Is subradical surgical treatment for carcinoma of the cervix uteri stage IB logical?

GYNECOLOGIC ONCOLOGY 32, 360-364(1989)

Is Subradical Surgical Treatment for Carcinoma of the Cervix Uteri Stage IB Logical?

JUAN SARDI, M.D., CARLOS SANANES, M.D., ALWLFO GIAROLI, M.D., NIDIA GOMEZ RUEDA, M.D., GUILLERMO DI PAOLA, M.D., SUSANA VIGHI, M.D., ALBERTO CACHAU, M.D., AND SILVIA BURLANW, M.D.

First Chair of Gynecology, Oncology Department, Cbrdoba 2351, CP 1120, Buenos Aires, Argentina

Received April 13, 1988

Twenty-eight patients with squamous carcinoma of the cervix FIG0 stage Ib were treated with three courses of neoadjuvant chemotherapy with a VBP modified scheme. Clinical response showed that the percentage of complete and moderate responses exceeds 95% of the cases. Clinical response was also related to tumor bulk measurement by ultrasound scanning. Twenty-three of the patients were then subjected to the Wertheim-Meigs operation. Pathological findings of surgical specimens showed absence of residual lesion in 6 patients (26.1%) and carcinoma smaller than 0.5 cm in 5 patients (21.7%). Tumor response to neoadjuvant chemotherapy was excellent in NG3, MG3 tumors when lymphoplasmomonocytic infiltration was present. In accord with this result a new protocol was developed. 0 1989 academic prepp, IX.

INTRODUCTION

The universally accepted surgical treatment for carcinoma of the cervix uteri stage Ib is the Wertheim- Meigs operation. The price of this cure sometimes causes damage to the urinary tract that can reduce survival and deteriorate the quality of life. Because the treatment results have not changed during the last decade, the possibility of subjecting the high-risk group to neoadjuvant chemotherapy was considered, keeping in mind the result obtained with the modified VBP scheme in stages II, III, and IV. Neoadjuvant chemotherapy with VBP in the treatment of advanced carcinomas of the cervix (FIG0 II, III, and IV) has been used at the First Chair of Gyne- cology of Buenos Aires University for the last 4 years.

The analysis of that protocol showed a remarkable regression of cervical tumor size and parametrial extension with low morbidity in a considerable number of cases, improving the conventional surgical or radiotherapic treatment [l]. The analysis of FIG0 parameters for clas- sifying cervical carcinomas as stage Ib shows that all clinical tumors of any topography, size, or growth confined to the cervix are included; thus a variety of lesions of

differing evolution and prognosis are found within these premises [2]. A great number of clinical or histologic factors have been studied in squamous carcinoma of the cervix in order to identify groups with a high risk of recurrence and to be able to predict their localization.

The relationship between the initial tumor bulk and the incidence of lymph node metastases with survival is very important [3,4]. The histologic prognostic factors relating to the tumor as vascular invasion are related to the possibility of regional recurrences [5,6], while poorly differentiated tumors have distant metastases [7]. In addition, other authors have determined that lymphoplas- mocytic infiltration [8] and eosinophilia [7] are good prognostic factors in those patients submitted to radiotherapy.

However, the clinical and histological factors that influence tumor response to chemotherapy, especially when used as first line treatment, have not been analyzed. Thus the objectives of this protocol with neoadjuvant chemotherapy in stage Ib are (I) to achieve a tumor regression that makes the surgical treatment easier and ensures greater success in radiotherapy; (2) to try to find histologic factors that can predict the tumor response to neoadjuvant chemotherapy; and (3) to perform a chemosensitivity test that would rationalize second-line treatment in all cases and third-line treatment in the high-risk group.

MATERIALS AND METHODS

Twenty-eight patients with squamous carcinoma of the cervix, stage Ib (FIGO), were treated with three courses of neoadjuvant chemotherapy with the modified VBP scheme [l]. Only those patients with cervical tumors larger than 2 cm in diameter colposcopically evaluated in the ectocervical surface and with cervical volumes greated than 27 cm3 measured by ecography were included in this protocol. All the patients were classified according

360 CWW3258/89 $1.50 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

DETERMINING A NEW THERAPEUTIC APPROACH 361

to the staging system proposed by FIGO. In order to evaluate the clinical response to chemotherapy, cervical ecography, colposcopy, and radioisotopic lymphography were performed before and after the neoadjuvant treatment. The morphologic changes were revealed by tumor biopsy after each course. The methodology for evaluating the clinical response to chemotherapy was classified into four categories: complete tumor regression (CTR), moderate tumor regression (MTR), stable disease (SD), and progressive disease (PD).

CTR was considered to have occurred when the tumor disappeared, when colposcopy revealed a reepithelized ectocervical surface, and when ecography indicated a cervical volume that did not exceed 27 cm3. MTR was considered to have occurred when the lesion was di- minished in extent and volume by at least 50%. Stable disease included those cases that showed no or very subtle changes. Finally, PD was indicated when an increase in the tumor bulk or the lesion extent was confirmed.

In the pathological study prior to neoadjuvant chemotherapy, the histologic grade, the nuclear grade, the mitotic grade, and the presence and intensity of lym- phoplasmocytic infiltration were evaluated to determine the histologic factors that influence the tumor response to chemotherapy. The histologic grade was classified according to tumor differentiation as Gl , G2, and G3, where Gl corresponds to differentiated tumors, G3 to poorly differentiated tumors, and G2 to intermediate tumors. The nuclear grade was classified as NGl , NG2, and NG3 depending on nuclear and cytoplasmatic atypia using a version of Black’s well-known scheme. Mitotic grade refers to the number of mitotic figures in 10 high-power fields: MGl up to 10 mitoses, MG2 from 11 to 20, and MG3 more than 21. The lymphoplasmomonocytic infiltration was determined by the absence or presence of lymphomonocytic and monocytic elements that appear among the carcinomatous cords, colonizing the fibrous tracts.

After chemotherapy, 23 patients were subjected to a Wertheim-Meigs operation with lumboaortic lymphadenectomy; the remaining 5 patients were irradiated according to the Fletcher technique because of surgical contraindications [9]. In the surgical group, the pathological residual tumor was established by multiple histological sections of the cervix (Burghardt technique).

The findings were classified as absence of invasive residual lesion, microscopic carcinoma (smaller than 5 mm in diameter), and macroscopic carcinoma (larger than 5 mm in diameter), thus evaluating the unmistakable response to cytostatic drugs. All histologic parameters were related to the prechemotherapeutic cervical tumor bulk. For this purpose, the tumors were classified as smaller or larger than 40 cm3 because tumors smaller than that

volume were consistently correlated to complete clinical tumor regressions.

RESULTS

Results include the study of the tumor response and the postoperative pathological findings in the surgical specimens as well as the relationship between them.

Table 1 shows the clinical tumor response to neoadjuvant treatment. It is evident that the percentage of complete and moderate responses exceeds 95% of the cases, with only one patient showing no response and no patients with progressive disease.

In these patients, the pretreatment ecographic volume (56.8 cm3) was reduced by about 50% (final average volume, 27.8 cm3). This fact, together with the high percentage of clinical responses, allows us to affirm the advantage of this therapy.

From Table 2 the importance of the initial tumor volume can be observed. The initial average volume in patients with complete tumor regression is remarkably less than that in patients with moderate tumor regression. It should be pointed out that the only patient who did not respond to treatment, and was classified as having stable disease, had an initial volume three times larger than that of patients with complete tumor regression. The percentage of tumor regression in this patient, measured by ecography, was the lowest in this series.

Analysis of the postoperative pathological findings in- dicates that the residual lesion did not exceed the microscopic carcinoma size (Table 3) in about 50% of the patients with clinically evident invasive carcinoma stage Ib (FIGO) before chemotherapy. Nevertheless, there was not an absolute correlation between the colposcopic and clinical response and the postoperative morphological findings, as demonstrated by the fact that in only 6 of the 10 surgical patients with clinical complete tumor regression could the absence of a histological lesion be verified.

As shown in Table 4, the correlation between the pathological findings in the surgical specimen and the initial average volume revealed that there was a consistent as- sociation between the cases without residual lesion and

TABLE 1 Clinical Response

Complete tumor regression (CTR) Moderate tumor regression (MTR) Stable disease (SD) Progressive disease (PD)

Total

No. of cases %

14 50 13 46.5 1 3.5 0 0

28 loo

362 SARDI ET AL.

TABLE 2 TABLE 4 Relationship between Clinical and Ecugraphic Response Morphological-Ecugraphic Correlation

Response

CTR MTR SD

No. of cases

14 13

1

Initial average volume

Cd)

40.1 65.5

122.0

Final average volume

(cm’)

22.0 32.5 74.1

Residual lesion

No lesion Microscopic carcinoma Lesion up to 1 cm Lesion larger than 1 cm

Initial Final average average

No. of volume volume cases (cm’) (cm’)

6 35.5 21.0 5 42.8 23.2 5 63.5 34.5 7 73.1 35.0

those patients with ecographically evaluated smaller volumes; thus the possibility of residual lesion increases in direct proportion with the initial volume.

The final volumes are similar for the group without residual lesion and the group with microscopic lesion; the same is true for residual macrocarcinoma, regardless of size.

lymphoplasmomonocytic infiltration was analyzed (Table 7).

Microscopic parametrial extension was verified in only one case and lymph node involvement in two, and both were related to bulky tumors (119 and 122 cm3); in one case the response to chemotherapy was classified as stationary.

With respect to histologic factors influencing neoadjuvant treatment, no relationship was found between the tumor grade and the residual tumor in the surgical specimen. The best responses (no invasive lesion and microscopic carcinoma) are similar in G2 (50%) and in G3 (42.7%). Because there are only three cases of Gl no valid conclusions can be drawn. However, it could be confirmed that the nuclear grade probably influences the tumoral response to neoadjuvant chemotherapy (Table 5).

In summary, 66% of the cases with NG2 had macroscopic lesions in contrast to 38% of the cases with NG3. Also, 38% of the cases with NG3 had no residual lesion, while this finding was verified in only 11% of the cases with NG2. An analysis of the influence of the mitotic grade on the response to chemotherapy is shown in Table 6. No lesion was found in 7% of the cases wih low mitotic index (MGl, MG2). On the other hand, no residual lesion was verified in 50% of the cases with MG3. However, cases with macroscopic residual lesion are more numerous in the first group (69%) than in the second (30%). Similar results were obtained when the

Of the patients with lymphoplasmomonocytic infiltration, 35% had macroscopic residual lesion and 35% had no residual lesion. On the other hand, when the infiltration was absent in the biopsy prior to chemotherapy only 11% of the cases responded favorably to neoadjuvant treatment and 77% had macroscopic carcinoma.

The pathological findings that seem to influence the tumoral response (NG-MG and lymphoplasmomonocytic infiltration) were correlated to the initial tumor volume measured by ecography, but only a relationship between MG and LPI with volume was verified (Tables 8 and 9).

It is evident that in tumors larger than 40 cm’, the best responses were verified in the group with lymphoplasmomonocytic infiltration; in two cases no lesion was found, in three cases only a microcarcinoma was found, and in the remaining four a macroscopic lesion was confirmed. In those patients with absent infiltration in the prechemotherapy biopsy, macroscopic tumor was always found. Similar results were observed in tumors smaller than 40 cm3.

When the response to neoadjuvant chemotherapy was analyzed and tumor volume was related to its mitotic grade, similar results were obtained, with better responses in the group with tumors smaller than 40 cm3 and of higher mitotic grade (Table 9). However, as can be observed from Table 9, there is a marked trend for the more bulky tumors to have lower mitotic index and vice versa.

TABLE 3 Postoperative Pathological Findings

No. of cases

No invasive lesion 6 Lesion smaller than 0.5 cm 5 Lesion larger than 0.5 cm 12

Total 23

%

26.1 21.7 52.2

loo

TABLE 5 Response to Neoadjuvant Chemotherapy Nuclear Grade

Residual lesion

Nuclear No. of Microscopic grade cases None carcinoma Macrocarcinoma

NGl 1 0 0 1 NG2 9 1 (11.1%) 2 (22.2%) 6 (66.6%) NG3 13 5 (38.4%) 3 (23.0%) 5 (38.4%)

DETERMINING A NEW THERAPEUTIC APPROACH 363

TABLE 6 TABLE 8 Response to Neoadjuvant Chemotherapy Mitotic Grade

Residual lesion

Response to Neoadjuvant Chemotherapy Relationship between Lymphoplasmomonocytic Infiltration and Tumor Volume

Mitotic grade No. of cases None

Microscopic carcinoma

Macro- carcinoma

MGI-MG2 13 1 (7.6%) 3 (23.0%) 9 (69.2%) MG3 10 5 (50.0%) 2 (20.0%) 3 (30.0%)

Volume Lymph.

inf. No. of Microscopic Macro- cases None carcinoma carcinoma

DISCUSSION

< 40 cm’ Absent 4 1 1 2 Present 5 3 1 1

40 cm’ Absent 5 0 0 5

> Present 9 2 3 4

The development of neoadjuvant chemotherapy in hu- man tumors is progressing. Various indications for its use include (1) treatment of subclinical metastases; (2) tumor regression which will improve radiotherapy or will make radical surgery possible in prechemotherapy in- operable cases; (3) observation of how the primary tumor reacts; (4) rationalization of postsurgical treatment; and (5) selection of postsurgical chemotherapy in high-risk cases [lo].

the beginning and less sensitive afterward. We have observed that when the neoplasia is smaller than 40 cm3, MG3 predominates and the lower mitotic grade is found in bulky tumors.

Although these arguments may justify its use in re- gionally advanced stages of the disease, they are not valid enough for its routine application in stage Ib. This is because it has not yet been demonstrated that adjuvant chemotherapy increases survival rates in cases at high risk for recurrence.

Excellent responses to chemotherapy, evaluated by the pathological residual lesion, were observed in tumors with MG3, especially when their size was smaller than 40 cm3. Similar findings were confirmed with tumors of similar size and lymphoplasmomonocytic infiltration prior to neoadjuvant chemotherapy.

Nevertheless, there is an international consensus that tumor volume influences survival, even in patients without parametrial infiltration or lymph node involvement, that is true stage Ib [I I]. With this in mind, we administered this treatment only to those patients with colposcopically measured tumors larger than 2 cm in the ectocervical surface. In addition, we were encouraged by the results obtained in stages IIb and IIIb with the modified VBP scheme.

Another factor that seems to underscore tumor sensitivity to cytotoxic drugs is the nuclear and cytoplasmatic atypia, because 38.4% of the patients with tumors with NG3 had no residual lesion and 23% had tumors smaller than 5 mm in diameter. The grade of tumor differentiation does not seem to be a prognostic factor of tumor response to cytotoxic drugs in this series.

The results obtained have demonstrated in vivo the validity of the theoretical equation of neoplastic growth [ 121. It states that when the tumor is small, the proliferating cellular population is high and when the tumor is bulky, that fraction is reduced. Since the neoplastic sensitivity to chemotherapy depends on the size of the proliferating fraction, tumors are very sensitive to chemotherapy at

According to the results obtained, we can assert not only that there has been a remarkable tendency toward a greater number of complete regressions compared with IIb but also that the percentage of patients without residual lesions in the surgical specimen was 27.2%, a percentage not ordinarily observed in the advanced stages of the disease. The prechemotherapy tumor volume plays an important role in these findings. The stage Ib average volumes were inferior to those observed in stage IIb (56.8 cm3 vs 91.7 cm3) [15].

TABLE 9 Response to Neoadjuvant Chemotherapy Relationship between

Mitotic Grade and Tumor Volume TABLE 7

Response to Neoadjuvant Chemotherapy Lymphoplasmomonocytic Infiltration

Residual lesion Volume Mitotic grade

No. Micro- of scopic Macro-

cases None carcinoma carcinoma

No. of cases

Absent 9 Present 14

None

1 (11.1%) 5 (35.7%)

Microscopic carcinoma

1 (11.1%) 4 (28.5%)

Macrocarcinoma

7 (77.7%) 5 (35.7%)

< 40 cm’ I

MGI-MG2 3 0 1 2 MG3 6 4 1 1

> 40 cm3 MGI-MG2 10 1 3 6 MG3 4 I 0 3

Residual lesion

Residual Lesion

364 SARDI ET AL.

Also, the cases without residual lesion in stage Ib had an average volume of 35 cm3; when the remaining lesion was equal to a microscopic carcinoma, the volume was 42 cm3 and the initial volume increases as the size of the residual carcinoma increases.

The main objective of this experimental trial was to increase survival in patients in stage Ib with bulky tumors and histological risk factors. However, the responses to the neoadjuvant chemotherapy, which were evaluated through pathological study of the surgical specimen, led us to believe that it is possible to determine which patients can benefit from a reduction in the magnitude of the surgical and conventional actinic treatment, thereby re- ducing or avoiding the morbidity caused by the treatment [13,14].

The results, together with the initial tumor volume, helped us to determine the group of patients for which a reduction in the surgical procedure could be planned. This group would have small volume tumors (smaller than 40 cm3) even when the ectocervical lesion is larger than 2 cm but with high mitotic index, remarkable nuclear and cytoplasmic atypia, and presence of lymphoplasmomonocytic infiltration in the biopsies done before the neoadjuvant chemotherapy. However, in these cases, a careful clinical, colposcopic, cytologic, and pathologic staging will be necessary after the neoadjuvant chemotherapy to evaluate such a possibility.

In summary, we are trying to change the definite risk of morbidity associated with radiation and radical surgery into a transitory one, represented by chemotherapy.

CONCLUSIONS

A new protocol for squamous carcinoma of the cervix uteri stage Ib is being developed. It includes the possibility of performing a total hysterectomy with bilateral salpingo- oophorectomy and upper third vaginal excision and pelvic lymphadenectomy, instead of the Wertheim-Meigs operation after neoadjuvant chemotherapy with modified VBP scheme. For this protocol to be feasible, the necessary conditions and the pre-VBP chemotherapy determinant factors include initial ultrasound volume less than 40 cm3, mitotic grade 3, nuclear grade 3, and lymphoplasmomonocytic infiltration present. The post-,VBP chemotherapy determinant factors are negative ectoen- docervical cytology, negative colposcopy , cervical en- doscopy, and endocervical curettage.

The absence of any of these factors before or after the neoadjuvant chemotherapy with VBP scheme will determine whether the Wertheim-Meigs procedure must be used as surgical treatment. Today, it seems sensible to assume that the possibility of a recurrence in this group would not be significant, because the small volume

tumors have a greater sensitivity to chemotherapy and a microscopic extension outside the uterus previous to the neoadjuvant therapy may not be frequent.

If the validity of this hypothesis is demonstrated, the use of subradical surgical techniques will be able to improve the quality of life or limit the morbidity of the urinary tract without an increase in the risk of a recurrence. Moreover, this is a dynamic protocol that will allow new standards to be incorporated in the future as our knowledge of tumor biology increases in the presence of this therapeutic approach.

REFERENCES

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Kapp, D., Fischer, D., and Gutierrez, E. Pretreatment prognostic factors in carcinoma of the uterine cervix, Inst. J. Radiat. Oncol. Biol. Phys. 10, 822 (1983). Kapp, D. The role of the radiation oncologist in the management of gynecologic cancer. Cancer 51, 2485 (1983). Morales, P., Hussey, D., Maor, M., Hanberger, A., Fletcher, G., and Taylor Wharton, J. Preliminary report of the M. D. Anderson Hospital randomized trial of neutron and photon irradiation for locally advanced carcinoma of the uterine cervix, Znt. J. Radiat. Oncol. Biol. Phys. 7, 1533 (1981).

Morrow, P., and Townsend, E., (Eds.), Synopsis of gynecologic oncology, Wiley, New York, p. 388 (1981). Rosen, G., and Caparros, D. Preoperative chemotherapy for os- teogenic sarcomas, Cancer 49, 1221 (1982). Arrighi, L., Vazquez Ferro, E., Sardi, J., Sananes, C., and Royer, M. La linfadenectomla en el cancer de cue110 uterino, in Proceedings, First World Congress Cervical Pathology and Colposcopy, Mar de1 Plats (1972).

Skipper, H., and Schaber, F. Cancer medicine, Lea & Febiger, New York, p. 269 (1983). Jacobs, A., Perez, C., Camel, L., and Kao, N. Complications in patients receiving irradiation and radical hysterectomy for carcinoma of the cervix, Gynecol. Oncol. 22, 273 (1985). Kristensen, G., Fridmont, P., Poulsen, H., and Ulbak, S. Persistent bladder dysfunction after surgical and combination therapy of cancer of the cervix uteri Stage Ib and Ha, Gynecol. Oncol. 18, 38 (1984). Sardi, .I., Sananes, C., Giaroli, A., di Paola, G., G6mez Rueda, N., Cachau, A., Vighi, S., and Burlando, S. Results phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix uteri, Gynecol. Oncol., in press.

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Is subradical surgical treatment for carcinoma of the cervix uteri stage IB logical?