26. Research needs – Cervical Carcinoma

In the context of the development of the S3 guideline on the diagnosis, therapy and follow-up of cervical carcinoma, deficits in the evidence base have been demonstrated. The majority of the agreed statements are consensus-based and not supported by prospective randomized studies, as is usually the case with sufficient evidence. This lack of evidence of high-quality systematic reviews and controlled randomized trials is not due to an insufficient systematic search, but to the real lack of evidence. 

Thus, in the context of the initiation and primary structuring of the guideline, PICO questions of particular clinical relevance (see guideline report) were developed from the topic complexes of lymph node metastases, surgery versus radiochemotherapy, radical hysterectomy for lymph node involvement and therapy for distant metastases (pM1). 

Due to financial constraints, not all of these topic complexes with underlying questions could be given to an external evidence search, so two topic complexes were focused on in the external evidence search:

Search strategy number 1:

Secondary hysterectomy, surgery versus radiochemotherapy, radical hysterectomy for lymph node involvement (see guideline report).

Search strategy number 2:

pM1, therapeutic lymphonodectomy before radiochemotherapy, lymph node metastases and neoadjuvant chemotherapy (see guideline report). 

This showed that, starting with the central question namely the indication for the choice of primary therapy, there is not a single study in the databases that has investigated a prospective randomized comparison between surgery and radiatio or radiochemotherapy as the primary single therapy option. Given that cervical cancer has now been treated for over 220 years after the initial treatment description using surgical therapy, this is extremely disappointing and shows that there is actually a very great need for studies. Based on this fundamental problem, the questions of secondary hysterectomy after radiochemotherapy, the question of radical hysterectomy with proven lymph node involvement in the pelvic localization and the further surgical strategy after proven lymph node involvement in the para-aortic localization are obvious problem areas with a lack of evidence. For none of the corresponding questions are there sufficient prospective randomized studies to make a clear therapy planning based on corresponding prospective randomized studies.

Both search strategy number 1 (see above) and search strategy number 2, which covered the topic areas of neoadjuvant chemotherapy with corresponding follow-up questions about the extent of surgical procedure after neoadjuvant chemotherapy, as well as the procedure for proven pelvic or para-aortic lymph node metastases, showed an identical lack of high-quality studies that could be used as an evidence base for recommendations. Thus, these questions and topics could also only be agreed upon as consensus-based recommendations. 

Only in areas involving the use of drug therapies are findings available that enable therapy planning at an evidence-based level. This concerns, for example, neoadjuvant chemotherapy, radiochemotherapy, adjuvant chemotherapy and drug therapies for recurrence diagnosis or metastases. Appropriate studies are being developed here with the support of industry. The questions concerning the basis of therapy, namely surgery or radio(chemo)therapy, are not investigated by industry-supported studies and apparently do not receive corresponding public research funding in any country. 

Thus, the need for research in the field of cervical carcinoma emphatically extends to studies comparing primary therapy (surgery versus radiochemotherapy) and the corresponding surgical modifications or modifications of diagnostic methods (surgical staging). In order to develop a clear therapy strategy with prioritization of the procedure that allows the lowest morbidity with the best recurrence-free and overall survival of the patient, corresponding public research funds must be made available. 

While the incidence of cervical carcinoma is decreasing in industrialized nations, it remains the most common female carcinoma worldwide, so the research option in western industrialized nations could have a tremendous impact on non-industrialized nations. 

In addition to this key clinical research need, in the absence of evidence, there is a need for research in the area of follow-up, long-term treatment consequences (including quality of life) and pathological prognostic factors and their impact on treatment choice. 

Another point that is becoming increasingly important, especially in industrialized countries, is in the area of health care structures. Of particular interest here is the effect of certified structural units and centralization on patient-relevant outcome parameters and the problem of consistent education and training as the number of cases decreases. With the falling incidence of cervical carcinoma, the question of lege artis care with corresponding expertise in both the surgical and radio-oncological fields is a question of health care research that needs to be solved in the long term. 

In summary, it was identified as a central need for research in cervical carcinoma, that in most areas of diagnostics, therapy, supportive measures, but also in aftercare, there is hardly enough high-quality evidence available. As these are mainly topics that are not supported by industry funding, these results can only be developed with the support of public funders. If possible, this should be addressed with an evaluation of therapy-specific quality of life as well as economic aspects.

Specifically, the guideline group addresses the following research questions for which a systematic evidence review is being conducted without usable results:

• Is percutaneous radio(chemo)therapy with or without brachytherapy, followed by secondary hysterectomy oncologically equivalent to percutaneous radio(chemo)therapy with brachytherapy?
• Does secondary hysterectomy after primary radio(chemo)therapy have an influence on the local recurrence rate, DFS, MFS, OS? 
• Should secondary hysterectomy be performed as radical or simple hysterectomy? 
• Are surgical therapy and radio(chemo)therapy equivalent in stages IB and II? 
• Should radical hysterectomy be omitted in the case of parametranous or pelvic lymph nodes? 
• Should radical hysterectomy be omitted for paraaortically affected lymph nodes? (Extent, anatomical structure, infra/supramesenteric). 
• What are the options for singular metastasis (radiofrequency ablation, surgery, radiotherapy)?
• Is systematic pelvic or paraaortic LNE useful prior to primary radiochemotherapy (e.g., for pN+)? Should only debulking be performed?
• Does pelvic radiotherapy or radiochemotherapy for pN1 pelvic (incl. singular micrometastasis) after therapeutic lymphonodectomy have an impact on local recurrence rate, DFS,  MFS, OS?
• Does para-aortic radiotherapy or radiochemotherapy for pM1 para-aortic (incl. singular micrometastasis) after therapeutic lymphonodectomy influence local recurrence rate, FS, MFS, OS?
• How are positive lymph nodes after neoadjuvant chemotherapy to be evaluated prognostically as well as for further therapy?

Specifically, the guideline group also addresses the following research questions, for which a systematic search has been conducted without usable results and for which, in the opinion of the experts of the guideline panel, no high-quality studies are to be expected in the near future either:

• What is the significance of pM1 (para-aortic) compared to pM1 (pulmonary, hepatic, osseous) for therapy? 
• Is neoadjuvant chemotherapy followed by surgery equivalent to primary radiochemotherapy (percutaneous + brachytherapy)? 
• Is neoadjuvant CHT followed by surgery equivalent to primary surgery? 
• Does surgical staging of locoregional tumor spread and lymph node status alter treatment planning? 
• Does surgical staging prior to neoadjuvant chemotherapy make sense? 
• Should surgical staging be the basis for therapy selection? 
• How should the sentinel lymph node biopsy be performed (e.g. unilateral/ bilateral, blue/radioactive, application)? 
• Is sentinel lymph node biopsy alone sufficient as a staging of the lymph nodes? If so, for which tumor stages?
• Does ultrastaging (possibly in conjunction with sentinel lymph node biopsy) of the lymph nodes improve the detection rate of lymph node metastases? 
• What is the significance of ultrastaging for further therapy or prognosis? 
• How to proceed in case of accidental cervical carcinoma after simple hysterectomy?  
• What is the prognostic significance of L1 in cervical carcinoma (preferably a prospective study of pT1b1 cases with and without lymph node metastases using a multivariate approach)?
• What is the prognostic significance of grading in cervical carcinoma (preferably a prospective study of pT1b1 cases with and without lymph node metastases with multivariate approach AND with different grading scores)?
• What is the interobserver variability related to grading in cervical carcinoma?
• What is the prognostic significance of deep stromal infiltration in cervical carcinoma (preferably a prospective study of pT1b1 and pT2a1 cases with and without lymph node metastases using a multivariate approach AND generating a ROC_curve to determine the optimal cut-off value [which was, after all, defined in the guideline as 66% infiltration of the cervical stroma])?
• Study of prognostic significance of tumor size in pT2b-CX (cases with and without LKM with multivariate approach), cut-off as in pT1b and pT2a.
• Quality control study on the completeness of pathology findings with respect to pathological-anatomical prognostic parameters and TNM-relevant information.
• What are the optimal follow-up intervals and examinations for cervical carcinoma? 
• What is the impact of follow-up on PFS, MFS, OS and quality of life?
• Analysis of health-related quality of life in cervical carcinoma-associated disease.
• To provide a systematic review of studies (results) published to date on health-related quality of life in cervical cancer-associated disease.
• Identification and summary of studies that 
• Report quality of life scores for various disease states,
• address quality of life in women survivors, or 
• Evaluate effects of cervical cancer-related interventions on health-related quality of life.
• Gap analysis for health economic evaluation of specific interventions (diagnostics, follow-up and rehabilitation) related to cost-effectiveness in cervical cancer.
• Identification and comparative interpretation of studies on the cost-effectiveness of specific technologies relevant to cervical cancer.
• Derivation of health economic research needs in this field