Therapeutic Value of Neoadjuvant Intra-arterial Chemotherapy (Cisplatin) and Irradiation for Locally Advanced Uterine Cervical Cancer

Therapeutic Value of Neoadjuvant Intra-arterial Chemotherapy (Cisplatin) and Irradiation for Locally Advanced Uterine Cervical Cancer

GYNECOLOGIC ONCOLOGY ARTICLE NO. 65, 421–424 (1997) GO974702 Therapeutic Value of Neoadjuvant Intra-arterial Chemotherapy (Cisplatin) and Irradiati...

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GYNECOLOGIC ONCOLOGY ARTICLE NO.

65, 421–424 (1997)

GO974702

Therapeutic Value of Neoadjuvant Intra-arterial Chemotherapy (Cisplatin) and Irradiation for Locally Advanced Uterine Cervical Cancer Takafumi Toita,*,1 Kaoru Sakumoto,† Masahiro Higashi,† Kazuhiko Ogawa,* Yasumasa Kakinohana,* Sanae Shinzato,* Hidehiko Moromizato,† Koji Kanazawa,† and Satoshi Sawada* *Department of Radiology and †Department of Obstetrics and Gynecology, University of the Ryukyus, Okinawa, 903-01 Japan Received November 12, 1996

We analyzed long-term treatment results in 51 patients with locally advanced uterine cervical carcinoma (IIB, 4; IIIB, 43; IVA, 4) treated with neoadjuvant intra-arterial (I-A) chemotherapy (cisplatin) via the uterine artery and irradiation. Thirty patients (58.8%) developed recurrence. Twelve had pelvic recurrence alone, 8 had distant metastases alone, and 10 had both pelvic and distant failure. The 5-year cumulative pelvic control rate, absolute survival rate, and disease-free survival rate were 55.3, 47.1, and 39.4%, respectively. Eight of 51 patients (15.7%) suffered late complications. These results suggest that our neoadjuvant I-A chemotherapy prior to irradiation has limited additional value for long-term prognosis in patients with locally advanced uterine cervical carcinoma. q 1997 Academic Press

INTRODUCTION

Patients with locally advanced uterine cervical cancer have a poor prognosis because they frequently develop both pelvic failure and distant metastases. To improve the outcome for these patients, treatment modalities additional to radical irradiation, such as systemic neoadjuvant chemotherapy, have been tried. However, the value of systemic neoadjuvant chemotherapy on long-term prognosis has not been confirmed [1–6]. In March 1987, a pilot study on neoadjuvant intra-arterial (I-A) chemotherapy using cisplatin prior to irradiation was started for locally advanced uterine cervical cancer with intent to improve pelvic control rate in our departments. We have previously reported our experience with 34 patients treated with this strategy [7]. In this paper, we have added 17 patients and analyzed the long-term outcome for patients treated with neoadjuvant I-A chemotherapy and irradiation. MATERIALS AND METHODS

From March 1987 to September 1995, 51 patients with locally advanced uterine cervical carcinoma were treated 1 To whom correspondence and reprint requests should be addressed at Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, 903-01, Japan. Fax: /81-98-8955700.

with I-A chemotherapy and radical irradiation at the Ryukyu University Hospital. The median age of the patients was 52 years (range, 31–75). Four patients were assigned Stage IIB, 43 were assigned to Stage IIIB, and 4 were assigned to Stage IVA according to the FIGO classification. Fifteen patients (29.4%) had hydronephrosis. Fifty patients had squamous cell carcinoma, and one had adenosquamous cell carcinoma. For the present study, the anteroposterior cervical diameter and pelvic node status were reassessed by pretreatment computed tomography (CT). Mean cervical size assessed by CT was 66.4 { 16.6 mm (range, 40–115 mm). Lymph node short-axis diameter greater than 10 mm was accounted as enlarged. The extent of parametrial infiltration was assessed by pelvic examination without general anesthesia. Cisplatin was administered via the unilateral uterine artery (dominant side of parametrial infiltration) at a dose of 120 mg/m2 over 2 hr under adequate hydration. The theoretical bases and technical details of our I-A chemotherapy have been described in a previously published paper [7]. Twentynine patients received I-A chemotherapy once and 22 patients received it twice. The second treatment tended to be administered to those who responded well to the first I-A chemotherapy. Forty-five patients were treated with radical irradiation consisting of external irradiation and intracavitary therapy. A total dose of 20–40 Gy was delivered through the whole pelvic field (mean dose, 37 { 5.1 Gy), and an additional external dose was delivered with a central shield (4 cm in width) up to 50 Gy. Boost irradiation was not routinely delivered to the infiltrated parametrium except in 6 patients (up to 56–60 Gy). These were delivered through anteroposterior and posteroanterior ports, using a high-energy (15-MV) photon beam, five times a week with a daily dose of 2 Gy. Intracavitary therapy was given by the remotely controlled afterloading system (high dose-rate, HDR) once a week. A single dose at point A was 6 Gy. Mean total dose of HDR intracavitary therapy was 16.4 { 4.6 Gy (range, 6-30 Gy). For 1 patient with adenosquamous cell carcinoma, low doserate (LDR) intracavitary therapy (18 Gy at point A) was

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0090-8258/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.

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used. Six patients were treated with external irradiation alone with a total dose of 43.2 to 70 Gy. The interval between the last administration of I-A chemotherapy and the beginning of irradiation was 9 – 49 days (mean, 23.3 { 5.7 days). Eight patients who had massive bleeding at initial presentation received a part of the radiation therapy (9 Gy/3 fr/3 days) prior to I-A chemotherapy to reduce the bleeding. Three patients underwent hyperthermia combined with external irradiation. Adjuvant surgery was performed on 4 patients who were suspected of having gross persistent central disease after the completion of radiotherapy. Response to I-A chemotherapy was evaluated by a combination of pelvic examination, CT, and needle biopsy prior to radiation therapy. The median follow-up of 51 patients was 24 months (range, 3–108 months). Fifty of 51 patients had complete follow-up. One patient was lost to follow-up and censored at 10 months. The probabilities of pelvic control and survival were calculated by the Kaplan–Meier method. Patients with persistent disease at the end of treatment were scored as pelvic failure at time zero. The generalized Wilcoxon test was used to compare the probabilities. RESULTS

time of data analysis. One patient who developed a lung metastasis was surgically salvaged and was still disease free after 40 months. Two patients who had para-aortic node recurrence were salvaged by lymphadenectomy and irradiation and were alive without disease for 52 and 83 months. No patients died of intercurrent disease. All three patients treated with hyperthermia developed pelvic recurrence and died. Two of four patients treated with adjuvant surgery were alive without disease for 48 and 64 months. Another two developed recurrence, one in pelvic and the other as peritonitis carcinomatosa, and died. The 5-year cumulative pelvic control rate (PC) for 51 patients was 55.3%. The 5-year absolute survival rate and disease-free survival rate (DFS) for these patients were 47.1 and 39.4%, respectively (Fig. 1). Significant differences were shown in PC (P Å 0.049), and DFS (P Å 0.026) between patients with a cervix õ70 mm and those with a cervix §70 mm in diameter. Patients with enlarged pelvic nodes demonstrated significantly worse PC (P Å 0.0036) and DFS (P Å 0.01) than those with none. There was no trend in outcome whatever the degree of parametrial involvement. Patients who had no response to I-A chemotherapy showed significantly worse PC (P Å 0.012) and DFS (P Å 0.0029) than those with response. No differences were noted in outcome between subgroups concerning the number of administrations of I-A chemotherapy.

Response to I-A Chemotherapy Eight patients who received a part of the radiotherapy prior to I-A chemotherapy and one with inadequate evaluation were excluded from analysis of response to I-A chemotherapy. Therefore, 42 patients were evaluable for response. Three patients (7.1%) demonstrated complete response (CR). Seventeen (40.5%) had partial response (PR), and 20 (47.6%) were evaluated as no change (NC). Two patients (4.8%) were assessed as suffering from progressive disease (PD). These two showed minor response in the central tumor but rapid growth of lymph node metastases: one in the pelvis and the other as a para-aortic lesion. Response rates according to cervical size were 53.3% (16/30) for õ70 mm, and 33.3% (4/12) for §70 mm. Patterns of Failure and Survival Rate (Table 1) Three of 4 patients who underwent adjuvant surgery had residual cancer cells in the resected specimen. Thirty of 51 patients (58.8%) developed recurrence. Twelve had pelvic recurrence alone, 8 had distant metastases alone, and 10 had both pelvic and distant failure. The sites of the distant metastases were as follows: lung in 7 patients, para-aortic lymph nodes in 8 patients, peritonitis carcinomatosa in 4 patients, liver in 4 patients, supraclavicular lymph nodes in 2, bone in 2 patients, groin lymph nodes in 1 patient, and skin in 1 patient. Twenty-four of 30 patients who had recurrent disease died. Three patients were alive with recurrent disease at the

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Late Complications Eight of 51 patients (15.7%) developed late complications. Rectal bleeding occurred in 4 patients, and cystitis occurred in 2. One patient experienced small bowel obstruction leading to surgical resection. She had been treated with lymphadenectomy and external irradiation (49 Gy/27 fr) to the paraaortic lymph node recurrence. Two patients developed rectovaginal fistula. These two also suffered central recurrence. DISCUSSION

In general, radical radiotherapy consists of external irradiation and intracavitary therapy in the treatment of uterine cervical cancer. An adequate regression of the central tumor before applications of intracavitary therapy is one of the most important factors in achieving favorable local control [8]. However, it is generally difficult to obtain adequate shrinkage of the central tumor using conventional external whole pelvic irradiation alone for patients with locally faradvanced tumors. To obtain satisfactory tumor regression before intracavitary therapy for those patients, neoadjuvant I-A chemotherapy has been tried prior to external irradiation in our departments. Higher concentration of the chemotherapeutic agent was expected using I-A infusion than systemic administration. Despite these attempts, the response rate to I-A chemotherapy demonstrated in our series was comparable with

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NEOADJUVANT I-A CHEMOTHERAPY FOR CERVICAL CANCER

TABLE 1 Treatment Outcome in Patients with Uterine Cervical Cancer Treated with Neoadjuvant I-A Chemotherapy and Irradiation

Characteristics

PC, 5-year rate (%)

No. of cases

DFS, 5-year rate (%)

Cervical size (mm) õ70 §70

32 19

63.8 42.1 P Å 0.049

48.1 25.3 P Å 0.0026

Enlarged node (ú 10 mm) No Yes

25 26

75.4 36.2 P Å 0.0036

54.4 25.6 P Å 0.01

Extent of disease IIB / uni.fixed Blt. fixed

35 16

54.5 56.3 NS

35 50 NS

No. of I-A chemotherapy Once Twice

29 22

61.6 47.4 NS

36.8 41.6 NS

Response to I-A chemotherapya Responder (CR / PR) Nonresponder (NC / PD)

20 22

69.3 32 P Å 0.012

57.6 19.9 P Å 0.0029

Note. PC, pelvic control rate; DFS, disease-free survival rate; NS, not significant.; uni.fixed, parametrial infiltration fixed to unilateral pelvic wall; blt.fixed, parametrial infiltration fixed to bilateral pelvic walls. a Eight patients who received a part of the radiation therapy prior to I-A chemotherapy and one with inadequate evaluation were excluded.

those to systemic neoadjuvant chemotherapy [1, 3, 5, 9]. Eventually, long-term pelvic control and survival for locally advanced uterine cervical cancer were similar to those for patients treated with irradiation alone reported in previously published literature [10]. This suggests that our neoadjuvant I-A chemotherapy has limited additional value to irradiation for patients with large central tumors. We consider that the main reason for our unsatisfactory results is the sequence of I-A chemotherapy and irradiation. Patients who showed no response to I-A chemotherapy had significantly worse long-

FIG. 1. Absolute survival and disease-free survival for 51 patients with uterine cervical cancer treated by neoadjuvant I-A chemotherapy and irradiation.

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term prognosis than responders in our series. This was consistent with the results for systemic neoadjuvant chemotherapy [5, 9]. This suggested that neoadjuvant I-A chemotherapy prior to irradiation also had a biological demerit especially for poor responders to chemotherapy [11, 12]. Recently, concomitant chemoradiotherapy has been tried in order to improve pelvic control [13–15]. Morris et al. have reported an excellent result using concurrent radiation and IA chemotherapy for locally advanced uterine cervical cancer [16]. Therefore, optimal sequencing of I-A chemotherapy and irradiation must be further investigated. Some might claim that radiation doses to central tumor (external beam and intracavitary therapy) in our series were insufficient to achieve tumor control. However, our total doses were comparable with those of several series which describe cases treated with high dose-rate intracavitary therapy [17, 18]. If larger irradiation doses are delivered, the incidence of late complications will increase. Patients who had pelvic node swelling demonstrated poor long-term pelvic control and survival in this study. First, this might be a consequence of the insufficient total irradiation dose delivered to the pelvic node regions. For all patients but one in our series, boost irradiation was not delivered to enlarged lymph nodes, even if bulky. Second, the effect of the route for I-A infusion must be taken into consideration. One patient had progressive pelvic nodal disease during IA chemotherapy despite minor response in the central tumor. In other patients with enlarged pelvic nodes, lymph node

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response to I-A chemotherapy tended to be poorer than that in the central tumor. These results suggested that drug concentration in the pelvic nodes was insufficient when the drug was delivered via the uterine artery. However, if a more proximal artery were to be selected for I-A infusion, drug concentration in the cervical tumor might decrease. Therefore, patients with enlarged pelvic nodes might be eliminated from I-A chemotherapy. The degree of parametrial infiltration seemed to have no effect on prognosis in this series. However, we must evaluate this result with caution. As in our series of patients treated with irradiation alone [19], this might have resulted from an inadequate evaluation of parametrial disease [20]. In summary, these analyses suggested that our regimen of neoadjuvant I-A chemotherapy prior to radical irradiation had limited additional value on long-term prognosis for patients with locoregionally advanced uterine cervical cancer. If further study of I-A chemotherapy is attempted, its indication and method, especially on the timing of I-A chemotherapy and irradiation, should be reassessed. We are now designing a phase I/II study of concurrent I-A chemotherapy and irradiation for locally advanced uterine cervical cancer without bulky pelvic lymph node metastases. However, patients included in this study developed frequent distant metastases. It is generally recognized that patients with locoregionally advanced uterine cervical cancer have a high risk not only of locoregional failure but also of distant metastases [10, 19, 21]. When effective chemotherapeutic agents and their combination are established in the future, systemic delivery should be indicated instead of selective I-A infusional chemotherapy for locoregionally advanced uterine cervical cancer.

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