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Original research
Adjuvant chemotherapy and radiation for patients with high-risk stage I endometrial cancer treated with curative intent surgery: impact on recurrence and survival
  1. Rachelle Findley1,
  2. Joni Kooy1,
  3. Beverley Lester2,
  4. Nhu D Le3,
  5. Gale Bowering4,
  6. Christie Rugayan2,
  7. Aalok Kumar5,
  8. Sarah Glaze1 and
  9. Jenny Ko6
  1. 1 Department of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
  2. 2 Radiation Oncology, BC Cancer - Abbotsford, Abbotsford, British Columbia, Canada
  3. 3 Biostatistics, BC Cancer Research Centre, Vancouver, British Columbia, Canada
  4. 4 Innomar Strategies Inc, Brandon, Manitoba, Canada
  5. 5 Medical Oncology, BC Cancer - Surrey, Surrey, British Columbia, Canada
  6. 6 Medical Oncology, BC Cancer - Abbotsford, Abbotsford, British Columbia, Canada
  1. Correspondence to Dr Jenny Ko, BC Cancer Agency Abbostford Centre, Abbotsford, BC V2S 0C0, Canada; jenny.ko{at}bccancer.bc.ca

Abstract

Background Survival benefits of post-operative systemic and radiation therapy in high-risk stage I endometrial cancer are uncertain.

Objective To compare recurrence patterns and survival outcomes of post-surgical treatment in patients with high-risk stage I endometrial cancer and to determine whether adjuvant therapy significantly improves outcomes.

Methods High-risk stage I endometrial cancer was defined as either stage IB grade 3 endometrioid histology or myoinvasive non-endometrioid histology. Consecutive patients diagnosed between January 2000 and December 2010 in eight cancer centers were included. Patients, disease, and treatment characteristics were summarized by descriptive statistics. Overall survival, disease-specific survival, and relapse-free survival were examined using Cox’s proportional hazards regression and log-rank test. Survival curves were estimated using the Kaplan-Meier method.

Results Of 2317 patients with stage I endometrial cancer, 414 patients had high-risk disease. Use of chemotherapy did not improve overall survival (relative risk (RR) 0.70, 95% CI 0.46 to 1.14, p=0.13) or disease-specific survival (RR 1.06, 95% CI 0.61 to 1.85, p=0.84). Significant improvement in recurrence-free survival was observed in patients who received chemotherapy (RR 0.61, 95% CI 0.39 to 0.95, p=0.03). Use of radiation therapy did not improve overall survival, recurrence-free survival, or disease-specific survival. Patients who received four cycles or fewer of chemotherapy versus five to six cycles had similar overall survival, disease-specific survival, and recurrence-free survival.

Conclusions Post-operative chemotherapy or radiation in stage I high-risk endometrial cancer is not associated with improved cancer-specific or overall survival. More than four cycles of chemotherapy did not improve survival compared with four cycles or fewer.

  • radiotherapy
  • endometrial neoplasms
  • endometrium

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

https://doi.org/10.1136/ijgc-2021-003087

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    HIGHLIGHTS

    • Multicenter, real-world data were collected for 414 patients with stage I high-risk endometrial cancer.

    • Adjuvant chemotherapy was associated with an improvement in progression-free survival but not overall survival.

    • Adjuvant radiation was not associated with an improvement in any survival indicator.

    INTRODUCTION

    Endometrial carcinoma is the most common malignancy encountered by gynecologic oncologists in the developed world.1 Most patients have disease limited to the endometrium, and the majority of these cases are low-risk endometrioid histologies with an associated low rate of recurrence requiring no adjuvant therapy. However, up to 20% of patients have an elevated risk of recurrence and many of these are stage I.2 3 Serous, clear cell, and International Federation of Gynecology and Obstetrics (FIGO) grade 3 endometrioid carcinoma are considered high-risk for recurrence and/or death even when diagnosed as stage I, as classified by the European Society for Medical Oncology/European Society of Gynaecological Oncology/European SocieTy for Radiotherapy and Oncology (ESMO/ESGO/ESTRO) consensus conference.4–6 Multiple strategies have been employed to target high-risk stage I disease, including adjuvant chemotherapy and radiation.

    Prospective randomized trials, notably PORTEC-3, GOG-249, and NSGO/MANGO have been hampered by small numbers, heterogeneous histologies, and stages.7–9 Retrospective studies, such as those caried out by Qu et al and Jutzi et al have similar flaws, and consensus has not been reached in national guidelines.10 11 For myoinvasive serous and clear cell endometrial cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend chemotherapy with consideration of external beam radiotherapy/vaginal brachytherapy or external beam radiotherapy with or without vaginal brachytherapy. The recommendations for uterine-limited undifferentiated/dedifferentiated endometrial carcinoma are for chemotherapy with consideration of external beam radiotherapy or vaginal brachytherapy while the recommendations for carcinosarcoma are for chemotherapy with vaginal brachytherapy, external beam radiotherapy, or both.12 The 2016 ESMO/ESGO/ESTRO Consensus guidelines recommend, for surgically staged IB grade 3 endometrioid cancer, adjuvant external beam radiotherapy or vaginal brachytherapy as a possible alternative while use of chemotherapy was investigational. In non-surgically staged patients, adjuvant external beam radiotherapy is recommended, and sequential chemotherapy should be considered rather than using chemotherapy or radiotherapy alone. For staged serous and clear cell cancers, vaginal brachytherapy alone could be offered in stage IA without lymphovascular space invasion, but with more advanced disease chemotherapy should be given with consideration for external beam radiotherapy. Chemotherapy with possible external beam radiotherapy was recommended for carcinosarcoma and undifferentiated tumors.6

    This multicenter retrospective study was undertaken to further understand the role of adjuvant therapy, particularly chemotherapy, in the treatment of high-risk stage I endometrial cancer in improving survival and reducing recurrence.

    METHODS

    This study included eight Canadian cancer centers across two provinces, Alberta and British Columbia. Inclusion criteria were diagnosis of stage I endometrial cancer between January 1, 2000 and December 31, 2010, surgical and/or adjuvant treatment at any one of the eight cancer centers, and uterine-confined high-risk endometrial carcinoma. This time period was chosen as carboplatin and paclitaxel were used regularly across all centers and provided a long enough interval to track long-term survival data. High risk was defined as: (1) FIGO stage I non-endometrioid carcinoma with any myometrial invasion; or (2) FIGO stage IB grade 3 endometrioid endometrial cancer. The revised 2009 FIGO staging system was used for staging.13 Patients were excluded if they did not undergo primary surgical management including at least a hysterectomy and bilateral salpingo-oopherectomy for their malignancy. The treating surgeon decided on lymph node sampling depending on patient factors, histology, and local guidelines. Adjuvant treatment recommendations were made based on local guidelines, patient factors, and tumor characteristics. Data cut-off date was January 1, 2019.

    Data were collected into a central database by trained individuals in Alberta and British Columbia with knowledge of the healthcare records. Data collected included age at diagnosis, pathology (including histology and lymphovascular space invasion), and FIGO stage as determined by surgical resection. Surgical factors collected comprised surgery including lymph node dissection. Adjuvant treatment included radiation delivered and mode of delivery (external beam radiotherapy, vaginal brachytherapy, or combination) and chemotherapy administered along with the number of cycles received. Patient outcomes included recurrence, location of recurrence, and statistics related to patient death. The primary outcomes for this review were overall survival, disease-specific survival, and recurrence-free survival. A subgroup analysis was performed for patients with stage IB grade 3 endometrioid endometrial carcinoma examining survival and recurrence outcomes based on adjuvant therapy.

    Ethics approval was received from the Health Research Ethics Board of Alberta – Cancer Committee and the British Columbia Cancer Research Ethics Board.

    Statistical Analysis

    Patient, disease, and treatment characteristics were summarized by descriptive statistics. Survival times were calculated from the date of diagnosis, defined as the date of initial biopsy confirming the diagnosis of endometrial cancer. Diagnosis of recurrence was made based on biopsy results, if available, or by imaging. Time of death due to any cause was considered for overall survival, and due to endometrial cancer was considered for disease-specific survival. Time to relapse or death due to any cause was considered for relapse-free survival.14 Survival curves were estimated using the Kaplan-Meier method. Survival analysis was conducted using Cox’s proportional hazards regression and log-rank test. All analyses were performed using R (https://www.r-project.org/).

    RESULTS

    Total Group

    A total of 2317 patients with uterine-confined endometrial cancer were identified during the study period. Most were deemed low risk of recurrence (n=1903) and 414 met high-risk criteria. The majority of these patients were FIGO stage IA for both low- and high-risk (1603 (84.2%) and 291 (70.3%), respectively). Both groups had a similar median patient age, 61 years (range 25 to 92) for low-risk versus 65 years (range 33 to 91) for the high-risk group. The patient and tumor characteristics are described in Table 1.

    View this table:
    Table 1

    Patient demographics and pathology

    The remaining analysis was focused on the high-risk group. The histologies represented were 88 high-grade serous carcinomas (21.3%), 34 clear cell carcinomas (8.2%), 133 mixed (32.1%), 80 undifferentiated/carcinosarcoma (19.3%), and 60 FIGO grade 3 endometrioid (14.5%). The remaining 19 (4.6%) comprised transitional cell or small cell carcinomas. One hundred and forty-four tumors (34.8%) had lymphovascular space invasion. In addition to hysterectomy and bilateral salpingo-oophorectomy, 240 (58.0%) patients had pelvic washing performed, 244 (58.9%) patients had a pelvic lymph node dissection, and 33 (8.0%) patients had a para-aortic lymph node dissection as detailed in Online supplemental table S1.

    Supplemental material

    Types of adjuvant treatment received are described in Table 2. The most common adjuvant therapy received by 235 patients (56.8%) was radiotherapy with 157 patients (37.9%) receiving this modality alone. Most of the radiotherapy was delivered as vaginal brachytherapy (21.5%) and 115 patients received external beam radiotherapy with brachytherapy (27.8%). The median dose delivered with external beam radiation was 4500 cGy (range 45 to 5200). Vaginal brachytherapy was delivered via either a high-dose or low-dose rate with a median dose per application of 700 cGy (range 500 to 5500). Median number of brachytherapy applications was 5 (range 1 to 5). Chemotherapy was administered to 99 (23.9%) patients. Seventy-eight patients (18.8%) had sequential chemotherapy and radiation treatment while 21 patients (5.1%) had chemotherapy alone. One hundred and fifty-eight (38.2%) patients received no adjuvant treatment.

    View this table:
    Table 2

    Adjuvant treatment and oncologic outcomes

    Outcomes

    Details of patient outcomes are shown in Table 2. The study follow-up period ranged from 9 to 19 years. In the high-risk group, 76 (18.4%) patients experienced a relapse compared with 8.8% in the low-risk group. In those who had a relapse, 77.6% did not receive adjuvant chemotherapy. During the follow-up period, 123 patients (29.7%) died from either their malignancy or an unrelated cause.

    The major patterns of recurrences included abdominal/pelvic recurrences and distant recurrences (8.5% vs 8.0%, respectively). Only 1.4% of patients had an isolated vaginal vault recurrence, as shown in Table 2. There was no significant association between the type of adjuvant therapy received (radiotherapy alone, chemotherapy alone, or combination chemoradiation) and recurrence (p=0.33). Similarly, no significant association with rate of relapse was identified in those who received external beam radiotherapy, vaginal brachytherapy, or combined external beam and vaginal radiotherapy (p=0.56). There was no significant difference between serous and non-serous histologies regarding rate of relapse (p=0.28) or pattern of relapse (p=0.98).

    Survival outcomes were analyzed based on chemotherapy or radiation received, either alone or in sequential combination, as shown in Figure 1. There was a statistically significant improvement in recurrence-free survival with patients receiving chemotherapy (relative risk 0.61; 95% CI 0.39 to 0.95; p=0.03). This translated into a median recurrence free survival of 8.52 and 6.92 years for patients receiving chemotherapy versus no chemotherapy, respectively. There were no significant improvements in either disease-specific survival or overall survival noted with administration of chemotherapy or radiotherapy. Adjuvant radiation was not associated with an improvement in recurrence-free survival.

    Figure 1
    Figure 1

    Overall high-risk group statistical analysis. (A) Disease-specific survival for adjuvant chemotherapy; (B) disease specific survival for adjuvant radiotherapy; (C) recurrence-free survival for adjuvant chemotherapy; (D) recurrence-free survival for adjuvant radiotherapy; (E) overall survival for adjuvant chemotherapy; (F) overall survival by adjuvant radiotherapy. DSS, disease-specific survival; OS, overall survival; RFS, recurrence-free survival.

    Of the 99 patients receiving adjuvant chemotherapy, 91 (91.9%) received carboplatin and paclitaxel every 3 weeks, 5 (5.1%) received single agent platinum, 1 (1.0%) received a single agent non-platinum agent, and 2 (2.0%) did not have the chemotherapy regimen clearly documented. Of these 99 patients, 82 (82.8%) had four cycles or fewer, while 16 (16.2%) had five to six cycles, and 1 (1.0%) had an unknown number of cycles. The increased number of cycles did not translate into an improvement in overall survival, disease-specific survival, or recurrence-free survival compared with patients who had four cycles or fewer, as seen in Figure 2.

    Figure 2
    Figure 2

    Stratification by number of chemotherapy cycles received. (A) Disease-specific survival for number of chemotherapy cycles received; (B) recurrence-free survival for number of chemotherapy cycles received; (C) overall survival for number of chemotherapy cycles received. DSS, disease-specific survival; OS, overall survival; RFS, recurrence-free survival.

    FIGO 3 Endometrioid Histology

    An additional analysis was done on patients with stage IB grade 3 endometrioid endometrial cancer and the details are summarized in Online supplemental table S1 and table 2. Sixty patients were identified in this subgroup. The most common adjuvant treatment delivered was radiotherapy (78.3%) and 56.7% had this treatment modality alone. Chemotherapy was administered in 23.3% of patients and 21.7% had both chemotherapy and radiotherapy.

    Similar to other patients with high-risk disease, 12 (18.3%) experienced a relapse and 19 (31.7%) died during the study duration. As shown in Table 2, the vast majority of recurrences were distant (15.0%) and no patients had an isolated vaginal vault recurrence. There was no statistically significant improvement in recurrence-free survival, disease-specific survival, or overall survival with administration of chemotherapy or radiotherapy (Figure 3).

    Figure 3
    Figure 3

    Stage IB grade 3 group statistical analysis. (A) Disease-specific survival for adjuvant chemotherapy; (B) disease-specific survival for adjuvant radiotherapy; (C) recurrence-free survival for adjuvant chemotherapy; (D) recurrence free-survival for adjuvant radiotherapy; (E) overall survival for adjuvant chemotherapy; (F) overall survival by adjuvant radiotherapy. DSS, disease-specific survival; OS, overall survival; RFS, recurrence-free survival.

    DISCUSSION

    Summary of Main Results

    Addition of chemotherapy yielded no significant difference in overall survival or disease-specific survival. It did, however, appear to confer a recurrence-free survival benefit with a relative risk of 0.61 (p=0.03), translating into just over 1.5 years of recurrence-free survival benefit. Adjuvant radiotherapy was not associated with an improvement in any survival outcomes. Our study analyzed 60 patients with stage IB FIGO grade 3 endometrioid endometrial carcinoma alone using a more current chemotherapy regimen. This group had no improvement with chemotherapy or radiation in overall survival, disease-specific survival, and recurrence-free survival, unlike the overall high-risk group. This high-risk group did have a recurrence rate of 18.3%, which was unchanged in patients who received chemotherapy versus those who did not.

    Results in the Context of Published Literature

    Stage I endometrial carcinoma is the most common gynecologic malignancy in Western countries.2 Most patients with low-risk pathologic features have an excellent prognosis with a local recurrence rate of less than 5% without adjuvant therapy.2 Certain pathologic risk factors within stage I disease have been associated with an increased risk of recurrence and reduced survival, yet the optimal adjuvant treatment has remained elusive.4 In trials that included other stages, such as stage III and IV endometrial cancer—namely, GOG 122 and PORTEC-3, chemotherapy had been shown to improve recurrence-free survival and overall survival in comparison with radiation alone. However, the benefit of chemotherapy in stage I disease has not been demonstrated.9 15

    No prospective study to date has evaluated the role of chemotherapy in stage I endometrial cancer with high-risk features alone. GOG 249, PORTEC-3, and NSGO/MANGO attempted to show improvements in survival associated with chemotherapy, but applicability to high-risk stage I disease is hampered by heterogeneity of included grades and stages. GOG 249 assessed vaginal brachytherapy plus chemotherapy versus external beam radiotherapy for patients with stage I and II high-intermediate-risk endometrioid histologies and stage I and II serous or clear cell tumors.7 This trial was unable to show any improvement in recurrence-free survival or overall survival with the addition of chemotherapy and cannot be applied directly to the high-risk stage I population with the inclusion of stage II disease and high-intermediate endometrioid disease. Similarly, the PORTEC-3 trial included a heterogeneous population of high-risk grade 3 endometrioid carcinoma, stage II and III cancers, and serous or clear cell carcinoma. including up to stage III.9 Improvement in overall survival and progression-free survival with chemoradiotherapy in long-term follow-up for stage III disease and serous carcinoma was demonstrated. However, its subgroup analysis showed no improvement in overall survival with addition of chemotherapy in stage I/II patients. The analysis was underpowered, casting doubt on the applicability to this stage. Lastly, the combined NSGO-EC-9501/EORTC-55991 and MANGO ILIADE-III trials included a heterogeneous group of stage I high-risk, occult stage II, and stage III diseases of all histologies and showed that adding three to four cycles of chemotherapy to radiotherapy resulted in an improvement in progression-free survival, disease-specific survival, and a trend towards overall survival improvement.8 With the smaller numbers of high-risk stage I disease included in these trials, the question of the use of chemotherapy for these patients is left unanswered. In the absence of level I, prospective evidence, our study responds to a clear need for a contemporary stage-specific, population-based multicenter retrospective study.

    Other smaller retrospective studies have attempted to answer the question of chemotherapy in high-risk stage I endometrial cancer. A multi-institutional retrospective review of adjuvant treatment of 414 patients with stage IA serous, clear cell, or mixed endometrial carcinoma by Qu et al showed an improvement in disease-free survival and local recurrence with chemotherapy, especially in incompletely staged patients, but no overall survival advantage was appreciated.10 Jutzi et al performed a retrospective cohort review comparing patients with stage IB grade 3 endometrial carcinoma or stage II endometrioid carcinoma receiving chemotherapy and radiation with historical controls receiving radiation alone. Fewer recurrences were seen among the 55 patients in the chemotherapy and radiation group.11 The study of Qu et al included patients with serous and clear cell tumors and mirrors our findings for improved recurrence-free survival and no improvement in overall survival. Their study was not inclusive of other high-risk histologies and the findings cannot be applied to all patients with high-risk, early stage disease. The review of Jutzi et al included a very small number of patients with high-risk endometrioid cancer. Our study was inclusive of all histologies and risk factors, was reflective of contemporary treatment modalities, and included many patients in all categories considered as being high-risk stage I endometrial cancer.

    Maggi et al performed a prospective trial including stages IB and II grade 3 endometrial carcinomas and stage III carcinomas of any histology comparing five cycles of chemotherapy with external beam radiotherapy and were unable to show an advantage in overall survival or progression-free survival with chemotherapy in this heterogeneous population.16 Susumu et al assessed chemotherapy versus radiotherapy in patients with deeply invasive stage I disease to stage IIIC disease of endometrioid histology. In a subgroup analysis, deeply invasive grade 3 endometrioid histology treated with chemotherapy was associated with an improvement in progression-free survival and overall survival.17 These data were a small subset of their analyzed population.

    If adjuvant chemotherapy is to be delivered for high-risk stage I disease, the optimal number of cycles is unclear. Both PORTEC-3 and RTOG-9708 stipulated two doses of radio-sensitizing cisplatin followed by four cycles of platinum-based doublet therapy, while the authors of GOG 258 compared that regimen with six cycles of carboplatin and paclitaxel.9 18 19 While GOG 249 was limited to stages I and II, critics suggest that the lack of overall survival benefit is related to the delivery of only three to four cycles of chemotherapy.7 We analyzed our data based on delivery of four cycles or fewer of chemotherapy versus five to six cycles. In our study cohort, receiving more than four cycles of chemotherapy was not associated with a statistically significant improvement in any survival outcome in comparison with receiving four or fewer cycles, and has the potential of adding toxicities.

    Strengths and Weaknesses

    Strengths of our study include inclusion of multiple institutions and provincial treatment guidelines that are applied uniformly within each province but are different between the provinces. For example, British Columbia recommends adjuvant chemotherapy in all patients with high-risk stage I endometrial cancer, while Alberta recommends adjuvant chemotherapy only in select cases of non-endometrioid, myoinvasive stage I endometrial cancer.20 21 The heterogeneity in practices among uniformly staged patients allowed population-based survival analysis with less selection bias. Other stages, including stages II and III, were not included in the analysis, further strengthening the applicability of data in stage I patients.

    This study has some limitations. The retrospective nature of this study brings with it bias that cannot be modified and may affect the data interpretation. We attempted to reduce the bias by including disease-specific survival in the analysis, which showed consistent results with overall survival. We found that despite the inherent selection bias favoring the chemotherapy group, overall survival was not improved with chemotherapy. Additionally, heterogeneous practices in lymph node resection were noted, mainly due to the differences in the local practices. The endometrial cancer guideline in one province does not routinely recommend full nodal dissection for endometrioid carcinomas, and para-aortic nodal dissection is at the surgeon’s discretion.20 This is in contrast to the recommendation of the other province included in the study for nodal dissection for all endometrial carcinomas, although this is optional if diagnosed with grade 1 endometrioid carcinoma.21 A lack of pelvic lymph node staging either by dissection or sentinel lymph node sampling may have the potential to downstage the cancer. Lastly, although the cohort encompasses many patients over a long period of time across multiple centers, the potential benefits of an intervention may not be apparent in subgroups due to the insufficient number of patients if the benefits are small in magnitude.

    If molecular testing results were available for patients with endometrioid carcinoma, this patient cohort might have been divided into low-, intermediate-, and high-intermediate-risk categories as defined by the 2021 ESGO/ESTRO/ESP endometrial cancer management guidelines.22 Mismatch repair data were unavailable for the vast majority of this group, and therefore further analysis based on molecular classification was not possible.

    Implications for Practice and Future Research

    We eagerly await the results of the prospective randomized trials ENGOT-EN2-DGCG (NCT01244789), which will assess the benefit of chemotherapy alone in stage I grade 3, serous and clear cell tumors; PORTEC-4a (NCT03469674), which will use a molecular profile to tailor treatment in high-intermediate risk early endometrial carcinoma; and TAPER (NCT04705649)), which will attempt to tailor treatment in early-stage endometrial carcinoma to p-53 and POLE-mutation status. We hope these trials will help to stratify early-stage endometrial cancer according to molecular risk profile and offer personalized treatment to prevent recurrence. Further data are needed to demonstrate improvements in outcomes with adjuvant treatment in each subtype and stage.

    CONCLUSIONS

    High-risk stage I endometrial cancer poses a challenge in optimal management due to a lack of level I evidence regarding survival benefits associated with adjuvant therapy. This retrospective review provides evidence that chemotherapy may be associated with improved recurrence-free survival, but not overall survival or disease-specific survival in patients with myoinvasive non-endometrioid stage I endometrial cancer, excluding grade 3, stage IB endometrioid endometrial cancer. More than four cycles of chemotherapy may not provide additional benefit.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplemental information.

    Ethics statements

    Patient consent for publication

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • RF and JoK are joint first authors.

    • Contributors JeK oversaw the conduct of the study, designed the study concept, and acts as guarantor of the study content. JeK, AK, and SG created the study protocol and participated in data curation. BL, GB, CR, AK, and JeK collected data by patient chart review. JeK, AK, and NDL were involved in statistical analysis. JoK, RF, JeK, AK, and SG analyzed and interpreted data. JoK and RF wrote the manuscript. All authors contributed to the manuscript by providing feedback and edits. All authors approved the final draft of the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.