Preoperative concomitant chemoradiotherapy in locally advanced cervical cancer: Safety, outcome, and prognostic measures

Gynecologic Oncology 107 (2007) S127 – S132 www.elsevier.com/locate/ygyno

Preoperative concomitant chemoradiotherapy in locally advanced cervical cancer: Safety, outcome, and prognostic measures G. Ferrandina a , F. Legge a,b , A. Fagotti b , F. Fanfani a , M. Distefano b , A. Morganti c , N. Cellini d , G. Scambia a,b,⁎ a

Gynecologic Oncology Unit, Catholic University of Campobasso, Italy b Gynecologic Oncology Unit, Catholic University of Rome, Italy c Radiotherapy Unit, Catholic University of Campobasso, Italy d Radiotherapy Unit, Catholic University of Rome, Italy Received 6 July 2007 Available online 28 August 2007

Abstract Objectives. To evaluate the morbidity, and the therapeutic value of surgery after chemoradiation in a large series of locally advanced cervical cancers (LACC). The prognostic role of different clinico-pathological factors has been also evaluated. Methods. Between October 1997 and October 2006, 161 LACC patients were treated at both the Gynecologic Oncology Units of the Catholic University of Rome and Campobasso. Radiotherapy was administered to the whole pelvic region in combination with cisplatin and 5-fluorouracil. Radical surgery was performed 5–6 weeks after the end of the treatment. Results. A clinical complete/partial response was observed in 153 patients and radical surgery was performed in 152 cases. The overall rate of surgical complications was 33% with 15 (10%) patients experiencing severe toxicities. At pathological examination 111 of 152 patients (73%) showed absent/microscopic residual disease. With a median follow-up of 28 months, the 5-year disease free-survival (DFS) was 83% and the 5-year overall survival (OS) 90%. Advanced FIGO (Federation Internationale de Gynecolgie et d'Obstetrique) stage, pathological response and lymph node involvement were found significantly associated with clinical outcome. Conclusions. We confirmed in a larger series the safety and efficacy of this multimodal approach in the treatment of LACC. The pathological assessment of response can allow not only a tailored surgery in selected patients, but also the identification of patients with higher risk of recurrence to be submitted to adjuvant therapies. © 2007 Elsevier Inc. All rights reserved. Keywords: Locally advanced cervical cancer; Preoperative chemoradiation; Radical hysterectomy; Complications; Prognostic factors

Introduction Between 1999 and 2002, 5 out of 6 clinical trials have demonstrated an advantage in terms of disease-free (DFS) and overall survival (OS) for locally advanced cervical cancer (LACC) patients treated with concomitant radiation and cisplatin-based chemotherapy [1–6] with respect to exclusive radiotherapy, so that it currently represents the gold standard in the treatment of these patients. On the other hand, different ⁎ Corresponding author. Gynecologic Oncology Unit, Department Obstetrics and Gynecology, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy. Fax: +39 06 35508736. E-mail address: [email protected] (G. Scambia). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.07.006

experiences from Europe and South America have shown a comparable absolute benefit of 15% at 5-year survival, using neoadjuvant chemotherapy followed by radical surgery in the same group of cases [7–9]. Indeed, EORTC is conducting a randomized phase III trial comparing these two treatment modalities. Nevertheless, the 5-year survival of LACC patients is around 70%, hence other therapeutic approaches must be tested in order to further improve prognosis [10]. In this context, the possibility to combine different strategies to maximize local control and eventually improve quality of life of these patients should be considered. Among different approaches to this issue (i.e., different drugs, schedules and doses), the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery, has been previously

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investigated [11,12]. Despite the initial disappointing results related to the high rate of surgical complications, the theoretical potential advantages to perform surgery after neoadjuvant chemoradiation, such as the removal of potential chemoresistant foci, the assessment of the pathological response and the potential favorable psychological impact of “feeling free of disease” should not be underestimated. We previously demonstrated that neoadjuvant chemoradiotherapy followed by surgery resulted in a high rate of complete response to treatment and an acceptable rate of DFS and OS. Moreover, a low percentage of intra- and postoperative complications were observed [13–15]. In the present study, we evaluated the short- and long-term morbidity, and the therapeutic value in terms of pathological responses, DFS and OS, of surgery after chemoradiation in a large single-institutional series of LACC patients. The prognostic role of different clinico-pathological factors has been also evaluated in this population. Patients and methods This study includes 161 consecutive LACC patients accrued between October 1997 and October 2006 at both the Gynecologic Oncology Units of the Catholic University of Rome and Campobasso. Inclusion criteria were the following: biopsy-proven carcinoma of the cervix (stages Ib2–IVa); no evidence of disease outside the pelvis; age b 80 years; Eastern Cooperative Oncology Group performance status b 2; adequate bone marrow function (WBC N 3000, platelets N 120,000/mm3); adequate renal function (blood urea nitrogen b 25 mg/dl, creatinine b 1.5 mg/dl); normal liver function (bilirubin b 2 mg/dl); and no prior cancer other than basal cell carcinoma. All patients signed a written informed consent agreeing to be submitted to all the procedures described and for their data to be used prospectively. Pretreatment work up included a medical history, clinical examination, chest radiography, abdominopelvic magnetic resonance imaging (MRI), complete blood count and measurement of liver and renal function; cystoscopy and proctoscopy were performed if there was a clinical suspicion of invasion. Neoadjuvant chemoradiotherapy was performed according to 4 different clinical trials of external radiotherapy plus concomitant cisplatin-5-fluorouracilbased chemotherapy: (1) Most of the patients (n = 112) were submitted to the whole pelvic irradiation in 22 fractions (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2, 2-h intravenous infusion) and 5-fluorouracil (1000 mg/m2, 24-h continuous intravenous infusion) (both on days 1–4 and 27–30) as previously described [13]. (2) In 30 patients, according to a phase I–II trial, in addition to the above reported schedule, a dose escalation of external radiotherapy was delivered on the primary tumor through the concomitant boost technique (0.9 Gy per fraction), delivering three different dose levels: one weekly boost for a total dose of 43.2 Gy (n = 9); two weekly boosts, total dose of 46.8 Gy (n = 4); three weekly boosts, total dose of 50.4 Gy (n = 17) [manuscript submitted]. (3) Nineteen patients, according to a phase II study ongoing, were submitted to the whole pelvic irradiation in 25 fractions (2.0 Gy/day, on weeks 1–2, 5–6, 9, totaling 50 Gy) in combination with cisplatin (20 mg/m2, 2-h intravenous infusion) and 5-fluorouracil (1000 mg/m2, 24-h continuous intravenous infusion) (both on days 1–4, every 4 weeks, for 3 cycles). Four weeks after the end of concomitant chemoradiotherapy, patients were evaluated for objective response and debulking based on a second MRI and clinical examination. Clinical responders underwent radical hysterectomy according to Piver et al. [16] and pelvic ± lumboaortic lymphadenectomy, 5 to 6 weeks after the end of chemoradiation.

Toxicity assessment was performed according to the Radiation Therapy Oncology Group acute and late toxicity criteria [17]. Patients were assessed weekly for acute toxicity during treatment. Operative complications were defined as bladder, ureteral, bowel, vascular injuries and estimated blood loss exceeding 500 ml. Early postoperative and long-term complications were defined as any adverse event occurring within or after 30 days, respectively, from surgery. Surgical morbidity was classified according to Chassagne's grading system [18]. In particular, complications were considered severe (grade 3) if life threatening, per se or because of the treatment required, with permanent organ damage. After surgery, patients underwent physical examination, complete blood count and blood chemistry every 3 months for the first 2 years and every 6 months thereafter. Chest radiography and abdominopelvic MRI were performed every 6 months for the first 3 years and every 12 months thereafter. Eighty-six percent of patients were followed for at least 1 year. The median follow-up time was 28 months (range 3–126 months). Objective tumor response was assessed according to the RECIST (response evaluation criteria in solid tumors) [19]. Pathologic response was defined according to the TNM classification. In particular, complete response included cases with absence of any residual tumor after treatment at any site level, and microscopic partial response included cases with persistence of only microscopic foci at any site levels. The χ2 test was used to analyze the possible correlation between different clinico-pathological variables. Disease-free survival was calculated from the date of surgery to the date of relapse or the date of the last follow-up, and overall survival was calculated from the date of diagnosis to the date of death or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by Kaplan–Meier methods [20] and the log-rank test was used to assess the statistical significance. Statistical analysis was carried out by using SOLO (BMDP Statistical Software, Los Angeles, CA, USA).

Results Patient characteristics are shown in Table 1. Since one patient developed hearth failure during chemoradiation and two other died during/after chemoradiation as a result of causes unrelated to the treatment, one hundred fiftyeight patients were evaluable for clinical response. Complete and partial clinical response was observed in 66 and 87 patients (totalling 96.8% of clinical responses), respectively, whereas 2 patients showed stable disease and 3 patients developed Table 1 Preoperative clinical characteristics of the study population (n = 161) Clinical variable Age (median, range) in years FIGO stage Ib2–IIa IIb III–IVa Histotype Squamous Adenocarcinoma/adenosquamous Tumor volume (cm) ≥4 Node status (MRI) Positive Grade G1–2 G3 n.a. a

53, 25–80 10/161 = 6% 118/161 = 73% 33/161 = 21% a 152/161 = 94% 9/161 = 6% 125/161 = 78% 62/161 = 39% b 51/123 = 42% 72/123 = 58% 38/161 = 20%

23 Cases IIIb, 1 case IVa. Only two cases with positive aortic nodes (both treated with extended-field radiotherapy). b

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progression of disease during the treatment: in particular two lung and one pelvic disease progressions were observed. Since 3 patients refused surgery, 152 of 155 not progressing cases were submitted to radical surgery. Types I–II radical hysterectomy was performed in 20 (13.1%) patients, whereas 102 (66.7%) and 30 (19.6%) cases underwent type III and types IV– V radical hysterectomy (including 1 anterior pelvic evisceration), respectively. Pelvic lymphadenectomy was performed in all patients, with a median number of lymph nodes removed of 36 (range 6–88). Fifty-three (34.9%) patients with positive pelvic nodes at frozen section or suspicious nodes at imaging/ palpation were submitted to aortic lymphadenectomy upper to the level of the inferior mesenteric artery (median nodes removed 11, range 2–50). Toxicity Chemoradiotherapy-related toxicity was evaluated in all patients. Thirteen patients required a brief interruption of treatment due to acute toxicity (n = 9) or a thrombotic event (n = 4). Seven patients required a reduction in the chemotherapy dosage (50% of the prescribed dose) in the last week of radiotherapy due to hematological toxicity. Overall, 32 patients experienced grades 3– 4 toxicity. In particular, grade 3 or 4 hematological toxicity was observed in 23 patients: 19 patients experienced neutropenia; 3 patients, thrombocytopenia; 1 patient, neutropenia plus thrombocytopenia. Seven patients developed grade 3 gastrointestinal toxicity; 1 patient, grade 3 skin toxicity; and 1 patient, grade 1 genito-urinary toxicity. Intra- and postoperative complications were evaluated in all patients submitted to surgery. Median operating time was 215 min (range 120–500) and median blood loss was 500 cm3 (range 100–1500). 48 of 152 (31.6%) patients experienced an estimated blood loss exceeding 500 ml during surgery and were transfused (12 autologous and 53 homologous transfusions). There were 13 intraoperative complications (8.5%) including 5 bladder, 2 ureteral, 2 rectal (1 requiring temporary colonstomy) and 2 vascular injuries, which were all managed during surgery with no major intervention; two intraoperative uterine ruptures were also observed. The postoperative febrile morbidity rate (N38 °C for 2 days) was 17.8% (27/152) and the median time of recovery was 7 days (range 4–18). In the early postoperative period, 5 (3.3%) severe (grade 3) complications were observed: 1 patient died of acute renal failure, 1 experienced postoperative bleeding requiring internal iliac embolization, 1 developed bowel obstruction requiring intestinal resection, 1 developed recto-ureteral fistula requiring surgery, 1 experienced enterocystoplasty dehiscence requiring bilateral permanent nephrostomy. Among the 12 (7.9%) grade 2 early complications: 2 patients showed bilateral hydroureteronephrosis requiring temporary nephrostomy, 3 experienced wound dehiscence which required re-intervention; 1 deep venous thrombosis, 1 pelvic abscess, 1 vesico-vaginal fistula, 1 pulmonary edema and 3 bowel subocclusions were managed by hospitalization without surgical intervention. Moreover, 5 symptomatic lymphocysts and 2 lower limb paraesthesia were observed and classified as mild (grade 1) complications.

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Table 2 Relapse and/or progression rate according to the different sites of recurrence (n = 161) Site Central pelvic Lymphatic Pelvic Aortic Abdominal Distant Mixed (extrapelvic ± pelvic) Median time to relapse/progression (months) a

34 (21.1%) 10.0% 11.2%

14 (8.7%) 4 (2.5%) 3 (1.9%) 4 (2.5%) 5 (3.1%) 4 (2.5%) 8 (0–100) a

62% recurred within 12 months, 88% recurred within 24 months.

As far as long-term toxicity is concerned, 10 (6.6%) severe complications were observed: 1 bowel obstruction after 60 months from surgery; 4 chronic renal failures (resulting from 6 ureteral stenosis); 3 bladder retention requiring longterm catheterization; and 2 long-lasting urinary incontinence. Two laparoceles and one long-term leg edema, interfering with normal activity were also observed and classified as grade 2 complications. In summary, according to Chassagne classification of surgical complications [18], we observed 15 (9.9%) grade 3 complications at the following organs: ureter/kidney (n = 7), urethra/bladder (n = 5), bowel (n = 2), vascular (n = 1). Pathological response Pathological response was assessed in all patients submitted to surgery (n = 152). Sixty-seven patients (44.1%) showed a complete response to treatment and 44 cases (28.9%) showed a microscopic residual disease, totalling 111 (73.0%) complete/ partial microscopic responses. A macroscopic residual disease was observed in 41 (27%) cases with 38 (25.0%) partial responses and 3 (2.0%) stable diseases. The pathologic response rate differed according to FIGO stage: a macroscopic residual disease was found in 14 of 30 stages III–IVa cases (46.7%) with respect to 27 of 122 (22.1%) stages Ib2–II cases (p = 0.011). The rate of pelvic lymph node metastasis was 12.5% (19 of 152 cases), including 7 cases with both pelvic and aorticpositive nodes. Lymph node positivity was significantly associated with the presence of macroscopic residual cervical tumor with 74% of node-positive versus 19% of node-negative cases presenting residual cervical tumor (p = 0.00001). Outcomes The median duration of follow-up was 28 months (range 3–126). To date, relapse/progression of disease was observed in 34 of 161 patients (21.1%), which were distributed as reported in Table 2. In particular, 18 (11.2%) recurrences/progressions occurred in the pelvic region and 16 (10.0%) were extrapelvic. While among stages I–II cases a similar number of pelvic (n = 9; 7%) and extrapelvic (n = 11; 8.5%) recurrences/progressions were found, in III–IV cases a higher rate of recurrences/

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Fig. 1. DFS according to pathological response. (A) All patients (n = 152). (B) Only stages Ib2–II patients (n = 140). CR = complete response; μPR = microscopic partial response; PR = partial response; SD = stable disease.

progressions was observed in the pelvic (n = 11, 34.4%) with respect to the extrapelvic regions (n = 3; 9.3%). The median time to relapse was 8 months (range 2–100), with the majority of cases (88%) recurring within 2 years from the completion of the treatment. The 2-year and 5-year DFS were 91% and 83%, respectively (median DFS: not reached). To date, death of disease was observed in 23 of 161 patients (14.3%). The 2-year and 5-year OS were 97% and 90%, respectively (median OS: 106 months). To date, all causes-death was observed in 28 of 161 patients (17.4%). Among the 5 no-cancer-related deaths, only 1 (one acute renal failure) is associated to the study treatments. The 2-year and 5-year all-causes-OS were 94% and 88%, respectively (median all-causes-OS: 101 months). Preoperative and pathological prognostic factors Among the possible preoperative prognostic factors analyzed (FIGO stage, lymph node status at imaging, grade and histotype) only advanced stage showed a significant association with worse DFS (0.004), and a trend to be associated with worse OS (p = 0.09).

Since no differences in DFS or OS were observed between patients with complete versus partial microscopic pathological response and between those with partial pathological versus stable disease, we analyzed, for prognostic evaluations, patients with absent/microscopic residual disease versus those with macroscopic disease. Thus, patients with absent/microscopic residual disease showed a significant longer DFS (p = 0.00001) and OS (0.00001) versus those with macroscopic disease at pathologic examination. The association between pathological response and outcome in terms of DFS and OS was also observed in stages Ib2–II (p = 0.0001 and p = 0.005, respectively) and stages III–IVa (p = 0.0001 and p = 0.005, respectively) (Fig. 1). As for the lymphatic status a worse prognosis in terms of DFS (p = 0.0001) and OS (p = 0.0013 )was observed in patients with pathologically positive nodes. This association was also maintained in stages Ib2–II patients (p = 0.004, for DFS; p = 0.011, for OS), whereas in stages III–IVa patients were found significant only for DFS (p = 0.009). In Table 3 the clinico-pathological factors found to be predictive for DFS and OS in our study population are summarized. Discussion To date more than 14 studies have investigated preoperative chemoradiation in about 1000 of LACC patients: all authors have administered radiation at a cumulative dose of 40–80 Gy, with cisplatin-based concomitant chemotherapy. The major differences between these studies are related to the additional use of brachytherapy and/or a second drug (i.e., 5-fluorouracil). The outcome measures have reported ranges from 57% to 85% for DFS and from 64% to 90% for OS [13–15,21,26,]. Our study, reporting data of the largest single-institutional series of LACC patients treated with chemoradiation followed by surgery confirm that this three-modality treatment can achieve OS and DFS rates at least comparable to exclusive chemoradiation [1–6,13–15]. The major concern about this treatment could be the morbidity related to surgery after chemoradiation. The overall rate of surgical complications in our series was 32.9% with 15

Table 3 Clinical and pathological prognostic factors in the study population (n = 161) Variable

Stages IB2–II III–IVA Pathological response Complete/partial microinvasive Partial/stable Lymph node status Negative Positive

Disease-free survival (DFS)

Overall survival (OS)

2-year DFS (%)

RR⁎

χ2

P

2-year OS (%)

RR⁎

χ2

P

93 51

ref 3.5

12.0

0.0004

97 72

ref 2.2

3.0

0.094

95 58

ref 10.5

35.2

0.00001

98 62

ref 10.6

23.6

0.00001

90 24

ref 5.8

21.8

0.00001

90 24

ref 4.4

9.9

0.001

RR⁎, unadjusted relative risk; ref = reference category.

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(9.9%) of 152 patients experiencing severe toxicities (grade 3 according to Chassagne's classification) [18,21]. Most of these complications are urinary, involving ureters and the subsequent kidney function (the only one death attributable to the surgical treatment was for acute renal failure) and the bladder function. Our short- and long-term morbidity is comparable to a recent multicentric French study, reporting a 7% of grade 3 morbidity [21]. In addition, the complication rate we reported seems quite acceptable considering that it is of the same magnitude of those reported for radical hysterectomies in untreated patients [22]. We do believe that the introduction of a new concept of radical surgery, whose extent could be tailored on the basis of intraoperative findings, might play an important role in diminishing the overall rate of complications. In particular, based on our previously published data [23,24], we tailored the extent of surgery by applying modified type II radical hysterectomy and pelvic lymphadenectomy in patients with a clinical complete response to treatment and absence of parametrial or lymph node involvement at frozen section analysis. This approach translated in a reduction of short- and long-term postoperative complications with respect to earlier experiences of radical surgery after preoperative chemoradiation [11–13]. Moreover, we demonstrated a 73% of pathological complete response or persistence of only microscopic disease, suggesting that the local control achieved with this scheme is very high and at least comparable to that obtained by other groups using preoperative chemoradiotherapy. Moreover, as previously reported by others [1,12,21,26] the rate of residual tumor increases according to the FIGO stage with about half of stages III–IVa cases in our series presenting residual macroscopic disease. Residual tumor on surgical specimen ranges in literature from 32% and 60%. depending on the radiation dose and FIGO stage [1,12,15,21,26]. The fact that a residual tumor is often present after chemoradiation advocates for the hypothesis that an adjuvant surgical resection could improve local control, the DFS and the OS. In the only randomized study published to date, Keys et al. reported an advantage in terms of local recurrence rate and 5-year DFS in patients treated with adjuvant hysterectomy versus those treated with radiotherapy and brachytherapy. In line with this, our outcome measures are at least comparable to exclusive chemoradiation protocols. Indeed, Eifel et al. [27] reported for the RTOG-90-01 study, by using a median dose to point A of 87Gy, rates of 5-year DFS of 68% and 5-year OS of 73% with 10.3% of locoregional failure, 11.3% of distant failure plus 6.7% mixed (pelvic plus distant failure) and 4.6% second primary tumors. Although caution has to be taken in comparing our series with that of RTOG-90-01 because substantial differences exist in critical factors such as the median follow-up (4.6 versus 2.4 years), and the percentage of stages III–IVa patients (30% versus 20%), the 5-year DFS of 83% and 5-year OS of 90% observed in our study population is very encouraging. With regard to the possible worsening of these data with a longer follow-up, it is important to consider that 88% of recurrences/progressions in our series of LACC occurred within the first 2 years, as also reported in other series

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[26]. In addition we have a low rate of locoregional (11.2%) and distant failure (10.0%): these results are particularly positives in stages Ib2–II with a local and distant control of 93% and 91.5%, respectively, while locoregional control was of 65.4% in stages III–IVa. The lower pelvic control found in these advanced cases may be related to an intrinsic aggressiveness of these tumors as suggested by the lower response rate we found in these tumors, and it could be likely ameliorated by increasing the radiation dose in these tumors with extensive pelvic involvement. Indeed, Houvenaeghel et al. [26], by using preoperative chemoradiation plus low dose brachytherapy and a parametrial boost in more advanced cases, delivering a total dose of 60Gy, obtained a pelvic control in 85% of Ib2/II cases and, more importantly 93% for stages III–IVa. In this context, we confirmed in a larger series the prognostic role of pathological response, in line with findings previously reported [12,15,21,28]. In particular, patients with absent or microscopic residual disease showed a longer DFS and OS with respect to cases with grossly present residual tumor. Interestingly enough, the predictive role of pathological response on outcome measures was maintained in Ib2–II as well as in III– IVA stages, configuring it as a crucial prognostic factor. On this basis it can be hypothesized that more effective neoadjuvant modalities would produce longer survival by increasing the pathological response rates. Moreover, the similar prognosis of patients with absent or microscopic residual disease, recently reported also by Classe et al. may suggest a role of surgery in eliminating microscopic tumoral foci [21]. On the contrary tumors grossly persistent after chemoradiation likely exhibit aggressive features that increases the probability of relapse apart from the treatment used. As for the lymphatic status we observed a rate of pelvic lymph node involvement of 12.5%, which is comparable to the 16% and 24% reported by Houvenaghel et al. [29] and Classe [21]. Moreover, we confirmed the association between the persistence of macroscopic tumor in the cervix and the lymph node positivity [21,29]. As an expected consequence, a worse prognosis in terms of DFS and OS was observed in patients with pathologically positive nodes. This association was also maintained in stages Ib2–II patients whereas in stages III–IVa patients it was found significant only for DFS. In conclusion, we confirmed in a larger series the safety and efficacy of this multimodal approach in the treatment of LACC. The possibility of assessing the pathological response to this treatment can allow not only a tailored surgery in selected patients to further reduce intra- and postoperative complications, but also the identification of patients with higher risk of recurrence to be submitted to adjuvant therapies. Moreover, since concurrent chemoradiotherapy without surgery showed less benefit in studies with a high proportion of III–IVa stages as compared to radiotherapy alone [30], three-modal treatments with adequate radiation doses, new chemotherapy regimens, and/or aggressive surgical approaches (e.g., pelvic evisceration) could be considered in patients with extensive pelvic involvement. Finally, significant attention should be given not only to maximizing the potential for control, but also to improving the quality of life. A prospective study aimed at evaluating the

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impact of different treatment modalities on quality of life, sexual impairment, and rectal/bladder dysfunctions in long-term cervical cancer survivors is ongoing in our Institution. Conflict of interest statement We declare that we have no conflict of interest.

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