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Preoperative chemoradiotherapy in locally advanced cervical cancer: Long-term outcome and complications
Gynecologic Oncology 99 (2005) S166 – S170 www.elsevier.com/locate/ygyno
Original Research Report
Preoperative chemoradiotherapy in locally advanced cervical cancer: Long-term outcome and complications Mariagrazia Distefano a, Anna Fagotti b, Gabriella Ferrandina a, Fanfani Francesco b, Daniela Smaniotto c, Giuseppe D’Agostino c, Alessio Morganti c, Giovanni Scambia b,* a Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy c Division of Radiotherapy, Catholic University of the Sacred Heart, Rome, Italy
b
Available online 8 September 2005
Abstract Objective. To demonstrate the efficacy and feasibility of preoperative chemoradiotherapy in a consecutive series of 100 locally advanced cervical cancer (LACC) patients. Methods. Between October 1997 and December 2004, 100 LACC patients were consecutively staged and treated at the Catholic University of the Sacred Heart of Rome. Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-FU (1000 mg/m2) (both on days 1 – 4 and 27 – 30). Radical surgery was performed 5 – 6 weeks after the end of the treatment. Results. A clinical complete or partial response was observed in 96 patients (56 and 40, respectively). Radical surgery was performed in 95 patients and an overall complication rate of 12.6% was observed in the early postoperative time. At pathological examination, 43 of 95 patients (45.2%) undergoing radical surgery showed complete response to treatment, 28 patients (29.5%) only had a microscopic disease, 18 patients (19%) had a partial response and 6 (6.3%) had no change of disease. With a median follow-up time of 25 months, the 5-year diseasefree survival was 76% and the 5-year overall survival was 78%. Conclusions. These data confirm the possibility of achieving encouraging rates of local control and OS in LACC patients submitted to chemoradiation plus surgery, with a low rate of toxicity and complications. D 2005 Elsevier Inc. All rights reserved. Keywords: Locally advanced cervical cancer; Preoperative chemoradiation; Radical surgery; Complications
Introduction In the last few years, 5 out of 6 recent clinical trials produced by the American Scientific Society have demonstrated an advantage in terms of disease-free (DFS) and overall survival (OS) for 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 experiences from Europe and South America have shown comparable results
* Corresponding author. Fax: +39 06 35508736. E-mail address: [email protected] (G. Scambia).
using neoadjuvant chemotherapy followed by radical surgery in the same group of cases [7– 9]. Finally, in spite of the enormous energies involved in all these studies, results are still unsatisfactory, with an OS rate for LACC patients corresponding to 53% [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, schedule and doses), the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery, has been previously 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
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.07.074
YGYNO-971123; No. of pages: 5; 4C:
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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 [13,14]. In the present study, we report the long-term follow-up and complications of preoperative chemoradiation in larger single-institutional series of LACC cases.
Patients and methods This study includes 100 consecutive LACC patients accrued between October 1997 and December 2004 at the Division of Gynecologic Oncology of the Catholic University of Rome. Inclusion criteria were the following: biopsy-proven squamous cell carcinoma of the cervix (stage IB2– IIIB); no evidence of disease outside the pelvis; age < 75 years; Eastern Cooperative Oncology Group performance status < 2; adequate bone-marrow function (WBC > 3000, platelets > 120,000/mm3); adequate renal function (blood urea nitrogen < 25 mg/dl, creatinine < 1.5 mg/dl); normal liver function (bilirubin < 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 MRI, cystoscopy and proctoscopy if there was a clinical suspicion of invasion, complete blood count and measurement of liver and renal function. Neoadjuvant chemoradiotherapy was performed as previously described [13]. Briefly, external radiotherapy was administered to the whole pelvic region in 22 fractions (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2, 2-h intravenous infusion) and 5-FU (1000 mg/m2, 24-h continuous intravenous infusion) (both on days 1 –4 and 27 – 30). 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. [15] and pelvic T 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 [16]. Patients were assessed weekly for acute toxicity during treatment. Operative complications were defined as bowel, bladder, ureteral, vascular injuries and estimated blood loss exceeding 500 ml. Postoperative
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complications were defined as any adverse event occurring within 30 days from surgery, and considered severe if they resulted in unplanned admission or a secondary surgical procedure. 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-nine percent of patients were followed for at least 1 year. The median follow-up time was 25 months (range 4– 110 months). Objective tumor response was assessed according to the World Health Organization (WHO) score. 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. 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 [17] and the log-rank test was used to assess the statistical significance.
Results Patient characteristics are shown in Table 1. Chemoradiotherapy-related toxicity was evaluated in all patients. Eleven patients required a brief interruption of treatment due to acute toxicity (n = 7) or a thrombotic event (n = 4). Five patients required a reduction in the chemotherapy dosage (50% of the prescribed dose) in the last week of radiotherapy due to hematological toxicity. Overall, 18 patients Table 1 Clinico-pathological characteristics of the patients Characteristics Number of patients Mean age (range) FIGO Stage IB2 IIB IIIA IIIB Tumor volume (cm) <4 4 Node status (MRI) Negative Positive Grade G1 – 2 G3 n.a.
100 52 (25 – 75) 3 73 7 17 27 73 64 36 31 44 25
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experienced grade 3– 4 toxicity. In particular, grade 3 or 4 hematological toxicity was observed in 15 patients (leukopenia) and 3 patients (thrombocytopenia). Six patients developed grade 3 gastrointestinal toxicity. Complete and partial clinical response was observed in 56 and 40 patients, respectively, whereas 2 patients showed stable disease. No patient developed progression of disease during the treatment (2 cases died after chemoradiation as a result of causes unrelated to the treatment) (Table 2). Ninety-five of 98 (96.9%) treated cases were submitted to radical surgery, since 3 patients refused surgery. Type I– II radical hysterectomy was performed in 17 (17.9%) patients, whereas 51 (53.7%) and 27 (28.4%) cases underwent type III and type IV – V radical hysterectomy, respectively. Pelvic lymphadenectomy was performed in all patients, with a median number of lymph nodes removed of 33 (range 6 – 73). Thirty-two (33.6%) patients with positive pelvic nodes were submitted to systematic aortic lymphadenectomy upper to the level of the inferior mesenteric artery (median nodes removed 11, range 2– 45). Median operating time was 225 min (range 120– 500) and median blood loss was 500 cm3 (range 100 – 1500). Thirty-five of 95 (36.8%) patients experienced an estimated blood loss exceeding 500 ml during surgery and were transfused (12 autologous and 23 homologous transfusions). Intra- and postoperative complications have been evaluated in all patients submitted to surgery. There were 6 intraoperative complications (6.3%) including 3 bladder, 2 ureteral and 1 vascular injuries, which were all managed during surgery with no major intervention. The postoperative febrile morbidity rate (>38-C for 2 days) was 13%. The median time of recovery was 6.2 days (range 4– 18). In the early postoperative period (<30 days), 12 (12.6%) major complications were observed: 1 patient died of renal failure, 2 patients showed bilateral hydroureteronephrosis requiring nephrostomy, 1 developed bowel obstruction requiring intestinal resection, 2 experienced wound dehiscence which required re-intervention. One deep venous thrombosis (DVT), 1 pelvic abscess, 1 vesico-vaginal fistula, 1 pulmonary edema and 2 bowel subocclusions were managed by hospitalization without surgical interven-
Fig. 1. Disease-free and overall survival curves in LACC patients submitted to preoperative chemoradiotherapy.
tion. Moreover, 3 symptomatic lymphocysts and 1 lower limb paraesthesia were observed and classified as mild complications. As far as long-term complications (>30 days) are concerned, 4 ureteral stenosis with renal failure and 1 bowel obstruction after 60 months from surgery were found. Pathological response was assessed in all patients submitted to surgery. Forty-three of 95 patients (45.2%) showed a complete response to treatment and 28 cases (29.5%) showed a microscopic residual disease. Eighteen cases (19%) had a partial response and 6 patients (6.3%) had no change in their disease (Table 2). Relapse of disease was observed in 17 (17.9%) patients, which were distributed as follows: 10 central pelvic, 3 lymph nodal (1 common iliac and 2 aortic), 3 abdominal and 1 lung metastases. The median time to relapse was 7 months (range 2– 100), with the majority of cases (12 out of 17, 70.6%) recurring within 1 year from the completion of the treatment. The 5-year DFS and 5-year OS were 76% and 78%, respectively (Fig. 1). Patients with pathologic complete response and microscopic residual disease showed a statistically significant longer DFS ( P = 0.003) and OS ( P = 0.0012) than patients with partial response or no change in disease (Fig. 2).
Table 2 Clinical and pathological response to treatment in LACC patients n (%) Clinical response All Complete Partial No change
98 56 (57.2) 40 (40.8) 2 (2.0)
Pathological response All Complete Microscopic Partial No change
95 43 28 18 6
(45.2%) (29.5%) (19.0%) (6.3%)
Fig. 2. Disease-free survival curves according to pathological response in LACC patients submitted to preoperative chemoradiotherapy.
M. Distefano et al. / Gynecologic Oncology 99 (2005) S166 – S170
Discussion This study shows long-term results of preoperative chemoradiation followed by surgery in a large prospective single-institutional series of LACC patients. Although caution has to be taken in interpreting these data given the series size, they suggest that the use of a three-modality treatment can achieve OS and DFS rates comparable to exclusive chemoradiation [1 – 6]. Moreover, we demonstrated a very high rate of pathological complete responses or persistence of only microscopic disease, suggesting that the local control achieved with this scheme is very high. In fact, patients with complete pathological response showed a longer DFS with respect to cases with partial response. Finally, the possibility of assessing the pathological response to this treatment can allow the identification of patients with a higher risk of recurrence to be submitted to adjuvant therapy. The major concern about this treatment could be the high-grade/rate toxicity related to surgery after chemoradiation. Although few studies have reported serious postoperative complications in this group of patients [11,12], we failed to find the same situation. The overall rate of complications in our series was 17.9% including severe short- and long-term morbidity, which significantly differs from those previously described by Resbeut et al. [11] and Jurado et al. [12] probably because of the use of brachytherapy or intraoperative radiotherapy in their series. In addition, the complication rate we reported seems quite acceptable considering that, although it refers to patients submitted to a three-modality approach, it is of the same magnitude of those reported for radical hysterectomies in untreated patients [18]. 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 [19,20], 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]. In conclusion, we confirmed in a larger series our preliminary data on the efficacy of this multimodal approach in the treatment of LACC. The observation of a low rate of intra- and postoperative complications compared to our previous series [13], could be explained by the application of a tailored surgery in selected patients. A larger number of cases and a longer follow-up time will allow us to define advanced cervical carcinoma standards of care where significant attention is given not only to maximizing the potential for control, but also to improving the quality of
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life. For instance, considerations should be given to the evaluation of the impact of different treatment-modalities on sexual relationship impairment, rectal and bladder dysfunctions in long-term cervical cancer survivors.
References [1] Keys HM, Bundy B, Stehamn FB, Muderspach LI, Chafe WE, Suggs CL, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;15:1154 – 61. [2] Morris M, Eifel PJ, Lu J, Grigsby PW, Levenbach C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high risk cervical cancer. N Engl J Med 1999;15:1137 – 43. [3] Whitney CW, Sause W, Bundt BN, Malfetano JH, Hannigan EV, Fowler WC, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB – IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group Study. J Clin Oncol 1999;17:1339 – 48. [4] Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;15:1144 – 53. [5] Peters WA, Liu PY, Barrett RJ, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18: 1606 – 14. [6] Pearcy R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966 – 72. [7] Benedetti Panici P, Greggi S, Colombo A, Amoroso M, Smaniotto D, Giannarelli D, et al. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian Multicenter Randomized study. J Clin Oncol 2001;20:179 – 88. [8] Neoadjuvant Chemotherapy For Cervical Cancer Meta-Analysis Collaboration. Neoadjuvant chemotherapy for locally advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomized trials. Eur J Cancer 2003;39:2470 – 86. [9] Sardi JE, Boixadera MA, Sardi JJ. Neoadjuvant chemotherapy in cervical cancer: a new trend. Curr Opin Obstet Gynecol 2005;17:43 – 7. [10] Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics. CA Cancer J Clin 2005;55:10 – 30. [11] Resbeut M, Cowen D, Viens P, Noirclerc m, Perez T, Gouvernet J, et al. Concomitant chemoradiation prior to surgery in the treatment of advanced cervical carcinoma. Gynecol Oncol 1994;54:68 – 75. [12] Jurado M, Martinez-Monge R, Garcia-Foncillas J, Azinovic I, Aristu J, Lopez-garcia G, et al. Pilot study of concurrent cisplatin, 5fluorouracil, and external beam radiotherapy prior to radiotherapy in locally advanced cervical cancer. Gynecol Oncol 1999:30 – 7. [13] Mancuso S, Smaniotto D, Benedetti Panici P, Favale B, Greggi S, Manfredi R, et al. Phase I – II trial of preoperative chemoradiation in locally advanced cervical carcinoma. Gynecol Oncol 2000;78:324 – 8. [14] Distefano M, Ferrandina G, Smaniotto D, Margariti AP, Zannoni G, Macchia G, et al. Concomitant radiochemotherapy plus surgery in locally advanced cervical cancer: update of clinical outcome and cyclooxygenase-2 as predictor of treatment susceptibility. Oncology 2004;67:103 – 11. [15] Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974;44: 265 – 72.
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[16] Perez CA, Brady LW. Overview. In: Perez CA, Brady LW, editors. Principles and practices of radiation oncology. 5th ed. Philadelphia’ Lippincott; 1992. p. 1 – 63. [17] Kaplan FL, Meier P. Non parametric estimation from incomplete observations. Am J Stat Assoc 1958;53:457 – 81. [18] Trimbos JB, Franchi M, Zanaboni F, Velden Jvd, Vergote I. State of the art of radical hysterectomy; current practice in European oncology centres. Eur J Oncol 2004;40:375 – 8.
[19] Scambia G, Ferrandina G, Distefano M, Fagotti A, Manfredi R, Zannoni GF, et al. Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients? Gynecol Oncol 2001;83: 319 – 24. [20] Fanfani F, Ludovisi M, Zannoni GF, Distefano M, Fagotti A, Ceccaroni M, et al. Frozen section examination of pelvic lymph nodes in endometrial and cervical cancer: accuracy in patients submitted to neoadjuvant treatments. Gynecol Oncol 2004;94:779 – 84.
Original Research Report
Preoperative chemoradiotherapy in locally advanced cervical cancer: Long-term outcome and complications Mariagrazia Distefano a, Anna Fagotti b, Gabriella Ferrandina a, Fanfani Francesco b, Daniela Smaniotto c, Giuseppe D’Agostino c, Alessio Morganti c, Giovanni Scambia b,* a Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy c Division of Radiotherapy, Catholic University of the Sacred Heart, Rome, Italy
b
Available online 8 September 2005
Abstract Objective. To demonstrate the efficacy and feasibility of preoperative chemoradiotherapy in a consecutive series of 100 locally advanced cervical cancer (LACC) patients. Methods. Between October 1997 and December 2004, 100 LACC patients were consecutively staged and treated at the Catholic University of the Sacred Heart of Rome. Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-FU (1000 mg/m2) (both on days 1 – 4 and 27 – 30). Radical surgery was performed 5 – 6 weeks after the end of the treatment. Results. A clinical complete or partial response was observed in 96 patients (56 and 40, respectively). Radical surgery was performed in 95 patients and an overall complication rate of 12.6% was observed in the early postoperative time. At pathological examination, 43 of 95 patients (45.2%) undergoing radical surgery showed complete response to treatment, 28 patients (29.5%) only had a microscopic disease, 18 patients (19%) had a partial response and 6 (6.3%) had no change of disease. With a median follow-up time of 25 months, the 5-year diseasefree survival was 76% and the 5-year overall survival was 78%. Conclusions. These data confirm the possibility of achieving encouraging rates of local control and OS in LACC patients submitted to chemoradiation plus surgery, with a low rate of toxicity and complications. D 2005 Elsevier Inc. All rights reserved. Keywords: Locally advanced cervical cancer; Preoperative chemoradiation; Radical surgery; Complications
Introduction In the last few years, 5 out of 6 recent clinical trials produced by the American Scientific Society have demonstrated an advantage in terms of disease-free (DFS) and overall survival (OS) for 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 experiences from Europe and South America have shown comparable results
* Corresponding author. Fax: +39 06 35508736. E-mail address: [email protected] (G. Scambia).
using neoadjuvant chemotherapy followed by radical surgery in the same group of cases [7– 9]. Finally, in spite of the enormous energies involved in all these studies, results are still unsatisfactory, with an OS rate for LACC patients corresponding to 53% [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, schedule and doses), the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery, has been previously 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
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.07.074
YGYNO-971123; No. of pages: 5; 4C:
M. Distefano et al. / Gynecologic Oncology 99 (2005) S166 – S170
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 [13,14]. In the present study, we report the long-term follow-up and complications of preoperative chemoradiation in larger single-institutional series of LACC cases.
Patients and methods This study includes 100 consecutive LACC patients accrued between October 1997 and December 2004 at the Division of Gynecologic Oncology of the Catholic University of Rome. Inclusion criteria were the following: biopsy-proven squamous cell carcinoma of the cervix (stage IB2– IIIB); no evidence of disease outside the pelvis; age < 75 years; Eastern Cooperative Oncology Group performance status < 2; adequate bone-marrow function (WBC > 3000, platelets > 120,000/mm3); adequate renal function (blood urea nitrogen < 25 mg/dl, creatinine < 1.5 mg/dl); normal liver function (bilirubin < 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 MRI, cystoscopy and proctoscopy if there was a clinical suspicion of invasion, complete blood count and measurement of liver and renal function. Neoadjuvant chemoradiotherapy was performed as previously described [13]. Briefly, external radiotherapy was administered to the whole pelvic region in 22 fractions (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2, 2-h intravenous infusion) and 5-FU (1000 mg/m2, 24-h continuous intravenous infusion) (both on days 1 –4 and 27 – 30). 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. [15] and pelvic T 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 [16]. Patients were assessed weekly for acute toxicity during treatment. Operative complications were defined as bowel, bladder, ureteral, vascular injuries and estimated blood loss exceeding 500 ml. Postoperative
S167
complications were defined as any adverse event occurring within 30 days from surgery, and considered severe if they resulted in unplanned admission or a secondary surgical procedure. 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-nine percent of patients were followed for at least 1 year. The median follow-up time was 25 months (range 4– 110 months). Objective tumor response was assessed according to the World Health Organization (WHO) score. 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. 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 [17] and the log-rank test was used to assess the statistical significance.
Results Patient characteristics are shown in Table 1. Chemoradiotherapy-related toxicity was evaluated in all patients. Eleven patients required a brief interruption of treatment due to acute toxicity (n = 7) or a thrombotic event (n = 4). Five patients required a reduction in the chemotherapy dosage (50% of the prescribed dose) in the last week of radiotherapy due to hematological toxicity. Overall, 18 patients Table 1 Clinico-pathological characteristics of the patients Characteristics Number of patients Mean age (range) FIGO Stage IB2 IIB IIIA IIIB Tumor volume (cm) <4 4 Node status (MRI) Negative Positive Grade G1 – 2 G3 n.a.
100 52 (25 – 75) 3 73 7 17 27 73 64 36 31 44 25
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experienced grade 3– 4 toxicity. In particular, grade 3 or 4 hematological toxicity was observed in 15 patients (leukopenia) and 3 patients (thrombocytopenia). Six patients developed grade 3 gastrointestinal toxicity. Complete and partial clinical response was observed in 56 and 40 patients, respectively, whereas 2 patients showed stable disease. No patient developed progression of disease during the treatment (2 cases died after chemoradiation as a result of causes unrelated to the treatment) (Table 2). Ninety-five of 98 (96.9%) treated cases were submitted to radical surgery, since 3 patients refused surgery. Type I– II radical hysterectomy was performed in 17 (17.9%) patients, whereas 51 (53.7%) and 27 (28.4%) cases underwent type III and type IV – V radical hysterectomy, respectively. Pelvic lymphadenectomy was performed in all patients, with a median number of lymph nodes removed of 33 (range 6 – 73). Thirty-two (33.6%) patients with positive pelvic nodes were submitted to systematic aortic lymphadenectomy upper to the level of the inferior mesenteric artery (median nodes removed 11, range 2– 45). Median operating time was 225 min (range 120– 500) and median blood loss was 500 cm3 (range 100 – 1500). Thirty-five of 95 (36.8%) patients experienced an estimated blood loss exceeding 500 ml during surgery and were transfused (12 autologous and 23 homologous transfusions). Intra- and postoperative complications have been evaluated in all patients submitted to surgery. There were 6 intraoperative complications (6.3%) including 3 bladder, 2 ureteral and 1 vascular injuries, which were all managed during surgery with no major intervention. The postoperative febrile morbidity rate (>38-C for 2 days) was 13%. The median time of recovery was 6.2 days (range 4– 18). In the early postoperative period (<30 days), 12 (12.6%) major complications were observed: 1 patient died of renal failure, 2 patients showed bilateral hydroureteronephrosis requiring nephrostomy, 1 developed bowel obstruction requiring intestinal resection, 2 experienced wound dehiscence which required re-intervention. One deep venous thrombosis (DVT), 1 pelvic abscess, 1 vesico-vaginal fistula, 1 pulmonary edema and 2 bowel subocclusions were managed by hospitalization without surgical interven-
Fig. 1. Disease-free and overall survival curves in LACC patients submitted to preoperative chemoradiotherapy.
tion. Moreover, 3 symptomatic lymphocysts and 1 lower limb paraesthesia were observed and classified as mild complications. As far as long-term complications (>30 days) are concerned, 4 ureteral stenosis with renal failure and 1 bowel obstruction after 60 months from surgery were found. Pathological response was assessed in all patients submitted to surgery. Forty-three of 95 patients (45.2%) showed a complete response to treatment and 28 cases (29.5%) showed a microscopic residual disease. Eighteen cases (19%) had a partial response and 6 patients (6.3%) had no change in their disease (Table 2). Relapse of disease was observed in 17 (17.9%) patients, which were distributed as follows: 10 central pelvic, 3 lymph nodal (1 common iliac and 2 aortic), 3 abdominal and 1 lung metastases. The median time to relapse was 7 months (range 2– 100), with the majority of cases (12 out of 17, 70.6%) recurring within 1 year from the completion of the treatment. The 5-year DFS and 5-year OS were 76% and 78%, respectively (Fig. 1). Patients with pathologic complete response and microscopic residual disease showed a statistically significant longer DFS ( P = 0.003) and OS ( P = 0.0012) than patients with partial response or no change in disease (Fig. 2).
Table 2 Clinical and pathological response to treatment in LACC patients n (%) Clinical response All Complete Partial No change
98 56 (57.2) 40 (40.8) 2 (2.0)
Pathological response All Complete Microscopic Partial No change
95 43 28 18 6
(45.2%) (29.5%) (19.0%) (6.3%)
Fig. 2. Disease-free survival curves according to pathological response in LACC patients submitted to preoperative chemoradiotherapy.
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Discussion This study shows long-term results of preoperative chemoradiation followed by surgery in a large prospective single-institutional series of LACC patients. Although caution has to be taken in interpreting these data given the series size, they suggest that the use of a three-modality treatment can achieve OS and DFS rates comparable to exclusive chemoradiation [1 – 6]. Moreover, we demonstrated a very high rate of pathological complete responses or persistence of only microscopic disease, suggesting that the local control achieved with this scheme is very high. In fact, patients with complete pathological response showed a longer DFS with respect to cases with partial response. Finally, the possibility of assessing the pathological response to this treatment can allow the identification of patients with a higher risk of recurrence to be submitted to adjuvant therapy. The major concern about this treatment could be the high-grade/rate toxicity related to surgery after chemoradiation. Although few studies have reported serious postoperative complications in this group of patients [11,12], we failed to find the same situation. The overall rate of complications in our series was 17.9% including severe short- and long-term morbidity, which significantly differs from those previously described by Resbeut et al. [11] and Jurado et al. [12] probably because of the use of brachytherapy or intraoperative radiotherapy in their series. In addition, the complication rate we reported seems quite acceptable considering that, although it refers to patients submitted to a three-modality approach, it is of the same magnitude of those reported for radical hysterectomies in untreated patients [18]. 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 [19,20], 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]. In conclusion, we confirmed in a larger series our preliminary data on the efficacy of this multimodal approach in the treatment of LACC. The observation of a low rate of intra- and postoperative complications compared to our previous series [13], could be explained by the application of a tailored surgery in selected patients. A larger number of cases and a longer follow-up time will allow us to define advanced cervical carcinoma standards of care where significant attention is given not only to maximizing the potential for control, but also to improving the quality of
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life. For instance, considerations should be given to the evaluation of the impact of different treatment-modalities on sexual relationship impairment, rectal and bladder dysfunctions in long-term cervical cancer survivors.
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