Multimodal treatment for the locally advanced stage IB, IIA, IIB patients of cervical cancer

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GYNECOLOGY & OBSTETRICS International Journal of Gynecology& Obstetrics 49 Suppl. (1995) $49-$57

Multimodal treatment for the locally advanced stage IB, IIA, liB patients of cervical cancer S.J. K i m Department of Ob-Gyn, Kangnam St. Mary's Hospital, Catholic UniversityMedical CollegeSeoul, Seoul, South Korea

Abstract By employing neoadjuvent chemotherapy (NCT) before radical hysterectomy (RS) and pelvic radiotherapy (RT) in bulky locally advanced cervical cancer (IB, IIA, liB), the study was focused to update the results of the author's therapeutic experience with multimodal treatment by observing tumor free survivals along with related prognostic factors in different treatment modalities with NCT. The chemotherapy regimen for induction is composed of Vinblastin, Bleomycin and cis-Platin regimen (VBP). The effect of neoadjuvent chemotherapy was evaluated by the WHO definition of clinical response (CR, PR, ST, PG). As a result of NCT study in the stage IA, IIA, and lib cervical cancer patients recurrence occurred in 50 out of 138 patients (35.5%) treated with radical hysterectomy only (RS) compared with 17 out of 92 patients (18.5%) treated with NCT followed by radical surgery. In conjunction with the NCT study in the cervical cancer, another two groups of patients who were treated by neoadjuvent chemotherapy followed by radical hysterectomy (NCST) and adjuvent radiation (NCSRT) were evaluated in the high-risk patients of cervical cancer with stage IB, IIA, and IIB. Primary responses in the NCST group (n = 61) were CR (68.9%), PR (22.9%), ST (4.9%) and PG (3.3%) respectively, while the chemoresponse of the NCSRT group (n = 101) were CR (65.3%), PR (18.9%), ST (4.9%) and PG (10.9%), respectively. The survival rates of the NCSRT group (n = 101) were 100% in all 1-5 years in CR group, while the rate of the NCST group was 100% at 1 year and 98.5% at 5 years in the CR group of patients. In contrast to CR, the patients who showed PR patients showed 40.1% of 5-year survival rate in NCST group, and 12.6% in NCRST group. Tumor size, lymphnode metastasis and primary chemoresponse pattern were correlated to each other, but 5-year survival rate of the CR group was much higher in the same stages IB, IIA and liB of cervical cancer. In the multivariate analysis of known risk factors, the response pattern to primary chemotherapy, the responsiveness revealed the highest value (R.R. = 3.26) as a survival predictor in the patient treated with a multimodal approach. Keywords: High risk cervical cancer; Neoadjuvent chemotherapy; Radical hysterectomy; Pelvic radiotherapy; Multimodal treatment; Primary chemoresponse

1. Introduction Invasive cervical cancer is the fifth most common cancer worldwide and is the second major cause of cancer-related deaths in women. A m o n g

the number of patients, 75% occurred in developing countries (Parkin et al., 1988). In the last decade, significant advances have been made in understanding the etiology and patterns of spread of the cervical cancer. Since

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S.J. Kim ~International Journal of Gynecology & Obstetrics 49 Suppl. (1995) $49-$57

the introduction of the pap smear, the death rate has decreased by 70% in many developed countries. The 5-year survival rate for stage has, however, not markedly improved, either in developed countries or worldwide. This indicates that the presently available treatment modalities for the primary treatment of high-risk patients with cervical cancer need to be considered (Peterson, 1991). Recently, however, various efforts have been made to lower death rate using adjuvant chemotherapy for the patients with locally advanced stages of high-risk cervical cancer. By employing neoadjuvant chemotherapy (NCT) before radical hysterectomy (RS) and pelvic radiotherapy (RT) for standard treatment modality in bulky locally advanced cervical cancer, several reports have announced significant improvements in survivals (Camel Cohon et al., 1982; Fried Lander et al., 1987; Albert et al., 1987; Kim et al., 1988, 1989; Sardi et al., 1990; Benedetti et al., 1991; Kim et al., 1991). Appropriate management of patients with locally advanced cervical cancer depends on how we can locate the risk factors and how to properly treat them with multimodal approaches under accurate evaluation of the factors. Therefore, the goals of the study presented here are: (1) to update the results of our therapeutic experience with multimodal treatment in the patients with high-risk locally advanced cervical cancer (stage IB, IIA, IIB); and (2) to observe recurrence and 3-5 -year tumor-free survivals along with related prognostic factors in different treatment modalities with NCT. The initial response to neoadjuvant chemotherapy (NCT) was also compared with the outcome of the patients to evaluate the possible role of an 'in vivo chemosensitivity test' between patients who received NCT followed by RS and those receiving NCST RS and RT sequentially. For comparing the initial chemoresponse with risk factors of cervical cancer, well-known multivariate analyses were performed. 2. Rationale of multidisciplinary approach

Currently, there is a lot of advancement in the knowledge of gene regulation in carcinogenesis at

the molecular biological level. Cancer pathogenesis can be explained by the breakdown of the signaling network with oncogenes, growth factors, tumor suppressor genes, and other intrinsic and extrinsic factors. Thereafter, abnormal growth, loss of differentiation, change in chromosomal structure and genetic change by expression of specific DNA sequence may follow (Vogelstein et al., 1988). The genetic alterations occurring by HPV infection or carcinogens may be followed by activation of oncogenes and mitogens resulting in growth of the tumor cell (Dyson et al., 1989). The virus-encoded oncoproteins, especially E6 and E7D protein of HPV 16/18, can transform the cervical epithelial cells into tumor cells by mutual action with cellular p53 and Rb turns suppressor proteins (Scheffner et al., 1990). Consequently, it can be explained that cancer mass at the clinical level already has a variety of cell populations and genetic heterogenicity. The rationales for multimodal treatment in cervical cancer are: (1) the development of tumor is a multistep process; (2) the nature of tumor cells is complex and heterogenous; and (3) all the patients have individuality. Heterogeneity is found within tumors at the earliest detection and cancer cells are different in their ability to metastasize, they are sensitive to therapy, and have the propensity to develop genetic variation. The failure of simple therapy can be explained by the tumor heterogeneity, e.g. multiclonal cell subpopulations. 3. Role of different treatment modalities

The basic methods for multimodal treatment are the proper combinations of chemotherapy, surgery, radiation and others such as immunotherapy hyperthermia and even in the future, gene therapy. Chemotherapy can be neoadjuvant and/or adjuvant to radical operation. Surgery should be a radical procedure, such as Wertheim's or Meig's procedure after localization of the tumor by preoperative chemotherapy or radiation and in cases with regional malignant disease. External radiation of the entire pelvis, with or without extended field approach, should

S.J. Ka'm /International Journal of Gynecology & Obstetrics 49 Suppl. (1995) $49-$57

apply with sufficient and homogenous doses to all structures of pelvis.

3.1. Role of surgery The role of surgery in multimodal treatment is the removal of tumor mass and possibly extended tissues by the extended hysterectomy with pelvic lymphadenectomy. Concerned about radicality of surgery, we divided the extended hysterectomy which modified from original Rutledge classification into types I, II and III, IV. Type I, II radical hysterectomy is a less aggressive surgical procedure, the cases are mostly in low-risk early stage patients, adjuvant surgery after chemotherapy or radiation. Type III and IV procedure is a more radical method of surgery to remove all primary lesions, and possibly metastatic macroscopic and microscopic remnants in pelvic cavity to improve survival rate.

3.2. Role of radiotherapy The role of radiation in multimodal treatment is to expect cellular events after irradiation, such as producing free radicals, promoting peripheral fibrosis and direct killing effects to the microscopic or macroscopic cancer cell. In general, postoperative radiation is known to be more acceptable than preoperative radiation in practice (Withers et al., 1988). We should consider the following factors before planning radiotherapy. Technically, they are the total dosage, daily dose, number of fraction, field size, sequence of therapy, and energy source. Clinically, they are tumor volume, cell type, anatomical factors, previous surgery, age, nutrition, and systemic disease.

3.3. Role of chemotherapy Chemotherapeutic agents kill a constant fraction of cells rather than a constant number of cells. So, it is necessary that sufficient courses of chemotherapy and effective combination therapy should apply for multimodal treatment to overcome recurrence of possible remaining microscopic cancer cells. As the role of neoadjuvant chemotherapy, the rationale of NCT before standard treatments of surgery and irradiation could be summarized as

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follows: (1) no charge in vascularity to cancer mass and resistance to anticancer drugs; (2) easy surgical removal after reduction of cancer mass by anticancer drugs and radiation therapy; (3) removal of micrometastasis in the early clinical stage; and (4) theoretical improvement in sensitivity of the tumor to anticancer drugs before surgery and radiation (Albert et al., 1987). Chemotherapy in the treatment of cervical cancer is basically a supplementary method for surgery and radiation. The gynecologic oncologists should be under consideration of following host factors such as age, general conditions, underlying disease, previous treatment, toxicities of drugs and other background conditions of patients. 4. Evolution of therapeutic modalities in the treatment of cervical cancer

According to our cancer center in the Catholic University Medical College, 2095 cervical cancer patients were registered from 1970 to 1992 and among them, 947 patients were treated at Kangnam St. Mary's Hospital, where the author works. One of the characteristic findings is the increasing incidence of stage IA patients, by the year, from 2.6% to 10.7% at Kangnam St. Mary's Hospital, and on the other hand, the patients with the disease above stage liB have occupied about 39.1%, compared to 18% of stage IIA. Our institute changed treatment protocols against cervical cancer by the year like many other institutes world wide. Radical hysterectomy or radiation is the only choice for treatment of cervical cancer in the earlier stages. From the early 80's, we could apply different therapeutic modalities such as radical surgery, radiation, adjuvant or neoadjuvant chemotherapy, or various combinations of treatment (Table 1). 5. Patient evaluation and assessment of risk factors before treatment

For proper assessment of the clinical stage in cervical cancers, tumor extent was analyzed by well-experienced gynecologic oncologists. The op-

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S.J. Kim /International Journal of Gynecology & Obstetrics 49 Suppl. (1995) $49-$57

Table 1 Evolution of therapeutic modalities by year for the locally advanced CXCApatients (stage IB, IIA & IIB) Year

Treatmentmodality

1970-1980 Radical hysterectomy(RH) + RT (Pelvic LN • only) 1981-1983 Radical hysterectomy_+Adjuvantchemotherapy + RT(LN ~ only) 1983-1985 Neoadjuvantchemotherapy+ RH + RT (LN • only) 1985-1989 Neo. & Adjuvant.Chemo.+ RH + RT (LN ~ only) 1989-Neo. & Adjuvant.Chemo.+ RH + RT) (LN ~,~) RH: Radical hysterectomywith pelvic lymphnodectomy RT: Radiotherapy,pelvic LN: Lymphnode,pelvic tional studies such as CT, MRI, ultrasonography, colposcopy, lymphangiography, etc are, no doubt, helpful to evaluate the patient, but the information from these cannot be changed by the clinical stage. Further diagnostic information may be useful in the proper management of patients in an advanced stage. The assessment of risk factors were analyzed by the following items: (1)

(2)

(3) (4)

sion over 1 cm, lympho vascular tumor involvement, lymph node metastasis, and extension to parametrium or corpus.

preoperatively; tumor size (Piver and Chung, 1975; Burchart et al., 1987), stage, age, cell type (Milsom and Friberg 1983), cell differentiation; postoperatively; lymph node metastasis (Fuller et al., 1982; Inoue and Morita 1990), depth of invasion (Boyce et al., 1981), lymphovascular involvement (Boyce et al., 1984), extension to parametrium or corpus (Inoue and Okumura 1984; Perez et al., 1981); during the course; tumor markers, e.g. CEA, TA4; optionally; oncogenes, tumor suppressor genes, HPV type, DNA ploidy (Kamura et al., 1992), chromosome analysis.

The criteria for the high-risk group in this study are the cervical cancer patients with over a 4-cm tumor size, cell type with adenocarcinomas, small cell carcinoma, poor differentiation, tumor inva-

6. Effect of neoadjuvant chemotherapy in the locally advanced stage IB-IIB of cervical cancer We tried to evaluate the effect of neoadjuvant chemotherapy on the response rate, recurrence rate, and the 5-year tumor-free survivals in locally advanced IB, IIA and liB cervical carcinoma patients treated by radical surgery with or without neoadjuvant chemotherapy. The chemotherapeutic regimen for induction is composed of a Vinblastin, Bleomycin, and cisPlatin combination (VBP). Preoperative chemotherapeutic patients numbered 92 cases and radical surgery without preoperative chemotherapy involved 138 cases. The clinicopathologic characteristics of the patients in the two study groups are relatively well matched for comparative analysis. The effect of neoadjuvant chemotherapy was evaluated by the definition of W H O clinical response into complete response (CR), partial response (PR), stable (ST) and progressive disease (PG). Each cycle of chemotherapy was administered every 3 weeks as follows: Vinblastin 4 m g / m 2 i.v. given on days 1 and 2, Bleomycin 15 m g / m z i.m. given on days 1, 2 and 14, Cisplatin 60 m g / m 2 i.v. given on day 1, Patients received two to five courses (2.6 _+ 0.6) of chemotherapy before surgery. The clinical response for NCT according to geographic contour of cervical lesions was significantly different in two groups of the endophytic and exophytic type. Of 70 exophytic typed patients, 87% showed clinical response. Of the 84 squamous cell carcinomas, 87% were responsive to NCT, but in adenocarcinomas, 38% were only partial responsive. The incidence of lymphnode metastasis was higher in the treatment surgery only group (34%; 47/138) than in the NCT group (17%; 16/92) (P = 0.005).

S.J. Kim ~International Journal of Gynecology & Obstetrics 49 Suppl. (1995) $49-$57 Table 2 Recurrence rate and time to recurrence between two different modalities Cases LN ( + )

Surgery 138 Preop. 92 chemotherapy

47(34.0)* 16(17.4)*

Recurrence Time to (%) recurrence (month) 50 (36.2)** 16.24 + 6*** 17 (18.5)** 21.26 4- 13.1"**

*Difference between percentages was significant by chisquare test ( P = 0.005). **Difference between percentages was significant by chisquare test ( P = 0.004). *** Difference between two groups was significant by the Wilcoxon rank test ( P = 0.0435).

Recurrence occurred in 50 out of 138 patients (35.5%) treated with radical surgery only compared with 17 out of 92 patients (18.5%) treated with NCT followed by radical surgery (Table 2). Even though there was no significant statistical difference in the 4-year tumor-free survival between the two different treatment groups having pelvic lymphnode metastasis in our study, the overall tumor-free survival in the preoperative NCT group was lower than that in the conventional RS group (P = 0.025). The 4-year tumor-free survival of locally advanced stage IB, IIA, and liB cervical cancer patients treated with NCT was significantly higher than those treated with RS only. The above mentioned results were similar with the 2-year follow-up results in stage IIB reported by Sardi et al. [19]. Kim et al. (1988) reported a remarkable 2-year survival rate (94%) of preoperative neoadjuvant chemotherapy in early stages of cervical cancer with bulky tumor. These discordent results might be obtained from the contribution of treatment failures in our chemoresistance adenocarcinoma patients and also from the shorter follow up period by other observers. (Kim et al., 1989; Sardi et al., 1990). 7. Multimodal Tx in high-risk patients with stage IB.HB of cervical carcinoma In conjunction with a previous study of NCT in cervical cancer, we tried to evaluate another two

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Table 3 Clinical characteristics of locally advanced cervical cancer (IB, IIA, IIB) patients treated by multimodal treatment (I & II) (162 cases) Characteristics

Age Average Range Stage IB IIA liB Tumor size (cm) 3-4 cm > 4 cm Cell type Squamous LNK LK SC Adeno & adenosquamous Tumor invasion < 1.0 cm > 1.0 cm Lymphovascular invasion Absent Present Histologic grade I II III Geogeaphic contour Exophytic Endophylic Lymphnode metastases a Negative Positive Chemoresponse CR PR ST/PG Chemoresponse course Average Range Follow-up (week) Median Range

Modality I (n = 61) (NCST)

Modality II (n = 101) NCSRT

48 35 -72

47 29-65

35 13 13

48 35 18

33 28

59 42

48 3 1 9

72 10 3 16

6 14

35 67

43 18

34 67

3 50 8

13 80 8

52 9

81 20

49 12

61 40

42 (6)b 14 5(3/2)

66 (3) b 19 16(5/11)

2.8 2-4

2.5 1-4

140 48-452

108 48-432

aafter neoadjuvant chemotherapy followed by radical hysterectomy with lymphnodectomy b Histologically no remnant NCST: Neoadjuvant chemotheray + radical hysterectomy NCSRT: Neoadjuvant chemotherapy + radical hysterectomy + radiotherapy

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groups of therapeutic experience who were treated by neoadjuvant chemotherapy followed by radical hysterectomy (NCST) and treated by neoadjuvant chemotherapy followed by radical surgery and adjuvant radiation (NCSRT) in the high-risk cervical cancer patients with stages IB, IIA, and IIB. NCST group is composed of 61 cases and 101 cases of N C S R T group is evaluable for the study. Clinicopathologic characteristics of two groups of patients treated by different modalities are summarized in Table 2. Age, stage, tumor size and depth of tumor invasion were similar in both groups but the lyml~h node metastatic rate was much higher in the multimodal group (NCSRT) than in the NCST group (Table 3). The clinicopathologic risk factors were analyzed multivariately by the recurrence rates and tumor-free survivals. Primary chemoresponses in the NCST group

(n = 61) were CR (68.9%; 42/61), PR (22.9%; 14/61), ST (4.9%; 3 / 6 1 ) and PG (3.3%; 2/61), respectively. Chemoresponses of the N C S R T group (n = 101) were CR (65.3%; 66/101), P R (18.8%; 1 9 / 1 0 1 ) , ST(4.95%; 5 / 1 0 1 ) and PG(10.9%; 11/101), respectively. The survival rates of the N C S R T group were 100% in all 1, 2, 3 and 5 years in CR, while the rate of the NCST group was 100%, and 98.5% in CR patients (Table 4). Actually, the pattern ( C R , P R , S T / P G ) of primary chemoresponse was not greatly different between both groups of NCST and NCSRT. The lymph node status is one of the most important prognostic factors to number of positive nodes is correlated with the poor prognosis in both groups of patients. T u m o r size, lymph node metastasis and chemoresponse pattern were correlated to each other, but 5-year survival rate of the C R group

Table 4 The correlation between clinicopathologiccharacteristics and survival rate in the locally advanced CXCA (IB, IIA &IIB) patient with complete chemoresponse by multimodal treatments (I, II)a (162 cases) Risk Factors (n = 108/162 cases)

Cell type (108) Squamous (92) Small (2) Adenosquamous(9) & Adenocarcinoma(5)

Survival rateb (%) 1 year

2 year

I (n = 42)

I

II (n = 66)

3 year II

95.8

100

I

II

100

I

II

100

100

100

100

100

100

100

100

100

100

Clinical stage (108) IB (60) IIA (30) lib (18)

100 100 100

100 100 100

100 100 66.7

100 100 100

100 100 66.7

100 100 100

100 100 66.7

100 100 100

NS

Lymphnodemetastasis (108) 0 (83) 1-2 (18) _>(7)

100 100 100

100 100 100

95.7 100 100

100 100 100

95.7 100 100

100 100 100

95.7 100 100

100 100 100

NS

Tumor size (cm) (108) 3-4 (64) > 4.0 (44)

100 100

100 100

100 88.9

100 100

100 88.9

100 100

100 88.9

100 100

NS

Depth of invasion (cm) (108) < 1.0 (65) > 1.0 (43)

100 100

100 100

95.7 100

100 100

95.7 100

100 100

95.7 100

100 100

NS

aI: Multimodal treatment (NCST), II: Multimodal treatment (NCSRT). bKaplan-Meier method, NS: No significance.

95.8

Significance (P = value)

5 year

95.8

100

NS

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From the above therapeutic results of locally advanced, stage IB, IIA and IIB cervical cancers with treatment of multimodal approaches, we could summarize as follows: (1) high-risk factors, influencing recurrence and survival rates, are lymph node metastases, tumor size, depth of invasion, and clinical response to neoadjuvant chemotherapy in this stage of patients; (2) the cases of early stage IB patients without node involvement and local extension (< 1.0 cm) showed no difference in outcome between different treatment protocols (NCST and NCSRT); (3) the cases of more advanced stage and locally extended groups (> 1.0 cm) showed low recurrence rate and prolonged survivals in the cases treated by multimodal approach NCSRT comparing the NCST group; (4) the clinically predictable factor is responsiveness to neoadjuvant chemotherapy. The survival rates, according to risk factors in stage IB-IIB such as cell type, tumor size (> 4

was much higher than other groups without any relationship to lymph node metastases and tumor size in the same stages (Tables 4 and 5). Postoperative adjuvant radiation was applied in the majority of patients with lymph node metastases. The recurrence was noted in a considerable percentage of both groups (NCST, NCSRT) of patients who had lymph node metastases and adjuvant radiotherapy could not improve the resuits of treatment significantly in stage IB, IIA and liB patients, whose nodes were involved (Table 5). The number of positive lymph nodes and recurrence rates were observed in both groups of patients. It's not easy, however, to compare the results with the NCST group because of higher lymph node metastases before RT treatment in the multimodality group (NCSRT), but the recurrence rates were relatively favorable in lymph node metastatic patients treated with multimodality (NCSRT).

Table 5 The correlation between clinicopathologic characteristics and survival rate in the locally advanced C X C A (IB, IIA & IIB) patient with partial chemoresponse by multimodal treatments (I,II) a (162 cases) Risk Factors

Survival rate b (%)

(n = 33/162 cases)

1 year I (n = 42)

Cell type (33) Squamous (25) Small (2) A d e n o s q u a m o u s (5) & adenocarcinoma (1)

100

Significance 2 year

II (n = 19)

92.9

I

3 year II

I

5 year II

I

( P = value) II

72.7

27.9

32.7

9.3

21.8

0.0

66.7

20.0

33.3

8.2

33.3

0.0

NS

100

100

Clinical stage (33) IB (14) IIA c (10) IIB c (9)

100 100 100

75.0 85.7 100

100 100 50.0

50.0 0.0 0.0

33.3 100 33.3

25.0 ---

16.7 100 33.3

12.5 ---

NS

Lymphnode metastasis (33) 0 (20) c 1 - 2 (6) > (7)

100 100 100

91.0 100 100

66.7 50.0 66.7

10.0 66.7 33.3

40.0 50.0 66.7

10.1 33.3 0.0

40.0 0.0 66.7

0.0 0.0 0.0

NS

T u m o r size (cm) (33) 3 - 4 (15) > 4.0 c (18)

100 100

88.9 100

83.3 50.0

44.4 11.1

50.0 50.0

14.8 0.0

33.3 33.3

14.8 --0

NS

D e p t h of invasion (cm) (108) < 1.0 (15) >_>_1.0 (18)

100 100

100 92.3

77.8 20.0

40.0 18.5

64.8 20.0

20.0 0.0

51.9 20.0

20.0 --

NS

aI: Multimodal treatment (NCST), II: Multimodal treatment (NCSRT). b Kaplan-Meier method. cp < 0.05: I vs. II by long-rank test, NS: No significance.

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S.Z Kim ~InternationalJournal of Gynecology & Obstetrics49 Suppl. (1995) $49-$57

cm), lymph node metastases, lymphovascular invasion, depth of invasion (> 1 cm) and primary chemoresponse (CR, PR, ST/PG) in two different multimodal treatment modalities, NCST and NCSRT, did not show any statistical difference except in stage IIB. In the multivariate analysis of known risk factors, lymph node metastasis, stage (IB,IIA, IIB), invasion depth, tumor size cell type, compared with the chemoresponses and the response pattern to primary chemotherapy, the chemoresponsiveness revealed the highest value as a survival predictor in the patient treated with multimodal Tx (Table 6). Benedetti et al. (1991) reported that all factors such as clinical substage, tumor size and parametrial involvement etc. can have an influence on survival as analyzed by multivariates. His result will agree with the author's but a more collective factor of prognosis may be no more than the degree of primary NCT. The concept of 'in vivo chemosensitivity' could be applied in the treatment of cervical cancer prospectively after randomized international studies. The author would like to suggest prediction criteria for low, intermediate, and high-risk groups of cervical cancer. The high-risk groups may be summarized as: (1) adenocarcinomas, or small Table 6 Prognostic factors related to survival rate in the locally advanced cervical caner (IB, IIA & liB) patients treated with multimodal treatment - - I, II (NCST & NCSRT) (162 cases) Prognostic factors factors

Risk Significance Lower and ratio a (P) upper 95% confidence limits of RR

Clinical response 3.26 1. Complete response (CR) 2. Partial response (PR) 3. Stable disease (ST) 4. Progressive disease (PG) Depth of invasion (1 cm) 1.45 Lymphovascular involvement 1.38 Tumor size (4 cm) 1.30 Age (years) 1.00 Cell type 0.92 Histologic grade (I, II, III) 0.76 Lymphnode metastasis ( - , + ) 0.65 Clinical stage (IB, IIA, IIB) 0.70 aStepwise Cox's regression.

0.0001

1.8-4.0

0.08 0.35 0,07 0,81 0,48 0.36 0.08 0.33

0.1-2.0 0.2-2.4 0.1-1.6 0.1-1.0 0.1-1.3 0.2-2.2 0.3-2.7 0.3-1.4

cell carcinomas and positive lymph nodes; (2) squamous cell carcinomas with lymph node metastases having > 4-era sized tumor mass; (3) two or more groups of positive lymph nodes; and (4) poor response to primary chemotherapy (NCT). 8. Prospectives for the future

For a better understanding of cancer, the gynecologic oncologists should have a new pathophysio-biologic concept against cancer that carcinogenesis is resulting from accumulation of many genetic and epigenetic changes. Metastatic capacity and biologic heterogeneity of cancer are the principal obstacles to its eradication. So, the knowledge of such a mechanism spurs on development of novel therapeutic modalities. This molecular knowledge ultimately leads to improvements in multimodal protocols, such as improved risk assessment, chemoprevention, early diagnosis and prediction for progression including chemosensitivity, gene therapy, development of new drugs, immunotherapies and development of a vaccine. Then we could promote the reduction of cancer mortality and prolong the survival of patients in the future. References [1] Sardi J, Sancr C, Giaroli A, Mayar G, DiPaola G. Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix uteri. Gynecol Oncol 1990. [2] Friedlander M, Swanbon CE, Tattersal MHN. Combination chemotherapy followed by surgery or ratiotherapy in patients with locally advanced cervical cancer. Br J Obstet Gynecol 1987; 94: 583-588. [3] Carmel Cohn Dopps G, Yanopoular K, Gusborg S. Testing with c/s-platinum, a new concept in the treatment of carcinoma of the cervix. Gynecol Oncol 1982; 13. [4] Alberts DS, Aristizabal S, Surwit EA et al. Primary chemotherapy for high-risk recurrence cervix cancer. In: Surwit EA, Alberts D, editors, Cervix cancer. Boston: Martin us Nijhoff, 1987: 161-183. [5] Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of 16 major cancers in 1980. Int J Cancer 1988; 41: 18797. [6] Petterson F, editor. Twenty-first annual report on the results of treatment in gynecological cancer. Int J Gynecol Obstet 1991; 36 (suppl): 27-130.

SJ. Kim ~International Journal of Gynecology & Obstetrics 49 Suppl. (1995) $49-$57 [7] Souhami L, Gil RA, Allan SE, Canary PCV, Araujo CMM, Pinto LHJ, Silveira TRP. A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol 1991; 9: 970-977. [8] Kun LE, Toohill RJ, Holoye PY et al. A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract. Int J Radiat Oncol Biol Phys 1986; 12: 173-178. [9] Martin M, Mazeron JJ, Brun B e t al. Neoadjuvant poluchemotherapy of head and neck cancer: results of a randomized study. Proc Am Soc Clin Oncol 1988; 7: 152. [10] Withers HR, Taylor JMF, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131-146. [11] Kim DS, Moon H, Kim KT, Hwang YY, Cho SH, Kim SR. Two-year survival: preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumor. Gynecol Oncol 1989; 33: 225-230. [12] Benedetti Panici P, Scambia G, Baiocchi G e t al. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Prognostic factors for response and survival. Cancer 1991; 67: 372-379. [13] Benedetti Panici P, Greggi S, Scambia G e t al. High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma. A preliminary report. Gynecol Oncol 1991; 41: 212-216. [14] Dottino PR, Plaxe SC, Beddoe A, Johnston C, Cohen CJ. Induction chemotherapy followed by radical surgery in cervical cancer. Gynecol Oncol 1991; 40: 7-11. [15] Kim SJ, Namkoong SE, Bae SN, Lee HY. Comparative study of neoadjuvant chemotherapy followed by radical surgery versus simple radical surgery in patients with locally advanced cervical cancer. Proc 3rd meeting Int Gynecol Cancer Soc 1991; 175. [16] Fontanelli R, Spatti G, Raspagliesi et al. A preoperative single course of high-dose cisplatin and bleomycin with glutathione protection in bulky stage IB/II carcinoma of the cervix. Ann Oncol 1992; 3: 117-121. [17] Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 1975; 46: 507-510. [18] Fuller JR AF, Elliott N, Kosloff C, Lewis JL. Lymph node metastases from carcinoma of the cervix, stage IB and IIA: implications for prognosis and treatment. Gynecol Oncol 1982; 13: 165-174. [19] Chung CK, Nahhas WA, Stryker JA, Curry SL, Abt AB, Mortel R. Analysis of factors contributing to treatment failures in stage IB and IIA carcinoma of the cervix. Am J Obstet Gynecol 1980; 138: 550-556. [20] Kim DS, Moon H, Hwang YY, Cho SH. Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage IB, IIA and lib with bulky tumor. Gynecol Oncol 1988; 29: 321-332. [21] Benedetti Panici P, Greggi S, Scambia G e t al. UCSC experience on neoadjuvant chemotherapy (NACT) & radical surgery (RS) in locally advanced cervical cancer

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