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Review Article

Editor's Choice - Free Access

Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer

Mallmann P.a · Mallmann C.b

Author affiliations

aKlinik und Poliklinik für Frauenheilkunde und Geburtshilfe Köln, Universitätsklinikum Köln (AöR), Cologne, Germany; bDepartment of General, Visceral and Vascular Surgery, Charité - University Medicine, Campus Benjamin Franklin, Berlin, Germany

Corresponding Author

Prof. Dr. med. Peter Mallmann

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Köln

Universitätsklinikum Köln (AöR)

Kerpener Str. 34, 50931 Köln, Germany

Peter.Mallmann@uk-koeln.de

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Abstract

Neoadjuvant chemotherapy is indicated in patients who can tolerate the side effects of a chemotherapy and with preoperative presentation of one of the following clinical risk situations: bulky disease with a maximal tumor diameter of > 4 cm, suspicious lymph nodes in magnetic resonance imaging (MRI), computed tomography (CT) scan or endosonography, histopathologically confirmed lymph node metastasis, or histopathologically documented risk factors such as G3 and L1V1. A neoadjuvant chemotherapy followed by surgery should be performed with cisplatin at a dosage of > 25 mg/m2 per week and an application interval of < 14 days. The previously published data suggests an improved rate of complete resection and reduced incidences of positive lymph nodes and parametric infiltration. Accordingly, the percentage of patients in need for adjuvant radiochemotherapy after operation can be significantly reduced. Some studies demonstrated a prolongation of progression-free and overall survival. Following the previously published studies, adjuvant chemotherapy after operation or after radiochemotherapy has no significant effect on the overall survival and, following the current guidelines, should be avoided.

© 2016 S. Karger GmbH, Freiburg


Considering the current German S3 guideline ‘Diagnostics, therapy and follow-up of cervical cancer' [1], primary surgical therapy of cervical cancer should be performed only in those patients without preoperative indication for adjuvant radiochemotherapy.

Evaluation of adjuvant chemotherapy should be performed if

- bulky disease with large tumor diameter greater than 4 cm,

- histopathological risk factors for locoregional failure such as deep stromal invasion, the presence of tumor cells in the capillary lymphatic (L1) or vascular spaces (V1), or G3 grading or

- lymph node metastases

are detected.

A Gynecologic Oncology Group (GOG) study of 575 women estimated that such risk factors exist in 25% of all stage Ib cancers and that these factors increase the risk of recurrence from 2% to 31% at 3 years [2]. In this clinical situation, a primary radiochemotherapy should be performed as standard of care. Alternatively, neoadjuvant chemotherapy, followed secondarily by an operation or radiotherapy, can be evaluated.

In a Cochrane analysis from 2012 [3], neoadjuvant chemotherapy utilizing cisplatin at a dosage greater than 25 mg/m2 per week with application intervals of less than 14 days, followed by surgery, may lead to an expansion of the progression-free survival (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.61-0.93; P = 0.008) and a prolongation of the overall survival (HR 0.77, 95% CI 0.62-0.96; P = 0.02) [3]. Using a random-effects model, no significant effect on the clinical course of disease could be detected (overall response (OR) 0.6, 0.95% CI 0.32-1.12; P = 0.11). However, the clinical value of these findings is limited by the low quality of all of these studies. Different chemotherapy protocols and a great heterogeneity of the patients led the authors to the conclusion that neoadjuvant chemotherapy should not be performed outside of clinical studies. Up to now there is no data of prospective randomized controlled studies available comparing neoadjuvant chemotherapy plus surgery versus primary radiochemotherapy or neoadjuvant chemotherapy plus radiochemotherapy versus radiochemotherapy alone.

Another meta-analysis from 2013 [4] was not able to detect a significant effect on either progression-free survival or overall survival in patients with cervical cancer stages IB1-IIA undergoing a neoadjuvant chemotherapy.

Summarizing all previously mentioned published data on patients undergoing a neoadjuvant chemotherapy, the rate of complete resection was improved (OR 1.55, 95% CI 0.96-2.50; P = 0.07) [4]; the incidence of positive lymph nodes could be reduced (OR 0.54, 95% CI 0.40-0.73; P < 0.0001), as could the rate of patients with parametric infiltration (OR 0.58, 95% CI 0.41-0.82; P = 0.002) and the probability of distant metastasis (OR 0.72, 95% CI 0.45-1.14; P = 0.16) [4]. In accordance with this data, by using a neoadjuvant chemotherapy, the percentage of patients in need for adjuvant radiochemotherapy could be significantly lowered (OR 0.57, 95% CI 0.33-0.98) [4].

Based on these findings, neoadjuvant radiochemotherapy should be discussed for all patients who can tolerate the side effects of chemotherapy and for whom the following clinical risk situation can be demonstrated preoperatively:

- bulky disease with a maximal tumor diameter measured by vaginal ultrasound or MRI greater than 4 cm,

- histopathologically documented risk factors like G3, L1, V1, and/or

- suspicious lymph nodes in CT or MRI or histopathologically confirmed lymph node metastasis.

In case of neoadjuvant therapy, patients have to be informed about possible risks and side effects of a dose-intensified platinum-based chemotherapy, such as nephrotoxicity, ototoxicity, and hematological side effects. Especially in younger patients, the alternative regimen of neoadjuvant chemotherapy instead of primary radiochemotherapy should be offered. They have to be informed that the neoadjuvant chemotherapy may improve the operability and may reduce the necessity of an adjuvant radiochemotherapy, but also that no significant effects on the progression-free and overall survival have so far been demonstrated.

Two ongoing phase III trials (European Organisation for Research and Treatment of Cancer (EORTC) 55994) [5] will hopefully delineate the impact of neoadjuvant chemotherapy followed by operation versus radiochemotherapy in women with high-risk cervical cancer.

In patients undergoing neoadjuvant chemotherapy, the remission of the tumor must be documented by vaginal ultrasound or MRI. It remains unclear which type of radical surgical procedure should be used in the context of the subsequent operation. Usually, a Piver III radical hysterectomy should be performed.

A previously published study of the GOG demonstrated an improvement of the overall survival of 3.7 months by adding bevacizumab to conventional platinum-based chemotherapy compared to conventional chemotherapy (cisplatin with paclitaxel and cisplatin with topotecan), in patients with advanced, recurrent, persistent and metastatic stages of cervical cancer [6]. This GOG 240 trial showed a statistically relevant improvement of the tumor response rates for those women randomized into the chemotherapy/bevacizumab arm compared to the approved chemotherapy with paclitaxel or topotecan. In 2014, Schefter et al. [7] assessed the efficacy of bevacizumab (10 mg/kg, q14) in combination with platinum-based radiochemotherapy in untreated patients with locally advanced cervical carcinoma. Findings of this trial presented a 3-year overall survival, disease-free survival, and locoregional failure (LRF) of 81.3% (95% CI 67.2-89.8%), 68.7% (95% CI 53.5-79.8%), and 23.2% (95% CI 11-35.4%), respectively [7]. Following these data, it seems that patients with high-risk cervical cancer may profit from addition of bevacizumab to conventional neoadjuvant chemotherapy. This positive effect of an anti-angiogenetic therapy in cervical cancer is based on the fact that angiogenesis in cervical cancer is directly related to a human papillomavirus (HPV)-associated inhibition of p53, which increases the expression of the vascular endothelial growth factor (VEGF) [8].

Adjuvant Chemotherapy

It is well documented that an adjuvant radiochemotherapy after radical surgery significantly reduces the risk of recurrence and prolongs the progression-free survival in women with stage Ib cervical cancer with the aforementioned histopathological high-risk factors. Up to now, no significant effect on the overall survival in patients undergoing adjuvant radio(chemo)therapy after operation could be documented. Several studies examined the effect of an adjuvant chemotherapy after operation or after radio(chemo)therapy [9]. However, due to the great heterogeneity of these studies and the small number of patients, the clinical value of adjuvant chemotherapy has not been definitively estimated. In any case, following the previously published studies, an adjuvant chemotherapy after operation or radio(chemo)therapy has no significant effect on the overall survival and, following the current guidelines, should be avoided.

Disclosure Statement

The authors declare no conflicts of interest.


References

  1. Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, Deutsche Krebsgesellschaft, Arbeitsgemeinschaft für gynäkologische Onkologie: S3-Leitlinie ‘Diagnostik, Therapie und Nachsorge der Patientin mit Zervixkarzinom'. www.awmf.org/uploads/tx_szleitlinien/032-033OLl_S3_Zervixkarzinom_2014-10.pdf, 2014 [last accessed July 12, 2016].
  2. Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352-357.
  3. Rydzewska L, Tierney J, Vale CL, Symonds PR: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev 2012; (12):CD007406.
  4. Kim HS, Sardi JE, Katsumata N, Ryu HS, Nam JH, Chung HH, Park NH, Song YS, Behtash N, Kamura T, Cai HB, Kim JW: Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis. Eur J Surg Oncol 2013;39:115-124.
  5. European Organisation for Research and Treatment of Cancer (EORTC): Chemotherapy followed by surgery vs radiotherapy plus chemotherapy in patients with stage IB or II cervical cancer. ClinicalTrials.gov, Bethesda, National Library of Medicine, 2000. http://clinicaltrials.gov/show/NCT00039338 [last accessed May 16, 2016].
  6. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-743.
  7. Schefter T, Winter K, Kwon JS, Stuhr K, Balaraj K, Yaremko BP, Small W Jr, Sause W, Gaffney D; Radiation Therapy Oncology Group (RTOG): RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys 2014;88:101-105.
  8. Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, Benedetti Panici P, Tomao S: Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther 2014;7:2237-2248.
  9. Tzioras S, Pavlidis N, Paraskevaidis E, Ioannidis JP: Effects of different chemotherapy regimens on survival for advanced cervical cancer: systematic review and meta-analysis. Cancer Treat Rev 2007;33:24-38.

Author Contacts

Prof. Dr. med. Peter Mallmann

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Köln

Universitätsklinikum Köln (AöR)

Kerpener Str. 34, 50931 Köln, Germany

Peter.Mallmann@uk-koeln.de


Article / Publication Details

First-Page Preview
Abstract of Review Article

Received: June 21, 2016
Accepted: August 11, 2016
Published online: August 23, 2016
Issue release date: September 2016

Number of Print Pages: 3
Number of Figures: 0
Number of Tables: 0

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: http://www.karger.com/ORT


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References

  1. Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, Deutsche Krebsgesellschaft, Arbeitsgemeinschaft für gynäkologische Onkologie: S3-Leitlinie ‘Diagnostik, Therapie und Nachsorge der Patientin mit Zervixkarzinom'. www.awmf.org/uploads/tx_szleitlinien/032-033OLl_S3_Zervixkarzinom_2014-10.pdf, 2014 [last accessed July 12, 2016].
  2. Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352-357.
  3. Rydzewska L, Tierney J, Vale CL, Symonds PR: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev 2012; (12):CD007406.
  4. Kim HS, Sardi JE, Katsumata N, Ryu HS, Nam JH, Chung HH, Park NH, Song YS, Behtash N, Kamura T, Cai HB, Kim JW: Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis. Eur J Surg Oncol 2013;39:115-124.
  5. European Organisation for Research and Treatment of Cancer (EORTC): Chemotherapy followed by surgery vs radiotherapy plus chemotherapy in patients with stage IB or II cervical cancer. ClinicalTrials.gov, Bethesda, National Library of Medicine, 2000. http://clinicaltrials.gov/show/NCT00039338 [last accessed May 16, 2016].
  6. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-743.
  7. Schefter T, Winter K, Kwon JS, Stuhr K, Balaraj K, Yaremko BP, Small W Jr, Sause W, Gaffney D; Radiation Therapy Oncology Group (RTOG): RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys 2014;88:101-105.
  8. Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, Benedetti Panici P, Tomao S: Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther 2014;7:2237-2248.
  9. Tzioras S, Pavlidis N, Paraskevaidis E, Ioannidis JP: Effects of different chemotherapy regimens on survival for advanced cervical cancer: systematic review and meta-analysis. Cancer Treat Rev 2007;33:24-38.
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