Oligometastatic Cancer Cervix – A Missed Opportunity ? Role of Radiotherapy

Cancer of the cervix is one of the commonest causes of female cancer-related deaths among women all over the world. Most of them are treated with Surgery or Concomitant Chemoradiation, with a disease-free survival (DFS) in Federation of Gynecology and Obstetrics FIGO stage IIB-IV of 61-76 per cent, suggesting that many patients will present with recurrence.

The recurrence rates of cervical cancer are 11% to 22% and 28% to 64% in (FIGO) stage IB-IIA and IIB-IVA disease, respectively. Despite intensive treatments, the prognosis of recurrent cervical cancer continues to be poor, with a 5-year overall survival rate less than 5%. The treatment for recurrent or metastatic diseases have conventionally been palliative, with chemotherapy.

However, there are mounting evidence that patients with few and small metastatic sites may benefit from local ablative procedures. In principle, local ablations impact local control and overall survival.

Local ablation directed treatments have already been established as standard-of-care in other primaries with oligometastatic disease (OMD), like colorectal and renal cell carcinomas and in lung carcinomas. These options have not commonly been considered for cancer cervix patients with OMDs.

RELOOK AT OLIGOMETASTASIS

Recently, in order to standardize reporting, metastatic or recurrent diseases have been classified based on the number of lesions, sites of involvement. Those with limited number of metastasis (usually <3-5) and involvement have been classified as oligometastatic disease (OMD), and have been thought to have a better prognosis than those with more numbers of metastasis.

ESTRO-EORTC group has classified OMD considering the timing of presentation of metastases, receipt of any systemic therapy before appearance of lesion and response of metastases to the systemic therapy. Moreover, a coordinated effort (ESTRO-ASTRO consensus) is in the process to define this patient population better so that they may benefit from curative treatment measures.

OLIGOMETASTATIC CARCINOMA CERVIX

The decision making is challenging for cancer cervix patients who are oligometastatic de novo or oligo recurrent. Although de novo oligometastatic patients are being treated with various modalities like SBRT, and Surgery for the metastatic sites followed by chemotherapy, no consensus exists among oncologists.

Dilemma exists regarding treatment directed for the metastatic sites, for the primary cervix alongside, the dose and fractionation of radiation, the sequencing and so on.

The incidence of picking up a metastasis at diagnosis ranges from five to eight per cent, the commonest sites being lung (21-39.3%), para-aortic lymph nodes (PALN) (11%), bone (16.3%), liver (12.2%), abdominal cavity (8%), brain (1.4%) and supraclavicular node (SCLN) (7%). Incidence of inguinal nodal metastasis at diagnosis is <2 per cent.

Approach to Oligometastatic Cervix Carcinoma – Nodal, Visceral

RADIOTHERAPY IN CERVICAL CANCER WITH OLIGO NODAL METASTASES

In a study by Kim HS, patients of carcinoma cervix, who had distant nodal metastases at presentation, receiving Concomitant Chemoradiotherapy (CCRT) followed by Brachytherapy (BT) had better PFS and OS and complete response (CR) rates as compared to those receiving Chemotherapy alone.

In similar studies, patients of metastatic cancer cervix have also been treated with definitive RT to sites of OMD, including SCLN, mediastinum, lung and PALN, the median OS was 50.7 months and PFS was 21.7 months with <3 per cent grade ≥3 toxicity. However, there was no consensus in these studies about the RT dose to the OMD sites, RT fractionation if any to the pelvis, nor about the target volume that were included.

RADIOTHERAPY IN CERVICAL CANCER WITH OLIGO VISCERAL METASTASES

Management of Carcinoma cervix patients with OMD in the viscera, evidences are sparse. The number of nodules, possibility of surgical resection (SR), time interval between the appearance of metastases and initial treatment and receipt of Chemotherapy do affect the outcomes. It has been suggested that the following conditions must be met before selecting a patient for curative treatment: the maximum number of five metastases should not be surpassed, and all of them must be safely treatable, whereas a controlled primary is optional.

In limited visceral metastases, resection or SBRT of metastases has traditionally been the treatment of choice with the majority of evidence comes from colorectal, lung, renal cancers showing excellent outcomes. But in spite of good LC in treated site, distant progression is a rule. Hence, combining systemic therapy with local treatment-Surgery or SBRT is justified. However, the sequencing of these therapies is important for adequate tumour control and survival.

In a study published in 2017 evaluating the role of SBRT in various OMD sites (lung, liver and nodes) in 45 patients, 9 out of them with cervix primaries, the CR was 64 per cent with no patients progressing after achieving CR at a median follow up of 40 months with no grade 3 or more acute or long-term toxicity.

PELVIC RADIATION IN PATIENTS WITH DE NOVO METASTATIC DISEASE

The primary aim of delivering local treatment to the primary disease is to eradicate the local disease which could translate into clinical and survival benefits. Stenger et al studied 3169 patients of upfront metastatic cervical cancer treated with Chemotherapy alone versus Chemoradiation to the pelvis. Pelvic RT showed significant benefit in survival (23.2 vs. 10.1 months). Further, the median survival was longer in patients receiving RT and brachytherapy.

European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO) and European Society for Radiotherapy and Oncology (ESTRO) guidelines also recommend treating pelvis (gross disease) with elective irradiation of immediate nodal level) and Chemotherapy in localized metastatic disease.

TRENDS OF PRACTICE WORLDWIDE

Results from a survey by the EMBRACE Research Study group showed that, all the participants agreed on delivering local RT in OMD, with 68.2% of respondents recommending chemo-radiation and brachytherapy for the primary pelvic site, 31.8% considered additional systemic therapy. 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis sites.

CONCLUSION

Thus, although we have started agreeing that oligo metastatic carcinoma cervix patients need a more radical approach to treatment, there is no consensus about the modalities of the treatment to be offered and in what sequence and dose. Intense treatment with RT to the pelvis and the oligo metastatic sites, especially with SBRT, has shown promising outcomes with improved OS and PFS.

More research is needed to generate a treatment protocol for oligo metastatic de novo or oligo recurrent carcinoma cervix patients.

Dr. Swarupa Mitra

Sr. Consultant and Chief of Gastrointestinal and Genitourinary Radiation Oncology

RGCIRC, Delhi