TMMR (Total Mesometrial Resection) Register Study
TMMR (Total Mesometrial Resection) Register Study
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.
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.
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.