GYNECOLOGIC

39, 34-39

ONCOLOGY

(1990)

Lymph Node Metastases in Carcinoma of the Cervix Uteri: Response to Neoadjuvant Chemotherapy and Its Impact on Survival ADOLFO GIAROLI, BASTARDAS,

M.D., CARLOS SANANES, M.D., JUAN E. SARDI, M.D., ANTONIO G. MAYA, M.D., MARIA L. M.D., LAZARO SNAIDAS, M.D., NIDIA GOMEZ RUEDA, M.D., SUSANA VIGHI, M.D., AND GUILLERMO R. DI PAOLA, M.D.

Oncology

Department,

Buenos

Aires

University,

Cordoba

2351,

CP 1120, Buenos

Aires,

Argentina

Received December 11. 1989

MATERIAL AND METHODS One hundred and sixty-nine patients with squamouscancerof the cervix uteri treated with three coursesof neoadjuvant cheOne hundred and sixty-nine patients with squamous motherapywith the modifiedVBP schemeare presented.All were carcinoma of the cervix uteri (stages IB bulky, II, and subjectedto a Wertheim-Meigs operationwith paraaorticlymphIII, FIGO) subjected to three courses of neoadjuvant adenectomy.The incidenceof lymph nodemetastases is analyzed chemotherapy with the modified VBP scheme were studaccordingto clinical stage,tumor volume, residualtumor in the surgical specimen,and clinical responseto neoadjuvant chemo- ied (Table I). therapy. A significant decreasein the incidenceof lymph node The following methods were used: clinical staging acinvolvement was observedin good responders.Survival rates, cording to FIGO, adding an ecography that was used to after 2 years of follow-up, improved in those caseswith small establish the approximate tumor bulk in the cervix before residualtumor, negativeparametria, and negative nodes. o 1990 neoadjuvant treatment. As a result, patients were clasAcademic

Press, Inc.

sified into four groups: ~30 cm3: frequently associated with 120 cm3: related to >5-cm tumors (barrel-shaped cervix, three times normal size or larger). Patients were then subjected to neoadjuvant chemotherapy with the modified VBP scheme: vincristine 1 mg/m’ on Day 1; &-platinum 50 mg/m* on Day 1; and bleomycin 25 mg/m* on Days 1, 2, and 3. Three courses were administered at IO-day intervals. Ten days after the last course of chemotherapy, restaging was performed, and at the same time response to neoadjuvant treatment was evaluated. As tumor response occurs with a centripetal pattern [4], the responses obtained with the above-mentioned scheme were classified as complete tumor regression (CTR), partial tumor regression (PTR), and stable disease (SD). In cases

INTRODUCTION

There is international agreement with respect to the efficiency of neoadjuvant chemotherapy in reducing tumor volume and tumor stage of the squamous carcinoma of the cervix uteri, especially if the scheme is based on the use of c&platinum and bleomycin in continuous infusion [l-7]. Though this central and parametrial response allows us to subject previously inoperable patients to oncological radical surgery, it has not been proved that a similar response would be obtained from lymph node metastases, despite certain assumptions about effectiveness [8,9]. Neither is there certainty about what impact an improvement in lymph node response would have on survival. Therefore, the objective of this report is to analyze the incidence of lymph node metastases in patients treated with this new strategy so as to establish: (1) lymph node response to neoadjuvant chemotherapy, (2) its relation to tumoral response, and (3) its impact on survival. 34

0090~8258/90$1SO Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.

LYMPH

NODE METASTASES

IN CANCER OF THE CERVIX

TABLE 1 Distribution According to Tumor Stage(FIGO) Stage

TABLE 3 Incidence of Lymph Node MetastasesRelative to Initial EcographicTumor Volume

Number of cases

IB IIA IIB IIIB

TABLE 2 Incidenceof Lymph Node Metastases Negative

IB IIA IIB IIIB

53 10 81 25

49 9 60 12

’

Negative

Positive

%

1 8 16 14

8.3 13.8 26.2 36.8

< 30 cm3 (~3 cm diam) 12 11 30-60 cm’ (3-4 cm diam) 58 50 61 45 60-120 cm’ (4-5 cm diam) >I20 cm3 (>5 cm diam) 38 24 x2 = 46.6, P < 0.001

classified as CTR, there was no clinical evidence of the tumor (the cervix was almost colposcopically completely reepithelialized and there was no evidence of parametrial infiltration, even it is had previously been infiltrated). In cases classified as PTR, tumor bulk was reduced at least 50% and there was no evidence of parametrial infiltration, even if the parametria had previously been infiltrated. SD cases showed partial reduction of parametrial infiltration or very subtle changes. Those cases in which there was an increase in tumor bulk or tumor extension were included in the SD group. After restaging a Wertheim-Meigs operation with paraaortic lymphadenectomy up to the lower mesenteric artery was performed. All the surgical cases have surgical margins free of disease. Pathological findings of the surgical specimen were classified as follows: (a) absence of residual tumor or microscopic carcinoma (smaller than 5 mm in diameter); (b) residual tumor between 0.6 and 1.9 cm; (c) residual tumor larger than 2 cm in diameter. The pathological residual tumor was established by multiple histological sections of the cervix (Burghardt technique). Also, multiple sections were performed in the parametrium to establish the residual lesion at that level; pelvic and paraaortic lymph nodes were completely studied, determining the level and number of lymph nodes involved. The number of nodes excised averaged 27.6. After the surgery, most of the patients were irradiated with 5000 rads to pelvis. A small number of cases with paraaortic metastases (7 cases) received adjuvant chemotherapy with c&platinum, methotrexate, vinblastine and cyclophosphamide due to the risk of distant metastases. All patients were followed for at least 2 years.

n

n

Initial volume

53 10 81 25

Stage

35

UTERI

Positive

%

4 1 21 13

7.5 10 25.9 52

RESULTS The incidence of lymph node metastases was analyzed relative to different risk factors: stage, tumor grade, initial tumor volume, and clinical, ecographic, and pathological response. Disease-free interval was established according to the different parameters, including the presence or absence of lymph node metastases, size of the residual lesion, persistence of parametrial infiltration, and number of affected nodes. Table 2 shows the incidence of lymph node metastases relative to tumor stage. Of 169 patients, 39 had positive nodes. This was verified in 7.5% of stage IB (4/53), 10% of IIA (l/10), 25.9% of IIB (21/81) and 52% of IIIB (13/25 patients. Lumboaortic metastases were not as common as expected: no cases were registered in stages IB and IIA; only 4 in 81 stage IIB (4.9%) cases; and 3 in 25 stage IIIb (12%) cases. With respect to tumor grade (G), it was established that 6% (2/33) of Gl, 22.2% (12/54) of G2, and 30.5% (25/82) of G3 tumors had lymph node metastases. Table 3 shows the relationship between initial ecographic tumor volume and frequency of lymph node metastases. We proved that the incidence of positive nodes in tumors smaller than 30 cm3, ecographically evaluated, was 8.3% (l/12); in those from 30 to 60 cm3 (3-4 cm), 13.8% (8/58); in those from 60 to 120 cm3 (4-5 cm), 26.2% (16/61), and in the bulky ones, 36.8 (14/38). These results demonstrate that the initial tumor volume is a significant prognostic factor, even for neoadjuvant treatTABLE 4 Incidenceof Lymph Node MetastasesRelative to Clinical Response Response

n

Negative

Positive

%

CTR” PTR SD

56 77 36

55 63 12 x2 = 5.23. P < 0.05

1 14 24

1.7 18.1 66.7

” CTR, complete tumor response; PTR, partial tumor response; SD, stable disease.

36

Incidence

GIAROLI

of Lymph

TABLE 5 Node Metastases Relative to Pathological Residual Tumor

TABLE 6 Incidence of Lymph Node Metastases Relative to Initial Ecographic Tumor Volume and Residual Lesion Diameter in the Surgical Specimen

Residual tumor diameter

(cm)

n

up to 0.5 0.6-1.9 >2

43 46 80 x2 = 35.67,

Negative 43 42 45 P < 0.001

ET AL.

Positive

%

0 4 35

0 8.7 43.7

ment. Statistically significant differences were found for tumors larger than 120 cm3 (>5 cm) (P < 0.001). Table 4 shows the frequency of lymph node metastases in relation to the different responses to neoadjuvant treatment. There is an obvious relationship between response to chemotherapy and the presence of lymph node involvement. Statistically significant differences were found among the three groups (P < 0.05). However, the issue is not that simple since there is a relationship between tumor volume and incidence of positive nodes. The same relationship is found between tumor volume and clinical response to neoadjuvant treatment. Therefore, it may be deduced that as complete responders had a smaller tumor volume, it is possible they never had lymph node metastases. As previously mentioned, lymph node response should be demonstrated relative to initial tumor volume, pathological residual tumor, and incidence of lymph node metastases (Tables 5 and 6). It may be clearly observed that there are statistically significant differences among the three groups. When the residual tumor pathologically measured in the surgical specimen was smaller than 0.5 cm, lymph node metastases were never found. On the other hand, of 80 patients with tumors larger than 2 cm in diameter, 35 (43.7%) had positive lymph nodes. Table 6 shows the relationship between initial tumor volume, residual tumor lesion, and incidence of lymph node involvement. For tumors initially 3 to 4 cm in diameter, no lymph node metastases were found (O/16) when the tumors were reduced to diameters less than 0.5 cm; 8% (2/25) of nodes were positive when the residual lesion was 0.6 to 1.9 cm in diameter; and 33% (6/18) of nodes were positive when the residual lesion was larger than 2 cm in diameter. Considering those tumors initially 4 to 5 cm in diameter, no lymph node metastases were found (O/12) when the tumors were reduced to diameters less than 0.5 cm; 7% (l/14) of nodes were positive when the residual lesion was 0.6 to 1.9 cm in diameter; and 45% (15/33) of nodes were positive when the residual lesion was larger than 2 cm in diameter.

Prechemotherapy Residual tumor diameter (cm) ~0.6 0.6-2 >2

-3 cm +/II

%

34 cm +/n

diameter 4-5 cm

%

+/n

7%

+5 cm +/n

%

0 O/16 0 O/l2 0 o/7 0 0 2125 8 l/14 7.1 l/6 16.7 33.3 6118 33.3 15133 45.5 13126 50 x2 = 10.72, P < 0.001

W3

O/I 113

For tumors initially larger than 5 cm in diameter, no lymph involvement (O/7) was evident when the tumors were reduced to diameters less than 0.5 cm; 16% (l/6) of nodes were positive when the residual lesion was 0.6 to 1.9 cm in diameter; and 50% (13/26) of nodes were positive when the residual lesion was larger than 2 cm in diameter. Statistically significant differences were found in tumors with initial volumes larger than 30 cm3 (3 cm in diameter). Statistical differences were also found (P < 0.01) between the number of positive nodes and the clinical response to neoadjuvant chemotherapy. Only one complete responder had lymph node metastases, and in this case only one positive node was found. Forty-two percent of the partial responders (6/14) had only one positive node; 21% (3/14) had more than 3. In the stable disease patients, 12% (3/24) had only one positive node and 70% (17/24) had three or more positive nodes. Table 7 analyzes the disease-free interval rates according to the number of lymph nodes. The percentage of patients without positive nodes who had a diseasefree interval was 89.2% (116/130); of patients with one positive node, 70% (7/10); of patients with two positive nodes, 66.6% (6/9). Only 25% (5/20) of patients with three or more positive nodes had a disease-free interval. Table 8 analyzes disease-free interval relative to clinical response and presence of lumph node metastases.

Disease-Free Number of lymph nodes 0 1 2 3 or more

TABLE 7 Interval (DFI) Relative to the Number Metastasic Lymph Nodes Total

NED

Recurrence

130 116 10 7 9 6 20 5 x2 = 7.62, P < 0.005

14 3 3 15

of

DFI (%) 89.2 70 66.6 25

LYMPH

NODE METASTASES

IN CANCER OF THE CERVIX

37

UTERI

TABLE 8 Disease-FreeInterval of Patients with or without Lymph Node MetastasesRelative to Clinical Response Negative nodes

Clinical response Complete Partial Stable disease x2 = 4.56, P < 0.05

Positive nodes

Total

NED

Recurrence

DFI (%)

Total

NED

55 72 13

53 64 9

2 8 4

96.4 88.8 69.2

1 14 24

-

Statistically significant differences were found only in the group with negative nodes (P < 0.05), between complete or partial responders and stable disease patients. In the positive lymph node group, no differences were observed in relation to tumor response, implying that when a lymph node is involved, response to chemotherapy is irrelevant. Table 9 shows disease-free interval relative to residual tumor diameter in the surgical specimen and presence of lymph node metastases. Significant differences were found in both groups when the residual lesion was more than 2 cm in diameter, suggesting that residual tumor volume is an important prognostic variable.

Table 10 compares the disease-free interval rates of the patients with or without positive nodes, in relation to the persistence of microscopic parametrial tumor in the surgical specimen. It is evident that in cases with negative nodes, the presence of residual microscopic parametrial tumor worsened the prognosis in terms of survival (91% vs 71%). The same was verified in the positive node group (69% vs 34%). Furthermore, statistically minor differences were found (P < 0.05) in the positive and negative parametrial groups with respect to the presence of positive nodes. DISCUSSION

There are no doubts about the sensitivity of squamous carcinoma of the cervix uteri to neoadjuvant chemotherapy. The main problem is to determine whether the TABLE 9 Disease-FreeInterval (DFI) of Patients with or without Lymph Node MetastasesRelative to ResidualLesionDiameter Diameter of residual lesion

(cm) up to 0.5 0.6-2 >2

Negative nodes Total

NED

43 42 42 39 45 35 x2 = 7.66, P < 0.01

Positive nodes

DFI (%)

Total

NED

DFI (%)

97.7 92.8 17.7

-

-

0 100 40

4 4 35 14 x2 = 4.21, P < 0.05

Recurrence

DFI (%)

1 6 14

8 10

57.1 41.6

central and parametrial response is accompanied by a response at the lymphatic level. According to Kim et al., the frequency of lymph node metastases in a group of 54 patients subjected to neoadjuvant chemotherapy was less than expected for the same stage and tumor size [93. Likewise, Mancuso er al. the Italian group, found a low incidence of lymphatic dissemination in 33 advanced or stage IB barrel-shaped cervix patients treated with methotrexate, bleomycin, and c&platinum [8]. However, this problem is highly complicated since several factors, such as tumor volume, stage, differentiation degree, and other factors that have not yet been determined, have an effect on these lymph node metastases. These same circumstances also influence tumoral response to chemotherapy. Therefore, it is almost impossible to determine the frequency of said dissemination, taking into account all the factors mentioned above, for a particular situation. Frequently, the anatomopathologic study of extirpated lymph nodes reveals evidence from which it may be inferred that neoadjuvant chemotherapy caused regression of previously existing dissemination. These images show large areas of necrosis, esclerosis, keratinization, etc., leading to the assumption of the previous existence of neoplastic cells. But, since there is no defined pattern, its existence cannot be asserted. In a previous study we determined that 62% of the suspicious radioisotopic lymphographies improved after

neoadjuvant chemotherapy, with the inherent limitations of the method, and that survival of those patients is different [lo].

TABLE 10 Disease-FreeInterval of Patients with or without Lymph Node MetastasesRelative to Positive or Negative Parametrium Lymph node status Negative Positive

Negative parametrium Total

NED

116 106 13 9 x2 = 3.86, P < 0.05

DFI (%) 91.4 69.2

Positive parametrium Total

NED

DFI (%)

14 10 71.4 26 9 34.6 x* = 4.94, P < 0.05

38

GIAROLI

Although in this group the incidence of lymph node metastases in stages IB, IIA, and IIB was significantly less than expected according to the international experience, in stage IIIB, it was in accordance with the frequency found in the protocols without neoadjuvant chemotherapy [l l-171. This may be due to the fact that stage IIIB patients had larger tumoral volumes and thus less tumoral response to chemotherapy, as discussed at the beginning. This was also reflected in the lymph node response. However, it is interesting to point out the low incidence of paraaortic metastases in every stage (Table 2). Other typical factors that have an effect on the appearance of lymph node metastases, such as differentiation degree and tumor volume [ 18-201, also were present in the patients treated with neoadjuvant chemotherapy. Analyzing the problem from the point of view of the initial tumor volume as ecographically evaluated, we observe that the incidence of lymph node metastases in the higher-risk group, represented by tumors more than 5 cm in diameter (+ 120 cm3), is 36.8%. Burghardt et. al. found 55% of lymph node metastases for these tumors, though a more sophisticated measuring method was used for this study (magnetic resonance imaging) [21]. The question is, then, what is the frequency of lymph node spread in this study, in basal conditions (not having been previously subjected to chemotherapy)? This would be represented by those patients that did not modify their original tumor volume and that did not respond to chemotherapy (group EE). According to this, the relationship between tumor bulk and frequency was as follows: tumors smaller than 30 cm’, 9%; from 30 to 60 cm3 (34 cm), 10%; from 60 to 120 cm3 (4-5 cm), 25%; and in those larger than 120 cm3 (