Long-term survival after concomitant chemoradiotherapy prior to surgery in advanced cervical carcinoma

Gynecologic Oncology 100 (2006) 338 – 343 www.elsevier.com/locate/ygyno

Long-term survival after concomitant chemoradiotherapy prior to surgery in advanced cervical carcinoma Gilles Houvenaeghel a, Loic Lelievre a,*, Laurence Gonzague-Casabianca b, Max Buttarelli a, Vincent Moutardier a, Anthony Goncalves c, Michel Resbeut b a Department of Surgery, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France Department of Radiation Oncology, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France c Department of Medical Oncology, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France

b

Received 24 April 2005 Available online 5 October 2005

Abstract Objective. To report the long-term survival of 35 patients who underwent surgery after concomitant chemoradiation for locally advanced cervical cancers. Methods. From 1988 to 1992, 20 bulky IB – IIB patients and 15 stage III – IVA patients underwent surgery after concurrent chemotherapy (CDDP and 5-FU) and radiotherapy. 26 had a hysterectomy, 8 had an exenteration, 1 had no tumor resection. 21 had a para-aortic lymphadenectomy. Endpoints were recurrence and distant metastasis rates, overall survival (OS) and disease-free survival (DFS) at 5 and 10 years. Analysis included FIGO stage, type of surgery (palliative or curative), response to chemoradiation or para-aortic lymphatic status. Results. Surgery had been only palliative in 6 cases (17.1%). A pelvic control has been achieved in 31 patients (88.6%). Pelvic recurrences occurred after a median interval of 7 months. Distant metastases occurred in 10 patients (28.6%), after a median interval of 20 months. So far, 16 patients have died (45.7%). The 10-year DFS is 56.7% in the whole series. Only the type of surgery significantly affected the OS. Only the paraaortic lymphatic status significantly affected the DFS. Conclusion. Associating chemoradiation with curative surgery, we obtained a 10-year DFS of 66.4% (OS 57.7%). Adjuvant surgery may increase the survival as it reduces the risk of local relapse. D 2005 Elsevier Inc. All rights reserved. Keywords: Cervical cancer; Chemoradiation therapy; Completion surgery; Survival

Introduction From 1999, concomitant chemoradiotherapy has become the standard treatment for locally advanced cervical cancers [1 –6]. The role of surgery is debated for bulky stage IB to IIB cancers [7– 9] and for stage III/IVA cancers [7] after concomitant chemoradiotherapy plus brachytherapy [7] or neoadjuvant chemotherapy [10 –15]. In 1994, we reported our experience of chemoradiotherapy in a series of 40 patients, of which 35 had an adjuvant surgical intervention [7]. The median follow-up was then 2.6 years (0.6 * Corresponding author. De´partement de Chirurgie, Chirurgie Oncologique 2, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, 13009 Marseille, France. Fax: +33 4 91 22 36 13. E-mail address: [email protected] (L. Lelievre). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.08.047

to 5.6 years). The aim of this new study was to evaluate the long-term results of this therapeutics. Materials and methods Between February 1988 and December 1992, 40 patients with biopsyproven cervical carcinoma entered the study and 35 underwent surgery (87.5%). They all had an examination under anesthesia and were staged according to the procedures described elsewhere [16] with the combination of clinical examination, cystoscopy, and vaginal and rectal endosonographies. The study included previously untreated patients with FIGO stage IB disease >5 cm, or with stage IIB disease only if distal parametrium involvement, and all patients with stage III and IV tumors. Pretreatment evaluation included lymphangiography and/or CT scan to check for suspicious para-aortic lymph nodes. Fine-needle aspiration was used to confirm metastases whenever possible. Patients with evidence of distant metastases and/or para-aortic lymph node involvement were not eligible (19 patients out of 88 who have been checked for eligibility [7]). Patients’ characteristics are summarized in Table 1.

G. Houvenaeghel et al. / Gynecologic Oncology 100 (2006) 338 – 343 Table 1 Patients’ characteristics (N patients = 40) Age Median Range Karnofsky index Median Range FIGO stage IB (bulky disease > 5 cm) IIB (distant parametrial invasion) IIIA IIIB IVA Histology Squamous cell carcinoma Adenocarcinoma (stage IIB) Anaplastic carcinoma (stage IIB) CEA (normal value < 5 ng/ml) Median Range SCC (normal value < 2.5 ng/ml) Median value Range

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Postoperative complications 48 years 31 – 71 years 80 50 – 100 6 15 1 6 12 38 1 1 2.3 5 – 198 4.9 4 – 73

Radiation therapy (45 Gy over 33 days) was administered at 1.8 Gy in one fraction per day in the first 20 patients, and 0.9 Gy per fraction twice a day in the last 20 patients. Concomitant chemotherapy was given on the first and 21st days of radiation therapy (Cisplatin CDDP, 60 mg/m2 plus 5-fluorouracil 5-FU 600 mg/m2/day continuous IV over 96 h, these doses were reduced to CDDP 40 mg/m2 and 5-FU 400 mg/m2/day for the last 23 patients) [7]. The radiation fractionation and chemotherapy dose were modified in the middle of the study due to diarrhea and postoperative complications. Intracavitary application was given to all cases with stage IB, IIB, III and to four good responders with stage IVA disease (30 patients among the 35 who underwent surgery). We used a low dose rate brachytherapy protocol consisting in a single intracavitary application using a linear source of Cesium 137 delivering an additional dose of 15 Gy on the reference isodose. The reference isodose encompasses at best the Gross Tumor Volume (GTV), while delivering no deleterious dose to the regional organs at risk: bladder and rectum. Then, a parametrial boost was given to stage IIB and III patients and to stage IVA patients in whom the tumor invaded the pelvic side wall with a total dose of 55 – 60 Gy. Surgery was carried out 1.5 months (median) after completion of chemoradiotherapy and brachytherapy (0.9 – 2.7 months). Only 3 patients underwent surgery after a 8-week delay due to the toxicity of chemoradiation: 2 patients had surgery at 2.3 months and 1 patient at 2.7 months. Prior to surgery, patients were re-evaluated by clinical examination. There was no systematic postchemoradiation imaging. A radical hysterectomy had been performed 26 times (extended to the ureter(s) in 5 cases) and 8 patients underwent a pelvic exenteration (anterior in 7 cases and total in 1 case). One patient had a laparotomy with no hysterectomy performed due to a massive para-aortic lymph node involvement. The resection was classified on per-operative and pathological data as curative or palliative if incomplete (R1 or R2, cervix or peri-cervical structures or positive lymph nodes, not removed). Statistics were performed using the SPSS 12 software for Windows. Overall survival and disease-free survival (DFS) rates were computed by the Kaplan – Meier method. Differences in the survival curves or in the DFS curves were estimated by the log-rank test. Other estimations were performed by the Fisher’s exact test. A P value of 0.05 was considered significant.

Results The mean duration of follow-up has been 106.2 months with a standard error (SE) of 12.4 and a 95% confidence interval of 81.8 –130.5.

Five stage IVA patients developed serious postoperative complications requiring a second surgery (as mentioned in the former study, [7]). In one patient, an enterocystoplasty had been changed to a transintestinal urinary by-pass 7 months later. All these complications occurred after radiation therapy using one fraction per day (P = 0.006). Besides, all these patients suffered from chemoradiation acute toxicity (mostly WHO grade 3 –4 diarrhea [7]). Surgical findings The distribution of responses according to the tumor stage is displayed in Table 2. Positive external iliac nodes were found in 2 cases (IIB and IVA) and positive para-aortic nodes were found in 5 cases (2 IIB and 3 IVA). Surgery had only been palliative in 6 cases (17.1%: 6/35): 3 times because of positive margins and 3 times because of a massive para-aortic lymph node extension. Tumor stages were FIGO I/II in 2 cases (10%: 2/20) and FIGO III/IV in 4 cases (26.7%: 4/15) (non-significant (NS)). Evolution 13 patients developed a pelvic or a distant metastatic relapse, both pelvic and distant metastatic in one case. Pelvic control (Table 3) A pelvic control was achieved in 31 of the 35 patients who underwent a surgical procedure (88.6%), representing 31 of the 34 cases for whom the tumor removal had been feasible (91.2%) and 28 of the 29 patients for whom the intervention had been curative (96.5%). Pelvic recurrences were observed during a period of 6 to 9 months (median 7 months) following the beginning of the treatment (Table 3). We obtained a pelvic control in 88.6% of the cases, respectively 85% for stage IB2/II patients (17/20) and 93% for stage III/IVA patients (14/15). One patient of the curative surgery group had a local recurrence at 9 months (1/29: 3.5%), this represented one stage IIB tumor out of the 18 stage I/II cases of this group (5.5%) and no recurrence occurred among the 11 stage III/IV cases of the group (NS). Three patients of the palliative surgery group had a local relapse (3/6: 50%; stage IB, IIB, IV).

Table 2 Histopathological response following surgery in 35 patients FIGO stage

IB (N = 6)

IIB (N = 14)

IIIB (N = 6)

IVA (N = 9)

Total

Complete response Partial response (>50%) No change

2

10

2

2

16

3

4

4

6

17

1

0

0

1

2

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Table 3 Pelvic recurrences and distant metastases Curative

Stage I/II Stage III/IV Total

Palliative

Total

P.R.

Metastasis

N.E.D.

P.R.

Metastasis

N.E.D.

1a 0 1

5 2 7

12 9 21

2 1 3

0 2 2

0 1 1

20 15 35

after chemoradiotherapy and 3 patients of the 16 with no residual tumor (or microscopic) after chemoradiotherapy (NS). Six metastatic patients were observed among 30 patients without para-aortic node involvement (6/30: 20%) in comparison with 4 metastatic patients among 5 patients with paraaortic node involvement (80%) (P = 0.016).

Distant metastases (Table 3) Ten metastases were observed (10/35: 28.6%) during a period of 6 to 80 months (median 20 months) following the beginning of the treatment. These metastases occurred in 1 stage IB patient (with pN+ pelvic or para-aortic unspecified), 5 stage IIB patients, 2 stage III patients and 2 stage IVA patients. When considering the curative surgery group versus the palliative surgery group, these metastases affected 8 patients of the curative surgery group (8/29: 27.6%, one patient having a local recurrence at the same time) and 2 patients of the palliative surgery group (2/6: 33%, stage III/IV tumors). The metastatic cases of the curative surgery group corresponded to 6 stage I/II cancers out of 18 and 2 stage III/IV cancers out of 11 (NS). Moreover, in this latter group, the metastatic spreading involved 5 patients of the 13 with residual disease

Outcomes To date, 16 of the 35 study patients have died (45.7%). Two patients died of cancer unrelated causes with no neoplastic evolution. One patient died of cancer progression 4 months after an anterior pelvic exenteration with positive margins. The survival rate at 60 and 120 months was respectively 62.2% (SE 0.08) and 52.3% (SE 0.09) in the whole series, 58.9% and 53% (SE 0.11) in stage IB –IIB patients, 66.7% (SE 0.12) and 53.3% (SE 0.13) in stage III – IVA patients (log rank: NS) (Figs. 1, 2). The disease-free survival rate at 60 and 120 months was respectively 63.98% (SE 0.08) and 56.7% (SE 0.09) in the whole series (Fig. 1), 58.7% and 58.7% (SE 0.11) in stage IB –IIB patients, 71.79% (SE 0.13) and 55.8% (SE 0.13) in stage III –IVA patients (log rank: NS). When comparing the curative versus palliative surgical groups, the overall survival rate was 69.3% at 5 years and 57.7% at 10 years versus 20% at 5 and 10 years, respectively (SE 0.18, P = 0.0058), the DFS was 75% at 5 years (SE 0.08) and 66.47% at 10 years (SE 0.09) versus 0% at 5 and 10 years (P < 0.0000). No significant difference in the survival or in the diseasefree survival has been observed between patients with microscopic or no residual tumor versus residual tumor on the surgical specimen: the 5-year and 10-year survival rates were 76.7% and 63.3% (SE 0.12) versus 47% and 41% (SE 0.12) (P = 0.09); the 5-year and 10-year DFS rates were 70.9%

Fig. 1. Overall and disease-free survival Kaplan – Meier curves. Numbers in bold are the survival rates at 60 and 120 months.

Fig. 2. Overall survival according to the FIGO stage.

P.R.: pelvic recurrence. N.E.D.: no evidence of disease. a 1 case of P.R. and metastasis.

Among the 16 patients who had a negative histopathological specimen after surgery, only one stage IIB patient developed a pelvic recurrence (6.25%) in comparison with 3 pelvic recurrences among 19 patients with residual tumor (15.8%) (stages IB, IIB, IVA) (NS).

G. Houvenaeghel et al. / Gynecologic Oncology 100 (2006) 338 – 343 Table 4 Overall survival and disease-free survival (DFS) according to the para-aortic lymphatic status N Survival (%) 5 years

DFS (%) 10 years

5 years

10 years

pN+ 5 40 (SE 0.22) 40 (SE 0.22) 20 (SE 0.19) 20 (SE 0.19) Unknown 14 39.7 (SE 0.13) 39.7 (SE 0.13) 60.2 (SE 0.14) 60.2 (SE 0.14) pN 16 75 (SE 0.12) 67 (SE 0.12) 81.2 (SE 0.11) 68.2 (SE 0.11) Overall survival: pN+ versus para-aortic status unknown: non-significant; pN versus para-aortic status unknown or pN+: almost significant (log rank: 0.058). DFS: pN versus para-aortic status unknown: non-significant; pN versus pN+: significant (log rank: 0.014).

and 63.8% (SE 0.12) versus 56.47% and 49.4% (SE 0.12) (P = 0.29). As for the para-aortic lymphatic status, only the difference in the 5-year and the 10-year DFS between pN and pN+ patients was significant: 81.2% and 68.2% (SE 0.11) versus 20% and 20% (SE 0.17) (P = 0.014, Table 4, Fig. 3). It is noticeable that no evidence of disease has been observed 109 and 119 months after surgery in two patients with para-aortic node involvement. Further calculations showed no significant difference between patients treated with once daily versus twice daily fractionation: the 5-year and 10-year survival rates were 57% and 57% versus 55% and 49% (SE 0.12), the 5-year and 10year DFS rates were 56.6% and 56.6% versus 63.7% and 56.7% (SE 0.12). Nor was any difference found between patients with pretreatment tumor diameter <50 mm versus greater than 50 mm: the 5-year and 10-year survival rates were 64.7% (SE 0.11) and 42.4% (SE 0.13) versus 60.2% and 60.2% (SE 0.11), respectively, the 5-year and 10-year DFS rates were 64.1% (SE 0.11) and 48.9% (SE 0.13) versus 64.4% and 64.4% (SE 0.12), respectively. Similar results were obtained when analyzing patients with total hysterectomy versus patients who had an exenteration: the 5-year and 10-year survival rates were 64.6% and 60.3% (SE 0.1) versus 50% (SE 0.17) and 25% (SE 0.15) (P = 0.12), the 5-year and 10-year DFS rates were 64.5 and 64.5% (SE 0.09) versus 54.7% and 36.4% (SE 0.20) (P = 0.38).

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Although being the treatment of choice of advanced cervical cancers, the benefit of chemoradiation for stage III and IVA cancers has not been clearly stated [1]. Moreover, an additional surgical resection has only been proposed by Keys et al. for stage IB2 tumors [2]. In that study, a residual cervical tumor was present in 59% of the cases after radiotherapy alone and in 46% of the case after chemoradiotherapy [2]. In addition, a pelvic control was obtained in 76% of the patients after radiotherapy alone versus 89% after chemoradiotherapy [2]. The rate of residual cancer after chemoradiotherapy on surgical specimen ranges from 32.5% and 58.6% depending on the study or the FIGO stage [2,8,17,18]. In our experience so far, we observed a residual cervical tumor in 48.6% of the patients (71/146) for stage IB2, bulky IIA, IIB, III and IVA cancers (unpublished data), 45.7% in this reported series. A previous multicentric study that we undertook showed similar results: tumor sterilization in 38.6% of the cases, microscopic residual tumor in 11.7% of the case and macroscopic residual tumor in 49.7% of the cases [17]. The rate of residual tumor after chemoradiation increases according to the FIGO stage: 43 to 52% for IB2 tumors [2,17,18], 41 to 56% for bulky IIA and IIB tumors, 51.6% to 68% for stage III tumors and 72.7 to 73.7% for stage IVA tumors [17,18]. The fact that a residual tumor is often present after radiotherapy or chemoradiotherapy and brachytherapy advocates for the hypothesis that an adjuvant surgical resection could improve the local control, the disease-free survival and the overall survival. Actually, a local recurrence is a major cause of treatment failure in patients with advanced carcinoma of the cervix [19]. Authors have shown that a residual tumor was associated with a higher rate of local recurrence [17,20,21] and a shorter disease-free survival [17]. Moreover, in a randomized study, Keys et al. reported a 5-year disease-free

Discussion Since we started chemoradiation for advanced cervical cancers in 1988, it has become the standard treatment on account of the results of several randomized studies comparing radiotherapy with chemoradiotherapy [2 –4]. As reported in the previous article of 1994, the radiation fractionation has been changed at the time of the study due to WHO grades 3 –4 diarrhea occurring during concomitant chemoradiation [7]. This could have been explained by the chemotherapy regimen which included 5-FU. Since 2000, the treatment consists in a 1.8 Gy/day monofractionated radiotherapy with concurrent Cisplatin only, 40 mg/m2 weekly, as it has been shown that Cisplatin alone was as effective as in combination with other drugs, with a lesser toxicity [4].

Fig. 3. Disease-free survival according to the para-aortic lymphatic status. Numbers in bold are the survival rates at 60 and 120 months.

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survival of 62% if hysterectomy and 53% if no hysterectomy for stage IB2 patients previously treated by radiotherapy and brachytherapy, with a relative risk of 0.72 ( P = 0.04) when comparisons were adjusted to the tumor size, the GOG performance status and the age [22]. This benefit was mainly due to a reduced rate of local recurrence after hysterectomy (15% versus 27%). Nevertheless, adjuvant surgery had no benefit on the 5-year overall survival in the whole series, although a significant benefit was observed in the group of tumors measuring 4 to 6 cm (relative risk: 0.6). In our series of 35 stage IB2 to IV patients who had an additional surgery, the disease-free survival was 60.4% at 5 years and 56.7% at 10 years, whatever the stage IB2/II or III/IV. We obtained a pelvic control in 88.6% of the cases, respectively 85% for stage IB2/II patients and 93% for stage III/IVA patients. With no adjuvant surgery to chemoradiation therapy, Eifel et al. reported global survival rates of 73% at 5 years (CI 95%: 67 –80), 67% at 8 years (CI 95%: 60– 75%), disease-free survival rates of 68% at 5 years (CI 95%: 62– 75%) and 61% at 8 years (CI 95%: 53– 68%), and pelvic recurrence rates of 18% at 5 and 8 years (CI 95%: 12 – 23%), with a median follow-up of 6.6 years [23]. Besides, that study showed different results for stage IB2/II cancers in comparison with stage III/IV cancers: respectively, the 5-year survival rate was 79% (CI 95%: 72 – 86%) versus 59% (CI 95%: 46 –72%), the 5-year disease-free survival rate was 74% (CI 95%: 67 – 82%) versus 54% (CI 95%: 41 – 67%) and the rate of pelvic recurrence was 13% (CI 95%: 7 – 19%) versus 29% (CI 95%: 16– 41%) [23]. The arguments against adjuvant surgery are the surgical morbidity after chemoradiation and the fact that the metastatic progression remains not modified (with the exception of distant metastases originating from local recurrences). The risk of surgical complications depends on the surgical procedure, but also on the way to evaluate it. For instance, grade 3 or 4 morbidity was not altered by hysterectomy if compared with non-operated patients (10% in each group) in the series of Keys et al. [22]. In the current study, the five re-interventions followed pelvic exenterations, one of which occurred at 7 months. In our multicentric study [17], the morbidity rate was 29%: grade 1 in 3.4% of the cases, grade 2 in 18.8% of the cases and grade 3 in 6.8% of the cases. This morbidity rate was 22% after colpo-hysterectomy with lymphadenectomy, in half the cases these complications were urinary. With the exception of pelvic exenterations for which the morbidity is high in all the studies, the morbidity of hysterectomy appears acceptable. Due to the improvements in the pelvic control, the metastatic dissemination of these advanced cancers constitutes a major problem. We observed a metastatic spreading in 28.6% of the patients after a median period of 20 months. Keys et al. observed distant metastases in 12% of stage IB2 cancer patients who have been operated on after chemoradiation with a median follow-up of 36 months [2]. Eifel et al. reported distant metastases in 18% of the patients after 5 years (CI 95%: 13 – 24%) and in 20% of the patients after 8 years (CI 95%: 14 – 26%) for stage IB2 to IV cervical cancers treated by chemoradiotherapy with a median follow-up of 6.6 years for living patients [23].

Conclusion With the combination of chemoradiation, brachytherapy and surgery, we obtained a local control of the disease in 96.5% of the cases after curative surgery, a 10-year survival of approximately 67% if no para-aortic node spreading and 60% after curative resection in locally advanced cancers. This longterm follow-up shows that most of pelvic relapses and distant metastases occur within the 5-year period following the treatment, as it has been shown after chemoradiation alone [23]. So far, there is no literature reporting criteria to select patients for surgery after chemoradiation. With new methods of investigation like FDG-PET, which appears to be useful for the management of cervical cancers [24], we are now able to select patients for surgery after chemoradiation with a greater accuracy than before. Actually, criteria like distant metastases or para-aortic lymph node involvement are better evaluated and surgery should be avoided in case of suspicion of extra-pelvic disease. The combination of FDG-PET, pelvic RMI and a cervical biopsy after completion of chemoradiation could be used to establish such criteria to select patients who could benefit from adjuvant surgery. This is being evaluated in a French study randomizing stage IB2/IIB patients for surgery after chemoradiation which is still in progress.

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