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TMMR (Total Mesometrial Resection) Register Study (TMMR-RS)

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ClinicalTrials.gov Identifier: NCT01819077
Recruitment Status : Unknown
Verified May 2015 by Dr. Paul Buderath, University Hospital, Essen.
Recruitment status was:  Recruiting
First Posted : March 27, 2013
Last Update Posted : May 27, 2015
Sponsor:
Information provided by (Responsible Party):
Dr. Paul Buderath, University Hospital, Essen

Brief Summary:

TMMR/tLNE was shown to result in very low locoregional recurrence rates and low morbidity in surgical treatment of cervical cancer stage IB-IIA without any adjuvant radiotherapy even in high risk situations. More and more this therapeutic strategy is implemented in clinical routine in specialized cancer centres, thus, treatment of cervical cancer could be performed for these stages in a systematically defined and reproducible radicality; adjuvant radiotherapy could be spared for recurrent disease, thus lowering morbidity and resource assignment in primary treatment dramatically. Due to the nerve-sparing character of the procedure bladder, bowel and sexual dysfunction would also be minimized and markedly benefit the patient.

This study is designed to follow up the results of this therapeutic concept adapted to clinical routine in a multiinstitutional register study accompanied by detailed assessment of pathological work-up, quality of life and bladder and sexual function following surgery.


Condition or disease Intervention/treatment
Cervical Cancer Procedure: TMMR

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Detailed Description:

Rationale for the multimodal treatment of cervical cancer in FIGO stages IB-IIA according to M. Hoeckel: Total mesometrial resection (TMMR) is a newly developed procedure for surgical treatment of cervical cancer of FIGO stage IB to IIB. The procedure is based on embryologically determined surgical anatomy that was generated from investigations of the embryonal and fetal development of the Müllerian organ system and of local tumor spread of cervical cancer at the macroscopic, microscopic and molecular level (11-13). The observation that the cervical cancer follows the embryologically derived compartment hierarchy led to the definition of a new principle of radicality for oncological surgery, i.e., the resection of a tumor within the borders of the compartment representing the morphogenetic unit of the tumor origin. A resection that follows this principle leads to high local control (>95%) without additional radiotherapy. The resection line of the vagina is located inside the compartment, therefore intraoperative frozen section examination of the TMMR specimen is necessary to achieve wide margins. Adjacent structures that belong to another morphogenetic unit can be saved in spite of immediate proximity to the tumor. The autonomic nerves are saved with the TMMR concept as well as the ureters, the urinary bladder and their mesenteries containing all blood vessels, and the rectum with the mesorectum.

Therapeutic LNE: With TMMR tLNE has to be done with therapeutic intent, so that in case of lymph node metastases a high regional tumor control without adjuvant radiotherapy can be achieved (27). Therapeutic pelvic tLNE needs the removal of the lymph node groups within the scope of the classical systematic pelvic LNE and additionally, the paravisceral fatty tissue inferior to the obturator nerve, perispinal, gluteal and presacral lymph nodes to S2. The therapeutic pelvic LNE is done with exposition and protection of the plexus hypogastricus superior, the nervus hypogastricus and the plexus hypogastricus inferior and all ureter supplying vessels, bilaterally. In case of intraoperative evidence of pelvic lymph node metastases in first line nodes stepwise ascending therapeutic para-aortic LND with protection of the plexus hypogastricus superior and the nervi splanchnici lumbales has to be done. To date no prospective, randomized trial has proven a survival benefit of adjuvant chemotherapy alone in patients with early cervical cancer and histopathological risk factors. However, retrospective studies and the results of Peters et al. (20), comparing adjuvant chemo-radiotherapy with radiotherapy alone in patients after surgery for cervical cancer suggest that adjuvant chemotherapy may exert an impact on survival. The possible effect of adjuvant chemotherapy should be taken into consideration when applying only surgical therapeutic concepts (23;25). Therefore, adjuvant chemotherapy in case of risk factors was performed Hoeckel's trial. The mono-institutional prospective study of the University of Leipzig, Department of Gynecology and Obstetrics, has shown that the treatment concept for cervical cancer FIGO stages IB-IIB including TMMR and therapeutic LNE without adjuvant radiotherapy achieves a markedly improved therapeutic index in comparison with historic controls (16;22): locoregional control was 96% versus 91%, relapse-free survival after three years was 93% vs. 84%, treatment-caused side effects were 9% exclusively grade II vs. 28% grade II and III (11-13).

Scientific aims

  1. Observation of results of standardization of radical hysterectomy and therapeutic lymphadenectomy in cervical cancer FIGO IB -IIA on the basis of ontogenetically defined compartment theory in a multicentric approach by TMMR/LND in clinical routine
  2. Assessment of locoregional recurrence in this concept without any radiation therapy showing that postoperative irradiation and associated morbidity can also be avoided and irradiation may be maintained for rescue in recurrency under conditions of clinical routine
  3. Confirmation of the low morbidity of TMMR due to autonomous nerve and vessel preservation by concomitant urogynecological and psychosexual subprotocols in clinical routine treatment

Requirements for participating centers of the register study

  1. Study of educational video (M. Hoeckel, Leipzig 2010; R. Kimmig, Essen 2012)
  2. Passed Participation of 2 day educational training concerning TMMR at "Leipzig School of Oncological Surgery"
  3. Performing at least 10 TMMR procedures at participating institution/year
  4. Evaluation of surgical technique at the participating institution by Prof. Hoeckel (Leipzig) or Prof. Kimmig (Essen) or substitute determined by M.Hoeckel or R. Kimmig
  5. Securing standardized workup of the surgical specimen by pathologists according to the protocol (Prof. Horn, Leipzig)
  6. Acceptance of study participation by the responsible project leader and commitment of online documentation of primary histopathological and clinical data as well as follow up data when assessed.

Primary outcome measures:

(1) Progression-free survival, defined as time from TMMR to a local or regional relapse, of a distant metastasis or to death of any cause whichever event comes first. Simultaneous occurrence of pelvic and distant metastases is considered as distant but should be documented in detail.

Secondary efficacy measures:

  1. Overall survival, defined as time from TMMR to death of any cause; Rate of locoregional relapse and rate of distant metastases at 3 years.
  2. Postoperative dysfunction of the bladder/urethra and of psychosexual function, assessed as described in the urogynecological and psychosexual subprotocol.

Secondary safety measures:

  1. Therapy-induced morbidity on bladder/urethra, rectum/bowel, vagina/vulva, assessed by the LENT-SOMA scoring system at the following times after surgery: subjective scale on day 1, week 1 and 2, month 3; subjective and objective scale on month 12 and 24. The questionnaires developed by Davidson (7) will be used; Time from surgery to first micturition; Acute complications of surgery; adverse and serious adverse events.
  2. Quality of life by EORTC-QLQ-C30 questionnaire at 12 and 24 months after surgery.

Aim of the study is to assess recurrence rate and morbidity following TMMR/LNE without additional radiotherapy in a multicentric observation of clinical routine treatment. In addition standardization of radical hysterectomy and of pathological work up for stage Ib to IIa cervical cancer will be achieved as described in "Requirements of participating centers". Two primary endpoints will be investigated, ranked according to their relevance: (1) PFS and (2) Late effects on bladder/urethra, measured by the subjective scale of the LENT-SOMA system. A hierarchical strategy will be used.

Further time to event endpoints will be illustrated by Kaplan-Meier plots and analyzed like the primary endpoint see above.


Study Type : Observational [Patient Registry]
Estimated Enrollment : 500 participants
Time Perspective: Prospective
Target Follow-Up Duration: 5 Years
Official Title: Register Study: TMMR and Therapeutic Lymphadenectomy According to M.Hoeckel for Treatment of Cervical Cancer FIGO IB-IIA
Study Start Date : March 2013
Estimated Primary Completion Date : January 2017
Estimated Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Group/Cohort Intervention/treatment
TMMR
Patients with cervical cancer Stages IB - IIA treated with TMMR and tLNE
Procedure: TMMR
Radical hysterectomy by Total Mesometrial Resection (TMMR) and therapeutic lymphadenectomy (tLNE)




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 60 months ]
    Progression-free survival, defined as time from TMMR to a local or regional relapse, of a distant metastasis or to death of any cause whichever event comes first. Simultaneous occurrence of pelvic and distant metastases is considered as distant but should be documented in detail.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 60 months ]
    Overall survival, defined as time from TMMR to death of any cause; Rate of locoregional relapse and rate of distant metastases at 3 years.


Other Outcome Measures:
  1. Sexual and bladder function [ Time Frame: 24 months ]
    Postoperative dysfunction of the bladder/urethra and of psychosexual function, assessed as described in the urogynecological and psychosexual subprotocol

  2. Quality of Life [ Time Frame: 60 months ]
    Postoperative Quality of Life as measured by the EORTC-QLQ-C30 questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with cervical cancer Stages IB - IIA treated with TMMR and tLNE.
Criteria

Inclusion Criteria:

  • Histologically proven cervical cancer: squamous cell carcinoma or adenocarcinoma; FIGO stages IB - IIA (preoperatively); Karnofsky-Index ≥ 70; unrestricted operability; BMI <35; age >=18 years.
  • Individual decision for treatment of TMMR and therapeutic LNE without adjuvant radiotherapy by the responsible clinic (clinician) on a clinical routine basis.
  • Informed consent of the patient

Exclusion criteria:

  • Neuroendocrine differentiation and all preoperative FIGO stage IA or >IIA;
  • Distant metastases except in para-aortic lymph nodes; sclerodermia, lupus erythematodes, mixed connective tissue disease; secondary malignancy; previous radiotherapy of the pelvis.
  • Patients with diseases of the connective tissue will be excluded because of unforeseeable (e.g. neurological) symptoms and disorders after surgery. Patients with a BMI ≥ 35 will be excluded because of very high risks regarding wound healing, infections and thrombosis independent on the type of surgery.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01819077


Contacts
Contact: Rainer Kimmig, Prof. Dr. 00492017232241 rainer.kimmig@uk-essen.de
Contact: Paul Buderath, Dr. 004920172385293 paul.buderath@uk-essen.de

Locations
Germany
University Hospital Essen Recruiting
Essen, NRW, Germany, 45122
Contact: Rainer Kimmig, Prof. Dr.    00492017232241    rainer.kimmig@uk-essen.de   
Contact: Paul Buderath, Dr.    004920172385293    paul.buderath@uk-essen.de   
Principal Investigator: Rainer Kimmig, Prof. Dr.         
Principal Investigator: Paul Buderath, Dr.         
Sponsors and Collaborators
University Hospital, Essen
Investigators
Principal Investigator: Rainer Kimmig, Prof. Dr. University Hospital, Essen

Publications:
Responsible Party: Dr. Paul Buderath, Prof. Dr. med. Rainer Kimmig, University Hospital, Essen
ClinicalTrials.gov Identifier: NCT01819077     History of Changes
Other Study ID Numbers: TMMR-RS
First Posted: March 27, 2013    Key Record Dates
Last Update Posted: May 27, 2015
Last Verified: May 2015

Keywords provided by Dr. Paul Buderath, University Hospital, Essen:
Cervical cancer
TMMR
therapeutic lymphadenectomy
register study

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female