Role of induction chemotherapy in invasive cervical cancer

GYNECOLOGlC

ONCOLOGY

41, 107-112 (1991)

Role of Induction Chemotherapy in Invasive Cervical Cancer TCHAN KYU PARK, M.D.,* DONG HEE CHOI, M.D.,* Soo NYUNG KIM, M.D.,* CHANG HOON LEE, M.D.,* YOUNG TAE KIM, M.D.,* GWI EON KIM, M.D. ,t CHANG OK SUH, M.D. ,t AND JUHN KYU LOH, M.D.? Departments of *Obstetrics and Gynecology

and TRadiotherapy,

Yonsei University

College of Medicine, Seoul 120-752, Korea

ReceivedAugust 23, 1990 The 386 casesof invasive cervical carcinoma treated with radiotherapy akme were statistically analyzed to delineate the high risk factors (HRFs) associatedwith a significantly high treatment failure rate; they were (1) stages HI-IV, (2) lesion 24.0 cm, (3) small cell carcinoma or adenocarcinoma, (4) stages I-II with lesion 34.0 cm, and (5) lymphographic evidence of nodal metastasis. Then, chemoradiotherapy (induction chemotherapy plus subsequent radiotherapy) was instituted to 113 invasive cervical carcinoma patients with at least one such HRF. Each patient received two to three cycles of induction chemotherapy at about 3-week intervals. For squamous cell carcinoma, cisplatin, 100 mg/m’ iv, was followed immediately by S-fhmrouracil, 1000 mg/m*, as a 24hr iv infusion x 5 days. For adenocarcinoma, cisplatin, 70 mg/m” iv, on Day 1 was followed by cytoxan, 250 mg/m”, on Day 2, and adriamycin, 45 mg/m’, on Day 3. Fiveyear survival of these patients according to each HRF, in the above order, was 69.1, 67.2, 68.1, 78.3, and 79.5% after chemoradiotherapy, all significantly higher than 57.4, 53.0, 54.5, 48.0, and 48.8% by radiotherapy alone. Drug toxicities such as leukopenia, hepatotoxicity, nephrotoxicity, and hypomagnesemia were seen in 46.5, 53.2, 47.1, and 55.4 % of all cycles, respectively. The toxicities altered drug schedule in 191(61.2%) ongoing induction chemotherapy cycles. Our cisplatin-based induction chemotherapy is considered an effective preradiotherapy adjunct that can reduce treatment failure in HRF-associated invasive cervical carcinoma. 0 1991 Academic Press, Inc.

found 51% objective response to chemotherapy and complete response to radiotherapy among chemotherapy responders in stages I-IV cervical carcinoma. Yet, some observed no significant effect with this mode of chemotherapy used in advanced stage diseases [7]. Weiner et al. reported its efficacy only in early diseaseswith positive nodes [8]. The role of chemotherapy as a first-line therapy in cervical cancer thus appears to merit further study. Cisplatin-based combination chemotherapy seems a good selection for the treatment of cervical cancer, since the efficacy of cisplatin as a single agent in squamous cell carcinoma of the cervix has been demonstrated [9,10] and combination chemotherapy usually produces higher response rates than single-agent therapy. This study was aimed at evaluating the value of cisplatin-based induction chemotherapy (administered prior to radiotherapy) in prolonging patient survival in invasive cervical carcinoma associated with one or more of the several HRFs we assigned. The validity of these prognostic factors was supported by our own retrospective survival analysis [ll] of invasive cervical carcinoma cases treated with radiotherapy alone at our institute. The toxicities of induction chemotherapy were also evaluated. MATERIAL

AND METHODS

INTRODUCTION Carcinoma of the cervix has been noted to have a high treatment failure rate and poor survival in association with

risk factors like advanced stage [ 1,2], regional lymph node metastasis [3], bulky tumor [3], or small cell carcinoma

PI.

The use of combination chemotherapy in cervical carcinoma prior to regional therapy is an interesting concept. Freidlander et al. [5] reported a 67% response rate with chemotherapy used in this fashion (prior to radiotherapy) in locally advanced cervical cancer. Symonds et al. [6]

Initially, the high-risk prognostic factors associated with a significantly low 5-year survival were retrospectively delineated by survival analysis of 386 invasive cervical carcinoma cases treated with radiotherapy alone and followed at Yonsei University Medical Center (YUMC) in Seoul from 1976 to 1984 (Table 1). After such delineation, from 1984 to 1989, 113 consecutive invasive cervical carcinoma caseswith at least one such HRF underwent clinical trial with chemoradiotherapy (induction chemotherapy plus subsequent radiotherapy) and were followed at YUMC. 107 0090-8258/91$1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

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FIG0 classification was used for clinical staging and histologic classification of squamous cell carcinoma was based on that of Wentz and Reagan [12]. The mean age of the chemoradiotherapy candidates was 52 years (range, 31 to 72 years). These patients were subgrouped according to each HRF with which the patients were associated. The 5-year survival of each subgroup after chemoradiotherapy was evaluated and compared with that of the respective subgroup treated with radiotherapy alone outlined in Table 1. All chemoradiotherapy candidates received no prior chemotherapy or radiotherapy. Each patient received 2 to 3 cycles (mean, 2.8 cycles) of induction chemotherapy, at approximately 3-week intervals, establishing a total of 312 cycles. Two different chemotherapy regimens were used for induction chemotherapy. For squamous cell carcinoma, 100 mg/m* of cisplatin was infused iv and was followed immediately by five consecutive daily administrations of 5fluorouraci1, 1000 mg/m2/day, each as a 24-hr iv infusion. For adenocarcinoma, 70 mg/m2 of cisplatin, 250 mg/m* of cytoxan, and 45 mg/m2 of adriamycin were administered iv on Days 1, 2, and 3, respectively. The response to induction chemotherapy or chemoradiotherapy was assessed. Complete response (CR) was complete disappearance of all measurable disease for at least 1 month. Partial response (PR) was more than 50% reduction in lesion diameter with no demonstrable disease progression elsewhere. Stable disease (SD) was less than 50% decrease or 25% increase in lesion diameter without new lesion appearance. Progressive disease (PD) was more than 25% increase in lesion diameter with or without new lesion appearance. Those showing CR or PR to induction chemotherapy were considered responders. Hematologic, renal, hepatic, cardiac, and lung functions were apparently normal in all 113 patients prior to induction chemotherapy. The 24-hr urine creatinine clearance was measured before each cycle was initiated; a minimum of 50 ml/min was considered eligible for chemotherapy. Complete blood count, SMA-12, and serum electrolytes were monitored daily before and during each induction chemotherapy cycle. Serum hemoglobin was maintained above 12 g/ml. Audiometry and neurologic examination were performed in the presence of suspicious oto- or neurotoxicity. “GOG Adverse Effect Criteria (December 1980)” was used for toxicity grading. Toxicity frequency was assessed in each induction chemotherapy cycle. Several different toxicities occurring in a given patient and the same toxicity recurring in the same patient in each induction chemotherapy cycle all added to overall toxicity data. Depending on the severity and duration of toxicity, drug dosage was reduced, or the ongoing drug schedule delayed or stopped.

TABLE

1

Prognostic Factors Investigated for Influence on S-Year Survival after Radiotherapy in Invasive Cervical Carcinoma

Prognostic factors Stage I-II III-IV Lesion (cm) C4.0 24.0 Histological type Squamous cell carcinoma Large cell Small cell Adenocarcinoma’ Stage and lesion (cm) I-II and ~4.0 I-II and 34.W Lymphography Negative Positive’

No. of patients

S-year survival (%I

201 185

73.6 57.4

148

76.5 53.0

P valueb CO.01

CO.01

97


70.8 62.5 49.4

91 45

80.6 48.0

53 24

77.9 48.8

co.05 co.05

” Obtained by the “Life-Table” ’ Obtained by the “Lee-Desu” ’ HRFs.

method. method [13].

The “Life-Table method” was used to obtain 5-year survival after radiotherapy or chemoradiotherapy. “LeeDesu” analysis 1131was used for comparing 5-year survival data. RESULTS The invasive cervical carcinoma cases studied showed significantly low 5-year survival after radiotherapy alone in relation to each of the following: (1) stages III-IV, (2) small cell carcinoma or adenocarcinoma, (3) lesion 24.0 cm, (4) stages I-II and lesion a4.0 cm, and (5) lymphographic evidence of nodal metastasis. Each of these was designated a HRF (Table 1). The distribution of HRFs in the patients treated with chemoradiotherapy and radiotherapy is shown in Table 2. The incidences of pretreatment lesion ~4.0 cm, small cell carcinoma, and lymphographic evidence of nodal metastasis were significantly higher in the chemoradiotherapy group than in the radiotherapy-alone group (P < 0.05); however, the incidence according to stage and histological type was not significantly different in each group (P > 0.1) (Table 2). 1. Response to Induction Chemotherapy and Chemoradiotherapy

The overall response rate to induction chemotherapy was 86.7%; CR and PR rates were 26.5 and 60.2%, re-

INDUCTION

CHEMOTHERAPY

IN CERVICAL

109

CANCER

TABLE 2 Distribution of HRFs in the Chemoradiotherapy and Radiotherapy Group

HRFs

Chemoradiotherapy grow No. (%)

-

46/113(40.7) 60/111(54.1) 20/106(18.9) 11/106(10.4) 9/106( 8.5) 27/111(24.3)

Stages III-IV Lesion size 24.0 cm Histological type Small cell carcinoma Adenocarcinoma Stages I-II and lesion 24.0 cm Positive lymphography

Radiotherapy group No. (%)

70

E 2

60

P value”

185/386(47.9) 97/245(39.6) 35/274(12.8) 8/274( 2.9) 27/274( 9.9) 45/245(18.4)

>O.l co.01 >O.l co.05 >O.l >O.l

24/77 (31.2)

<0.05

19/112(17.0)

E

.$Q 50 7 9 E a

40 30

ap 20 10 0

e---o

Chemoradiotherapy

L---i

Radiotherapy

(ne

10)

(~=Js)

P < 0.05 ’ 0

6

12

16

24

30

36

42

46

54

60

Months

FIG. 2. Comparison of 5-year survival following chemoradiotherapy and radiotherapy in small cell carcinoma or adenocarcinoma.

” Obtained by the x2 test.

spectively. There were 15 nonresponders (6 SDS and 9 PDs), and two of these 15 died at 6 and 14 months followup, respectively. With completion of chemoradiotherapy, an additional 9 (69%) of the 15 cases previously unresponsive to induction chemotherapy and 96 (98.0%) of 98 cases responsive to induction chemotherapy showed CR, achieving an overall CR rate of 92.9%. Treatment failure after chemoradiotherapy occurred in 16 patients; of these, 11 had persistence and 5 had recurrence. Nine of these 16 died within 2 years of follow-up. 2. Comparison of 5-Year Survival in Relation to Each HRF; Chemoradiotherapy vs Radiotherapy

As illustrated in Figs. 1 to 5, different 5-year survival was noted in relation to each HRF when the group treated with chemoradiotherapy was compared with the group treated with radiotherapy alone. Stages III and IV dis-

eases had a significantly higher 5-year survival after chemoradiotherapy than after radiotherapy alone (69.1% vs 57.4%; P < O.Ol), as did the cases with small cell carcinoma or adenocarcinoma (68.1% vs 54.5%; P < O.Ol), lesion size a4.0 cm (67.2% vs 53.0% ; P < O.Ol), stage I or II with the lesion size ~4.0 cm (78.3% vs 48.0%; P < 0.01) and lymphographic evidence of nodal metastasis (78.3% vs 48.8%; P < 0.01). 3. Toxicity of Chemoradiotherapy

Toxicities from induction chemotherapy such as nausea, vomiting, and alopecia, though varied in degree, were present in all 312 cycles. Details of toxicity data are summarized in Table 3. These toxicities were mild to moderate, reversible, and tolerable. No toxic death occurred. Anemia, leukopenia, and thrombocytopenia, though more frequent during radiotherapy after induction che-

L--, f E fj $

70

1

(69.1).

t---7

60

c

- - 1

2 2 2 f

- - i5i,4)4

50

g ;

40

5

30

s

k--1--7c7

g

H

Chemoradiolherapy(n=

A- - 4

20

Radiotherapy

46)

(ns

f’ 5

p 0

< 6

60

16

24

30

36

42

46

54

60

Months

FIG. 1. Comparison of 5-year survival following chemoradiotherapy and radiotherauv . . in stages III-IV.

(67.2)

---a

l

A.-------

I

L - -. (53.0)

50 40

O--O

Chemoradiotherapy

(n=60)

30

10

0.01 12

I

&--i--..

s 20 A---A I

165,

10 0

70

I 0

Radiotherapy

(n=or)

p s 0.01 6

12

18

24

30

36

42

46

54

60

Months

FIG. 3. Comparison of 5-year survival-following chemoradiotherapy and radiotherapy with lesion 24.0 cm.

110

PARK ET AL.

80 2 I? 2

70 L----------------, 60

, .-.

2 50 p 2) 40

2

3.

d

20

(46.0)

ee I

10 I

01

0

Chemoradiother;apy

c - -A Radiotherapy

(n = (n =

45)

30

36

27)

p < a.ot 6

12

16

24

42

46

54

60

Months

FIG. 4. Comparison of 5-year survival following chemoradiotherapy and radiotherapy in stages I-II with lesion 24.0 cm.

motherapy than during conventional radiotherapy, did not decrease radiation dose or stop the ongoing radiotherapy. DISCUSSION

cases that received induction chemotherapy in this series were HRF-associated early stage diseases (stages I-II; 59.3%). It has been reported that an increased cisplatin dose can further augment tumor response to radiation in a mouse tumor [32]. However, it is not clear whether the higher dose of cisplatin in our regimen than those in the regimens of others [5,6,20] actually played a part in raising survival, since other drugs in the regimens we used are different from theirs and there are a number of possible confounding variables that need to be controlled (e.g., patient characteristics and remission criteria). Symonds et al. [6] proposed the prognostic value of a response to chemotherapy given before radiotherapy in advanced cervical cancer. In this study, CR obtained after radiotherapy was 98 and 69% in those responsive and unresponsive to induction chemotherapy, respectively. The significantly higher 5-year survival obtained in this series in relation to each high-risk prognostic factor in patients after chemoradiotherapy than that in patients after radiotherapy suggests its efficacy in treating invasive cervical carcinomas associated with these risk factors. Although leukopenia was more frequent in this series than in others [29,34), with careful patient monitoring, it caused no serious infection. No chemotherapy-related death occurred in this series. The incidence of nephrotoxicity was low (2.9%). Hepatotoxicity was rather frequent (S3.2%), but was rarely symptomatic. Toxicity of radiotherapy in this series was not enhanced by the preceding induction chemotherapy and remained tolerable, as also noted by others [6,7,30,33,35,36]. In summary, induction chemotherapy with our cisplatin-based regimens, despite their toxicity, is considered tolerable and safe provided a meticulous scheme of patient monitoring is applied. It may be a useful adjunct to radiotherapy, capable of reducing treatment failure and increasing survival in invasive cervical carcinoma associ-

Chemotherapy alone appears to be unable to induce satisfactory remission for an extended period of time even when a combined cisplatin-based regimen is used [14]. Combination of chemotherapy and radiotherapy is interesting in that chemotherapy may serve a radiosensitizing role in cervical cancer treatment since “chemical debulking” attained with cytotoxic drugs could induce better oxygenation of the previously hypoxic tumor cells, thereby facilitate subsequent radiation [15]. Chemotherapy is also considered effective in eliminating unrecognized systemic microscopic metastasis [16]. There is a growing trend to use chemotherapy in an adjuvant fashion in invasive cervical carcinoma, especially in the cases associated with poor prognosis, in combination with radiotherapy or surgery t&17-27]. Choo et al. [21] reported no enhanced toxicities by adding cisplatin to radiotherapy in cervical carcinoma and l-----suggested cisplatin as a potentiator of radiation. The value $ 70 of cispiatin in the treatment of squamous cell carcinoma z A- - - 7 2 60 of the cervix has also been demonstrated by Thigpen et __---ta8.8,' I-------t 50 al. [93. Cisplatin probably is an appropriate agent in comf i 40 bined agent induction chemotherapy in cervical cancer. 3 3o N Chemoradiotherapy(n = t@> While some reported favorable results with cisplatinbased neoadjuvant chemotherapy in cervical carcinoma s 20 b - * Radiotherapy Ctt: 24) [S,8], others noted otherwise [7]. The overall response IO P < 0.0 t rate after induction chemotherapy in this series was 0 54 60 46 24 30 36 42 12 16 0 6 slightly higher than that reported by others [6,7,8,28,29), Months but it rose to a much higher (92.9%) level after chemoradiotherapy than those reported by others [5,6,8, FIG. 5. Comparison of 5-year survival following chemoradiotherapy 17,29,31]. This may be because a significant number of and radiotherapy with lymphographic evidence of nodal metastasis.

INDUCTION

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IN CERVICAL

111

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TABLE 3 Toxicity of Induction Chemotherapy Toxicity grade” Toxicity

I No.~(%)

II No.(%)

III No.(%)

Hematologic WBC Granulocytes Platelets Anemia

lOl(32.4) 45(14.4) 22( 7.1) 54(17.3)

42( 13.5) 36(11.5) 4( 1.3) ll( 3.5)

2( 0.6) 27( 8.7) O( 0.0) O( 0.0)

4(1.3j O(O.0) O(O.0)

145( 46.5) 112( 35.9) 26( 8.3) 65( 20.8)

Gastrointestinal Nausea/vomiting AST/ALT

19( 6.1) 151(48.4)

34(10.9) 14( 4.5)

259(83.0) l( 0.3)

O(O.0) O(O.0)

312(100.0) 166( 53.2)

Renal BUN/Cr Creatinine clearance

9( 2.9) 138(44.2)

O( 0.0)

O( 0.0) O( 0.0)

O(O.0) O(O.0)

9( 2.9) 147( 47.1)

9( 2.9)

IV No.(%)

O(O.0)

Total No.(%)

” According to “GOG Adverse Effect Criteria (December 1980):’ ’ Number of induction chemotherapy cycles.

ated with the described HRFs. However, the optimum number of induction chemotherapy cycles that could maximize its efficacy and minimize toxicity remains to be established. REFERENCES 1. Jampolis, S., Andreas, E. J., and Fletcher, F. H. Analysis of sites and causes of failure of irradiation in invasive squamous carcinoma of the cervix, Radiology 115, 681-685(1975). 2. Perez, C. A., Breaux, S., Madoc-Jones, Bedwinek, J. M., Camel, H. M., Purdy, J. A., and Walz, B. J. Radiation therapy alone in the treatment of carcinoma of the cervix. 1. Analysis of tumor recurrence, Cancer 51, 1393-1402 (1983). 3. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastasis in cervical carcinoma, Obstet. Gynecol. 46, 507-510 (1975). 4. Van Nagell, J. R., Jr., Donaldon, E. S., Parker, J. C., van Dyke, A. H., and Wood, E. G. Prognostic significance of pelvic node morphology in carcinoma of the uterine cervix, Cancer 39, 26242632 (1977). 5. Friedlander, M. L., Atkinson, K., Coppleson, J. V. M., Ellitot, P., Green, D., Houghton, R., Solomon, J., Russel, P., and Tattersall, M. H. N. The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study, Gynecol. Oncof. 19, l-7 (1984). 6. Symonds, R. P., Burnett, R. A., Habeshaw, T., Kaye, S. B., Snee, M. P., and Watson, E. R. The prognostic value of a response to chemotherapy given before radiotherapy in advanced cancer of cervix, Br. J. Cancer 59, 473-475 (1989). 7. Soeters, R., Bloch, B., Levin, W., Dehaeck, C. M., and Goldberg, G. Combined chemotherapy and radiotherapy in patients with advanced squamous carcinoma of the cervix (cb-platinum-bleomycinvincristine) , Gynecol. Oncol. 33, 44-45 (1989). 8. Weiner, S. A., Aristizabel, S., Alberts, D. S., Surwit, E. A., and Deatherage-Deuser, K. A phase II trial of mitomycin, vincristine,

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