genital tract tumors. World Health Organization, Geneva (1975). 16. Lee, Y. N., Wang, K. L., Lin, M. H., Liu, C. H., Wang, K. G., Lan, C. C., Chuang, J. T., Chen, A. C., and Wu, C. C. Radical hysterectomy with pelvic lymph node dissection for treatment of cervical cancer: A clinical review of 954 cases, Gynecol. Oncol. 32, 135-142 (1989). 17. Hricak, H. Carcinoma of the female reproductive organs, Cancer Suppl. 67, 1209-1218 (1991). 18. Delgado, D., Bundy, B., Zaino, R., Sevin, B. U., Creasman, W. T., and Major, F. Prospective surgical-pathological study of disease-free interval in patients with stage Ib squamous cell carcinoma of the cervix: A gynecologic oncology group study, Gynecol. Oncol. 38, 352-3.57 (1990). 19. Onnis, A., Marchetti, M., Maggino, T., de Toffoli, J., and Piazza,
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20.
21.
22. 23.
24. 25.
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M. Clinical experience in gynecological cancer management, Eur. .I. Gynaecol. Oncol. 12, 11-26 (1991). Onnis, A., and Marchetti, M. Adequate staging for an adequate management in uterine cancers, Eur. J. Gynecol. Oncol. 12, 99102 (1991). Fuller, A. F., Elliot, N., Kosloff, C., Hoskins, W., and Lewis J. L., Jr. Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage Ib and IIa carcinoma of the cervix, Gynecof. Oncol. 33, 34-39 (1989). Averette, H. E., Ford J. H., Jr, and Dudan, R. C. Staging of cervical cancer, Cfin. Obstet. Gynecol. 18, 215-219 (1975). Rotmensch, J., Senekjian, E., Javaheri, G., and Herbst, A. Evaluation of bolus c&platinum and continuous 5fluorouracil infusion for metastatic and recurrent squamous cell carcinoma of the cervix, Gynecol. Oncol. 29, 76-81 (1988). Kumar, L., and Bhargava, V. L. Chemotherapy in recurrent and advanced cervical cancer, Gynecol. Oncol. 40, 107-111 (1991). Weis, G. R., Green, S., Hannigan, E. V., Boutselis, J. G., Surwit,
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E. A., Wallace, D. L., and Alberts, D. S. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A southwest oncology group study, Gynecol. Oncol. 39, 332-336 (1990). 26. Soeters, R., Bloch, B., Levin, W., Dehaeck, C. M. D., and Goldberg, G. Combined chemotherapy and radiotherapy in patients with advanced squamous carcinoma of the cervix (cis-platinum-bleomycin-vinblastine), Gynecol. Oncol. 33, 44-45 (1989). 27. John, M., Flam, M., SikiC, B., Rotman, M., Cooper, J., Malec, M., Hannigan, J., and Phillips, T. Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: A phase I-II prospective intergroup NCOG-RTOG study, Gynecol. Oncol. 37, l-5 (1990). 28. Heaton, D., Yordan, E., Reddy, S., Bonomi, P., Lee, M. S., Lincoln, S., Graham, J., Dolan, T., Miller, A., Phillips, A., Kirschner, C., Bergen, S., and Wilbanks, G. Treatment of 29 patients with bulky squamous cell carcinoma of the cervix with simultaneous cisplatin, 5-fluorouracil, and split-course hyperfractionated radiation therapy, Gynecol. Oncol. 38, 323-327 (1990).
