Exclusion of Non-involved Uterus From the Target Volume in Locally Advanced Cervical Cancer

Exclusion of Non-involved Uterus Form the Target Volume: an Individualized Treatment for Locally Advanced Cervical Cancer Using Modern Radiotherapy and Imaging Techniques

Both toxicity and local relapse are major concerns in the treatment of locally advanced cervical cancer. The purpose of this study is to ameliorate both by integrating modern imaging (diffusion weighted magnetic resonance imaging; DW-MRI) into the treatment planning of modern radiotherapy. We want to evaluate the safety and effect of excluding the unaffected uterus (as determined on magnetic resonance imaging) from the treatment field. Meanwhile we want to explore the possible use of apparent diffusion coefficient values (DW-MRI) as biomarker of treatment response.

In our previous research we successfully implemented Intensity Modulate Arc Therapy with concurrent administration of cisplatin 40mg/m2 weekly (IMAT-C) in the multimodality treatment of Locally Advanced Cervical Cancer (LACC) . By delivering a higher biological dose to the tumor and lowering the dose to the Organs at Risk (OARs), toxicity significantly dropped and local control improved. However, there remains room for improvement for both toxicity and response to the treatment. Macroscopic tumor rest on hysterectomy reflects the existence of chemoradiation (CRT) resistant foci and correlates with outcome. We hypothesize that both radiotherapy (RT)-related toxicity (a) as well as local response on CRT (b) can be improved by respectively:

1. Reducing the dose on OARs by omitting iconographical non tumor-bearing parts of the uterus from the Clinical Target Volume (CTV).
2. Performing a dose-escalation to those regions within the gross target volume (GTV) pointed out by Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) to be at risk for treatment failure.

To objectivize our hypotheses, we aim at:

1. Demonstrating that omitting iconographical unaffected uterus from the treatment volume leaves no tumor behind in the non-targeted parts of the uterus, leads to lower doses to the OARs and decreases (acute) toxicity.
2. Validating that a high baseline apparent diffusion coefficient (ADC) and an increase in ADC 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on hysterectomy specimen and to consider the possibility for a further dose-escalation on tumors/intratumoral regions at risk for treatment failure.

Importance to the field: Both toxicity and local relapse are major concerns in the treatment of LACC. Grade ≥ 2 toxicity influences daily life of patients significantly and is present in the majority of patients treated and even with image guided BT local relapse remains the major cause of treatment failure.

Inclusion Criteria:

• Biopsy proven carcinoma of the uterine cervix
• locally advanced disease (FIGO IB2 or >FIGO IIB or node positive) proven by clinical examination, 18-fluorodeoxyglucose positron emission tomography scan (18FDG PET-CT) and MRI
• no more than 2 distant metastases (other than para-aortic lymph nodes);
• WHO 0-2;
• adequate kidney function for CRT, if inadequate kidney function radiotherapy can be the sole therapeutic regimen;
• not pregnant or breastfeeding
• absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; - willing and able to sign a written informed consent.

Exclusion Criteria:

• Patients unable to undergo MRI for any reason.