Trial Information

Register Study: TMMR and Therapeutic Lymphadenectomy According to M.Hoeckel for Treatment of Cervical Cancer FIGO IB-IIA

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.