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ORIGINAL ARTICLE
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Is postoperative radiotherapy (PORT) a viable option in high-risk early-stage cervical cancer after upfront or downstaged radical surgery? A comparative study


1 Department of Surgical Oncology, Division of Gynecological Oncology, Delhi State Cancer Institute (GNCT of Delhi), Dilshad Garden, Delhi, India
2 Molecular Oncology Department, Delhi State Cancer Institute (GNCT of Delhi), Dilshad Garden, Delhi, India
3 Surgical Gynecological Oncology, Delhi State Cancer Institute (GNCT of Delhi), Dilshad Garden, Delhi, India
4 ICMR-National Institute for implementation Research in Non-Communicable Diseases, New Pali Rd, Air Force Area, Jodhpur, Rajasthan, India
5 Department of Radiation Oncology, Maulana Azad Medical College (MAMC), Delhi, India

Date of Submission29-Jan-2022
Date of Decision03-May-2022
Date of Acceptance03-May-2022
Date of Web Publication27-Oct-2022

Correspondence Address:
Viniita Kumar Jaggi,
Assistant Professor, Department of Surgical Oncology, Division of Gynecological Oncology, Delhi State Cancer Institute (GNCT of Delhi), Dilshad Garden, Delhi – 110 095
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_253_22

 > Abstract 


BACKGROUND: Radical surgery for cervical cancer has inherent benefits, and as upfront or post neoadjuvant chemotherapy (NACT), is extendable to locally advanced cancer cervix (LACC), with postoperative radiotherapy (PORT) for high-risk factors. Objective of the study was to compare the effectiveness and survival between non-PORT and PORT in high-risk early stages.
MATERIALS AND METHODS: Radical hysterectomies conducted between January 2014 and December 2017 were evaluated and followed till December 2019. Clinical, surgical–pathologic characteristics, and oncological outcomes were compared between non-PORT and PORT groups. A similar comparison was made between alive and dead patients within each group. The impact of PORT was assessed.
RESULTS: Of 178 radical surgeries, early-LACC constituted 70%. Most (37%) of the patients belonged to stage 1b2, while stage 2b formed 5%. Mean age of patients was 46.5 years; 69% were below 50 years of age. Abnormal bleeding (41%) was the predominant symptom, followed by postcoital (20%) and postmenopausal bleeding (12%). Upfront surgeries formed 70.2%, and the average waiting period was 1.93 months (range: 1–10 months). PORT patients were 97 (54.5%) in number and the remaining formed the non-PORT group. Mean follow-up was 34 months, with 118 (66%) alive patients. Significant adverse prognostic factors were tumors >4 cm (44.4% patients), positive margins (10%), lymphatic vascular space invasion (LVSI; 42%), malignant nodes (33%), multiple metastatic nodes averaging seven (range: 3–11), and delayed (>6 months) presentation, but not deep stromal invasion (77% patients) and positive parametrium (8.4% patients). PORT overcame the adverse effects of tumors >4 cm, multiple metastatic nodes, positive margins, and LVSI. Total recurrences (25%) were balanced for both groups, but recurrences within 2 years were significantly more for PORT. Two-year overall survival (78%) and recurrence-free survival (72%), median overall survival (21 months), and median recurrence-free interval (19 months) were significantly better for PORT, with the complication rates being similar.
CONCLUSION: PORT had significantly better oncological outcomes compared to non-PORT. Multimodal management is worthwhile.

Keywords: High-Risk Early-Stage Cervical Cancer, pathologic staging, postoperative radiotherapy (PORT), radical hysterectomy, survival (overall and recurrence free)



How to cite this URL:
Jaggi VK, Ansari MA, Khanna A, Gehlot S, Sharma A, Singh K. Is postoperative radiotherapy (PORT) a viable option in high-risk early-stage cervical cancer after upfront or downstaged radical surgery? A comparative study. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=359814




 > Introduction Top


Cervical cancer is a common gynecological malignancy worldwide and has high incidence and mortality in regions with insufficient public health infrastructure.[1] Quantum of disease differs within each Figo stage and substage and affects survival accordingly.[2] When patients delay reporting, growth becomes voluminous and locally extensive. Locally advanced cervical cancer (LACC) is a heterogenous group which lacks precise definition. Either it is large tumor within the cervix or has spread into tissues around the cervix, but without distant metastasis, ranging from 1b2 to 4a. Early-LACC like stages 1b2 to 2b can be operated after downstaging. To assess Figo stage at presentation, clinical examination and oncoimaging are used for tumor size measurements and assessment of vaginal, parametrial, and nodal status.[3]

Standard treatment for early-stage cervical carcinoma (ESCC) is either nerve-sparing radical hysterectomy (NSRH) with pelvic lymph node dissection or pelvic radiotherapy for radiosensitive tumors, with similar survival rates found between the two modalities.[4] Choice of modality depends on the side effect profiles, patient-related factors, and patient's or physicians' preferences.

Standard treatment for LACC is by concurrent radical chemoradiation to the pelvis.[5],[6],[7] Oncological effectiveness of NSRH in LACC is not well established.[8] In USA, surgery for LACC increased from 22.6% to 31.2%.[6] In Japan, both ESCC and LACC are treated with radical hysterectomy.[9] Surgical techniques for cancer cervix are evolving since 1912, and radical surgery cures, by removing primary growth radically with clear margins, along with draining lymphatics and nodes.[10],[11] Surgery benefits patients by allowing for preservation of ovarian and vaginal functions; thorough nodal dissections are especially advantageous for removal of malignant nodes, pathologic analysis and staging, guiding adjuvant therapy, and prognosis, thus optimizing, individual care.[12]

Early-LACC patients pose a dilemma in management between upfront radical pelvic chemoradiotherapy alone, or radical pelvic surgery either upfront or after downstaging with neoadjuvant ch emotherapy (NACT). Very often, postsurgery, these patients are required to be treated with postoperative radiotherapy (PORT) for the high-risk pathologic features encountered. Multiple modalities thus used for high-risk early stages may enhance the probability of complications, compared to use of the single modality chemoradiation.

Objective of this study was to compare survival and other oncological outcomes in high-risk, early-stage cervical cancer managed with radical pelvic surgery as the mainstay treatment, with or without PORT.


 > Materials and Methods Top


This study was conducted in a tertiary cancer institute in northern India after obtaining approval from the Institutional Ethics Committee. Data collection was conducted between January 2014 and December 2019. Participants were patients who had undergone type 3 NSRH and pelvic nodal dissection for cervical cancer consecutively between January 2014 and December 2017, with subsequent follow-up status available till December 2019 (total period of 72 months).

Information related to participants' individual demographic, clinical, and surgical–pathologic characteristics, type of treatment, and follow up was collected from the medical records department (MRD).

During the stated study period, Figo 2009 system was the basis of clinical staging preoperatively.[2] Pelvic magnetic resonance imaging (MRI) and positron emission tomography with contrast-enhanced computed tomography (PET-CECT) were used for determining T (Tumor), N (Nodes), and M (Metastases) (TNM) status and defining the disease burden precisely.[13] Management was decided by the institutional multidisciplinary team. Surgery performed was NSRH type 3 involving removal of uterus and cervix with contiguous parametrium and paracolpos, uterosacrals, upper third vagina, bilateral pelvic lymphadenectomy till aortic bifurcation, and both ovaries except in young.

ESCC comprising 1b1 and borderline 1b2 underwent upfront surgery. Early LACC patients comprising voluminous tumors staged as 1b2, 2a1, and 2a2 and early 2b underwent downstaging with NACT comprising carboplatin and paclitaxel every 21 days for two or three cycles, as indicated, before undergoing radical surgery.

NSRH surgical specimen was pathologically staged with details on tumor size or site, cell type, grade, type of growth, depth of stromal invasion (absolute in mm and relative in fractional thirds), uterine, ovarian, vaginal, and parametrial invasions, paracervical and vaginal resection margins, number and histology of dissected nodes, and lymphatic vascular space invasion (LVSI).

Eligibility criteria for PORT were tumor >4 cm, higher grades, positive or <1 cm clear resection margin, single or multiple metastatic nodes, deep stromal invasion (DSI) >33%, positive parametrium, and LVSI. In patients staged Figo 1b1, PORT was given as per the Delgado score.[14]

PORT dose was 54 Gy over 27 fractions by external beam pelvic radiotherapy and three fractions of 7 Gy each by vaginal brachytherapy.

We ensured 100% follow-up during the study period. Time to clinical or radiological recurrence, if any, was noted along with its details as regards to pelvic recurrence alone, distant failure, or widespread metastasis at the initial presentation. Death of patient as an event was noted. Overall survival (OS) was calculated from the date of registration, and recurrence-free survival (RFS) from the date of surgery.

Those who did not receive PORT constituted the non-PORT group. Both groups were further subanalyzed for alive and dead patients. Demographic, clinical, and surgical–pathologic characteristics, complications, and oncological outcomes were compared between both groups and within each group. Difference in survival, due to PORT, on individual significant high-risk factors was assessed.

Data was computed using Statistical Package for the Social Sciences (SPSS) statistical software, version 16.0. Statistical significance (P) was calculated using Sig. (two-tailed) method of independent t-test and Chi-square t-test. Quantitative parameters, represented as mean with range, were compared by unpaired t-test. Survival curves were obtained by Kaplan–Meier method. P value was defined as ns (nonsignificant; P > 0.05), *(significant; P < 0.05), **(very significant; P < 0.01), and ***(highly significant; P < 0.001).


 > Results Top


There were 178 participants, all of whom (100%) underwent radical pelvic surgery. Early-LACC patients were 125 (70%) in number, while the rest of the patients (30%) were ESCC. Non-PORT group patients numbered 81 (45.5%) and the remaining 97 (54.5%) constituted the PORT group. Clinical stage comprised ESCC as 1b1 (30%) and early-LACC as 1b2 (37%), 2a (28%), and 2b (5%). Mean waiting period for surgery was 1.93 months (range: 1–10 months). Upfront surgery was performed in 125 (70.2%), while others were downstaged. Overall, 119 (67%) received more than a single modality and 31 (17.4%) received all the three.

Mean follow-up was 34 months (range: 04–72 months). At the end of the study period, 118 (66%) patients were alive, while 60 (34%) patients succumbed to the disease. There were 44 (25%) recurrences, of which 17 (38.6%) presented as widespread, 16 (36.4%) as distant, and 11 (25%) as locoregional failures.

Mean age of patients was 46.5 years (range: 25–71 years). Also, 123 (69%) patients were aged below 50 years. Mean body mass index (BMI) was 23.7 (range: 13.3–42.8). Predominant symptom was abnormal uterine bleeding (AUB) in 73 (41%), followed by foul discharge in 48 (27%) and postcoital and postmenopausal bleeding in 36 (20%) and 21 (12%), respectively. Mean duration of symptoms was 5.2 months (range: 0.14–36 months). Most of the patients, that is, 141 (79%), presented within 6 months and the remaining presented beyond this period. On correlating duration of symptoms with patient status, 102 (86.4%) were alive when the duration of presentation was less than 6 months, which showed a statistically significant difference compared to 16 (43.3%) patients who were alive with duration of symptoms greater than 6 months. This significance was not observed for those who died of the disease, as 39 (65%) had presented within 6 months.

Most common cell type was squamous (148 [83.2%]), followed by adenocarcinoma (9%) and adenosquamous (3.4%). Adverse surgical–pathologic prognostic factors were tumor >4 cm in 79 (44%), DSI greater than one third in 137 (77%), parametrial invasion in 15 (8.4%), metastatic nodes in 59 (33%), positive LVSI in 75 (42%), and positive resection margins in 18 (10%). Regarding multiple metastatic nodes in a single patient, the mean was 7 (range: 3–11).

Clinical and pathologic characteristics were compared between non-PORT and PORT groups [Table 1]. Age, Figo stage, cell type and grade, NACT status, average nodal dissection per patient, that is, 27.4 (range: 12–56), parametrial invasion, and mean vaginal length of 3.7 cm (range: 1.2–6.5) had statistically nonsignificant difference in both groups. Significant increase in PORT use was observed for tumor size >4 cm, positive or close resection margins, DSI >33%, positive LVSI, and malignant nodal status, irrespective of their numbers.
Table 1: Comparison of cancer cervix patients' characteristics between non-PORT and PORT

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In subgroup analysis of alive and dead patients of the non-PORT group, no statistically significant difference was observed for age, BMI, clinical stage, NACT status, surgery waiting period, cell type or grade, depth of stromal invasion, number of dissected nodes, parametrial invasion, and vaginal length. Both patients of adenosquamous carcinoma survived. Statistically significant difference was seen with delay in reporting beyond 6 months, tumor size >4 cm, positive LVSI and resection margins, and malignant nodal status, especially with multiple metastatic nodes [Table 2].
Table 2: Comparison of cancer cervix patients' characteristics between alive and dead patients of the non-PORT group

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Characteristics of alive and dead patients in the PORT group are compared in [Table 3]. Statistically nonsignificant difference was observed in relation to mean age, clinical symptoms, BMI, Figo stage, surgery waiting period, and pathologic variables like cell type and grade, status of resection margins, DSI, presence of LVSI, number of dissected nodes, and mean malignant nodes per patient. Significant statistical difference was observed for delayed visit >6 months, tumor size >4 cm, and malignant nodal status.
Table 3: Comparison of cancer cervix patients' characteristics between alive and dead patients of the PORT group

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In subgroup analysis of the non-PORT group, statistically significant difference was noted for positive LVSI, resection margins, and multiple metastatic nodes, but the same was not observed for PORT group. Parametrium positivity and greater than one-third of the depth of stromal invasion were statistically nonsignificant in both groups [Table 2] and [Table 3].

Oncological outcomes like number of alive patients, total recurrences, and treatment complications had nonsignificant differences between both groups. Recurrences within 2 years were significantly more in PORT group. However, PORT patients had significantly better 2-year OS, 2-year RFS, recurrence-free interval, and median OS. Mild treatment complications encountered were wound sepsis, incisional hernia, pulmonary and urinary infections, while severe ones involved functional obstruction of either gastrointestinal or urinary tract, which required surgical correction [Table 4] and [Figure 1].
Table 4: Comparison of treatment outcomes in Non-PORT and PORT groups of patients

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Figure 1: Overall and recurre nce-free survival curves of 178 patients of high-risk early-stage Carcinoma/ Cancer cervix treated with radical pelvic surgery (±PORT). PORT = postoperative radiotherapy

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Impact of PORT was assessed individually on tumor size >4 cm, LVSI, delayed presentation (>6 months), and malignant nodal status. Statistically significant advantage related to OS and RFS was observed for each of them [Table 5] and [Figure 2] and [Figure 3].
Figure 2: Overall survival (OS) curves of high-risk early-stage cancer cervix treated with radical surgery (+/-PORT) as correlated with adverse prognostic factors like a) Duration of symptoms, b) Tumor size c) Nodal metastasis

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Figure 3: Recurrence free survival (RFS) curves of high-risk early-stage cancer cervix treated with radical surgery (+/-PORT) as correlated with adverse prognostic factors like a) Duration of symptoms, b) Tumor size c) Nodal metastasis

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Table 5: Impact of adverse prognostic factors and PORT on overall survival and recurrence-free survival

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 > Discussion Top


When patients delay reporting early stages of cervical cancer, they present with large growths and increased cancer burden with high-risk pathologic features, creating dilemma on its management with either chemoradiation as a single modality or triple modalities of NACT, radical surgery, and PORT.

In our study, total of 178 radical surgeries for such patients were staged as 70% early-LACC and 30% ESCC. Their median age was 46.15 years and median follow-up was 34 months. Further, early-LACC patients were distributed as 2b (5%), 2a (28%), and 1b2 (37%). Significantly better 2-year OS (78%) and RFS (72%) were observed for the PORT group compared to the non-PORT group which showed OS (72%) and RFS (70%). Significant adverse prognostic factors in our analysis were tumor size >4 cm (44.4%), positive resection margins (10%), LVSI (42%), malignant nodes (33%), average multiple metastatic nodes of seven and a maximum of 11, and delayed reporting beyond 6 months. Malignant cell varieties, like squamous cell carcinoma (83%), adenocarcinoma (9%), adenosquamous (3.4%), and rare varieties (4.5%), were not a significant factor. We had 67% of adenosquamous cancer patients who were alive. Greater than one-third of the DSI was noted in 77% of our patients, but it was not observed to be a significant adve rse factor. Significant increase in PORT was observed for tumor >4 cm, single or multiple metastatic nodes, positive surgical margins, positive LVSI, and >33% DSI, but not for age, Figo stage, cell type or grade, morphology of growth, and positive parametrium detected in 8.4%, which were also not found to be significant adverse factors. Significantly improved OS and RFS were seen with PORT use in patients with tumors >4 cm, positive margins and LVSI, and multiple malignant nodes. Total recurrences were not significantly different for both treatment types, but recurrences within 2 years were significantly more for the PORT group. However, PORT use showed significant benefit in median OS (21 months) and median recurrence-free interval (19 months). Complication rates were not significantly different.

In contrast to our study, Sakuragi et al.,[15] in their study on 121 radical hysterectomies, had 63% of ESCC and 37% of LACC. Median age was 42 years. Positivity rate was nodes (27%) and LVSI (45%). Adjuvant was given to 68 (89%) patients as chemotherapy (n = 63) and radiotherapy (n = 5) for multiple (>5) positive nodes. Five-year OS for LACC was 82%. They considered surgery with adjuvant chemo a favorable option.

Unlike our observation, malignant cell type was observed to be an independent predictor of survival in a gynecologic oncology group study (GOG) study[16] of 813 patients. GOG study had surgically staged Figo 1b patients, with squamous (79%), adeno (13%), and adenosquamous (8%) varieties. They reported adenosquamous to have higher risk of death, which is not observed in our study. Farley et al.[17] reported adenosquamous carcinomas to have poor outcome in advanced stages, but not in early stages.

Kimberly et al.[18] studied PORT for high-risk factors and found positive nodes and LVSI to be significant recurrence risk factors, but not positive surgical margins and DSI, which was similar to our study. They reported 5-year disease free survival (DFS) as 89.5% and found PORT to benefit local control in 83 ESCC patients.

Gauthier et al.,[19] in a multifactorial analysis of clinical and pathologic factors, demonstrated DSI to be the most important determinant of survival, which was in contrast to our finding.

In another study of 1b patients with negative nodes, Abdulhayoglu et al.[20] observed that besides tumor volume, DSI closer to serosa was an indicator for recurrence, even with negative parametria. PORT was suggested for local control. Obermair et al.,[21] in a multivariate analysis of 166 radical hysterectomies for stage 1b, observed micro-vessel density, positive nodes, tumor size, and PORT, but not LVSI, to be independent prognostic factors for survival. Baltzer et al.[22] studied the pathologic factors in 718 squamous cancer specimens. Tumor volume and LVSI significantly correlated with increased metastasis, and decreased 5-year survival, with vascular invasion (70%) and lymphatic invasion (31%) succumbing. Fuller et al.,[23] in their study on 431 radical hysterectomies for 1b and 2a, studied 71 patients with nodal metastasis and observed it to correlate with tumor size, extracervical extension, and adenocarcinoma. Unlike our study, they did not find PORT to overcome adverse factors, and their patients failed systemically without improvement in OS.

A multicenter european organization for research and treatment of cancer (EORTC) trial[24] on 620 patients staged 1b2–2b studied the outcome of treatment randomized between either NACT and surgery or pelvic chemoradiation. Their 5-year OS was 72% and 76%, respectively, with no significant difference between them. PORT was required by 36.3% for positive nodes, parametrium, and margins. Their median follow-up was 8.2 years, with 31% deaths. They concluded long-term toxicity issues to be decisive for therapeutic modalities.

Survival of Figo 2b patients treated with primary surgery versus concurrent chemoradiation was studied by Kasamatsu et al.[25] and Yamashita et al.[26] The former reported successful surgery in 99% (n = 139) with positive parametrium in 50% and PORT in 65%. On comparison with chemoradiation (n = 66), the 5-year survival (69%) and 3-year relapse-free survival (72%) were similar for both modalities.

Yamashita reported comparable 3-year progression-free survival (PFS), local RFS, and OS (80% vs. 75%) between surgery with PORT (n = 34) and concurrent chemoradiation (n = 25). Positive surgical margins constituted 21%, and late complication rate for PORT was 26%.

Rotman et al.,[27] in GOG, a randomized trial of 1b patients with poor prognostic features, showed PORT to significantly reduce recurrence and prolong PFS, especially for adeno and adenosquamous cancers.

Relating time and survival, duration from diagnosis to treatment was a significant prognostic indicator in a population-based nationwide study.[28] Treatment after 90 days had 1.33 times higher risk of death and lower OS. Nassali et al.[29] reported patient's journey from community to treatment as 6 months, median duration of symptoms as 120 days (range: 1–1290 days), and median wait for surgery as 60 days (range: 29–279 days). They concluded that delays in management were multifactorial. We observed that reporting late in early stages increases the high-risk factors, which require aggressive management, unlike conservative management options utilized for low-risk early stages.[30]

Strength of this study is its prospective nature with single-institutional experience of reasonably high volume of high-risk early-stage cervical cancers opting for radical surgery as the mainstay treatment, resulting in the use of multiple modalities. Limitations of the study are its small to medium sample size of 178 radical hysterectomy patients and short-term follow-up.


 > Conclusion Top


Delay in presentation results in early-stage cervical cancer becoming locally advanced with high-risk features. PORT after radical surgery has significantly better oncological outcomes in high-risk early stages, compared to the non-PORT group. Hence, use of multiple modalities in these patients is a worthwhile option. However, for radical surgery with PORT to become the standard of care, prospective studies in a multi-institutional setting with a long-term follow-up must be undertaken for comparison between surgery-based multiple modalities and chemo-radiation based single modality.

Acknowledgements

The Medical Records Department of Delhi State Cancer Institute is acknowledged for its help.

Highlights

  • Delayed presentation results in high-risk early-stage cervical cancer (70% in our study) curable with multiple modalities.
  • Surgery with postoperative radiation (PORT) had a 2-year overall survival of 78% and recurrence-free survival of 72%, compared to 72% and 70% in non-PORT, respectively, which was a significant difference.
  • In both non-PORT and PORT groups, deep stromal invasion and parametrial invasion were not significant adverse factors, but delayed visit >6 months was significant.
  • Tumor >4 cm and metastatic nodes were significant in both groups, but positive margin and lymphatic vascular space invasion were significant in non-PORT patients.
  • Mean multiple malignant nodes per patient was 0.58 in non-PORT and 1.82 in PORT, with significant adverse impact observed in non-PORT patients.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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