A Regional Experience of Adult Granulosa Cell Tumours: A Retrospective Analysis

Simple Summary

Adult granulosa cell tumours (AGCT) of the ovary are rare cancers that usually carry a good prognosis. However, up to one quarter of patients experience a recurrence of disease. Our retrospective analysis of AGCT patients is the largest cohort reported in the literature to date. Fertility sparing management can be considered with appropriate follow-up and consideration of delayed completion surgery. Surgery remains the mainstay of management of recurrence; however, this increases the risk of complications.

Abstract

Background: Adult granulosa cell tumours (AGCT) of the ovary account for 2–5% of ovarian tumours, with 30% occurring in women of childbearing age. Despite a good prognosis, up to 25% recur. There is a paucity of high-quality evidence to guide management. Objective: To describe management of AGCT across multiple gynaecological cancer centres. Methods: Retrospective analysis of electronic patient records from six gynaecological cancer centres in Southwest England between 2000 and 2021 (n = 119). Results: We included 107 patients with a median follow-up of 60 months (0–261 months). Most (97/107; 90.7%) were diagnosed with stage I disease (31.8% stage Ic). Primary management was staging surgery in 33/107 (30.8%), hysterectomy and bilateral salpingo-oophorectomy (BSO) (28/107; 26.2%), or conservation of an ovary (17/107; 15.9%). Three had a subsequent pregnancy. A quarter (27/107; 25.2%) were diagnosed with recurrent disease. Fifteen patients (15/107; 14%) had multiple recurrences. Recurrence was more likely if cyst rupture was reported at surgery (38.7%) compared with no rupture (14.3%; p < 0.001). The recurrence rate was higher with ovarian conservation (6/17; 35.3%) compared with BSO (21/90; 23.3%; p < 0.01), and all recurrences involved the residual ovary. Of the 11 deaths, 6 (54.5%) were attributed to progressive disease. Conclusions: Although survival with early-stage disease is good, ovarian cystectomy or unilateral ovarian conservation was associated with increased risk of recurrence. There is no conclusive evidence to support a contralateral oophorectomy in pre-menopausal women, but completion surgery should at least be considered, either immediately or after childbearing/assisted reproductive treatment.

1. Introduction

Adult granulosa cell tumour (AGCT) of the ovary is a subtype of sex-cord stromal tumours and accounts for 2–5% of all ovarian tumours [1]. Over 90% are diagnosed at an early stage and have a good prognosis with an 85–95% 10-year survival [1,2]. AGCTs have a typically indolent course, but up to 25% recur [3]. A significant proportion recur more than 5 years from primary treatment and recurrences have been reported up to 30 years later [4]. Granulosa cell tumours are rare, and there are only retrospective data to guide management.

Primary surgery is the treatment of choice for the majority of patients. Usual practice is a staging laparotomy, including omentectomy and full assessment of the upper abdomen and pelvis, including peritoneal biopsies. The route of surgery is not thought to impact oncological safety in stage 1 disease [5]. Routine lymphadenectomy is not indicated due to extremely low rates of lymph node metastases [6,7]. The evidence does not suggest improved outcomes with the use of adjuvant chemotherapy or radiotherapy in early-stage disease [8,9], although adjuvant treatment may have a role in higher-stage disease [10] or where there is residual disease following surgery.

About 30% of women with AGCT are of childbearing age, and a fertility preserving procedure may be considered in early-stage disease [1]. Studies support the oncological safety of a unilateral salpingo-oophorectomy as a fertility preserving procedure [10], with high rates of subsequent pregnancy [11]. However, incomplete staging is associated with increased risk of recurrence. There is controversy about the role of completion surgery, either after childbearing or at the age of menopause, versus awaiting recurrence, but the majority of patients are monitored, allowing the benefit of preserved ovarian function [12]. Less is known about surgery for recurrent disease, specifically regarding timing.

Recurrences are traditionally managed surgically, as there is evidence that progression-free survival is prolonged by optimal cytoreductive surgery [13]. Adjuvant bleomycin, etoposide and cisplatin (BEP) chemotherapy is often recommended, especially if optimal cytoreduction at surgery is not achievable [10]. There are ongoing trials of chemotherapy as first-line management of recurrent AGCT [14] as well as consideration of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) [15]. Hormone-based treatments (GnRH agonists, tamoxifen, progestin, and aromatase inhibitors) have limited evidence in an adjuvant setting but are considered useful in the management of advanced or recurrent AGCT [10]. High response rates (25.8% complete response and 45.2% partial response) have been reported with the use of aromatase inhibitors, which is thought to be due to the high aromatase activity in granulosa cells [16]. However, the PARAGON trial examining the role of anastrozole as sole treatment for recurrent AGCT found a low response rate of 10%, but noted that 60% of patients for whom data were available were progression-free (had stable disease) at 6 months [17]. There was, however, some response in up to 80% of patients with recurrent or metastatic AGCT (Clinical Benefit Ratio of RECIST criteria). It is not clear whether this reflects indolent disease or true benefit and emphasises the difficulty in identifying which patients will benefit most from adjuvant treatment.

In view of the paucity of retrospective studies for recurrent granulosa cell tumours, our aim was to review surgical management of recurrent granulosa cell tumours in multiple gynaecological cancer centres across our region.

2. Materials and Methods

In this retrospective analysis, we report all AGCTs of the ovary recorded across six UK sites across the Southwest of England (University Hospitals Bristol and Weston NHS Foundation Trust, Royal United Hospital Bath NHS Foundation Trust, Somerset NHS Foundation Trust, Gloucestershire Hospitals NHS Foundation Trust, Royal Devon and Exeter NHS Foundation Trust and Royal Cornwall Hospital Trust) between 1 January 2000 and 31 December 2019. The primary objective was to describe the management of AGCT. Secondary objectives included identifying factors which correspond to increased risk of recurrence, management of recurrences and overall survival.

Patients were identified using local pathology and surgical databases at each site. Local hospital ethical approval for the audit was obtained, and data collection was undertaken in 2021. There were data-sharing agreements between hospitals. Inclusion criteria were primary diagnosis of AGCT between the study dates and age over 18 years at diagnosis. We excluded those with a primary diagnosis prior to the study dates or those with no follow-up information available. Demographic data were collected on each patient along with details on primary management, stage, adjuvant treatment, recurrence (time since primary treatment, site, management), and survival (including cause of death). The follow-up duration was recorded up to the date of last follow-up or death, with the final date for data capture 31 December 2021. Event-free survival (EFS) was defined as the time from the date of diagnosis until the date of recurrence or progression. Overall survival was defined as the time from diagnosis to date of death from any cause. Statistical analysis on survival data was performed using Kaplan–Meier curves. Patient characteristics were summarised using descriptive statistics. We performed a Cox regression (proportional hazard) analysis to compare survival and progression curves. A p value threshold of 0.05 was considered statistically significant.

3. Results

We initially identified 123 patients, although 11 patients were excluded as they had recurrent AGCT, with the primary diagnosis prior to the study period. Two patients had inadequate information available and three patients were lost to follow-up and were also excluded, leaving 107 patients for analysis. The median length of follow-up was 60 months (0–261 months). The median age at diagnosis was 57 years (range 28–88). The majority had stage I disease at diagnosis (97/107; 90.7%), 60/107 (56.1%) stage Ia, 3/107 (2.8%) stage Ib, and 34/107 (31.8%) stage Ic. Approximately a third (34/107; 31.8%) had stage Ic disease, but information about substage was limited (see

Table 1. Demographic and clinical characteristics of patients included in the analysis (n = 107).

Median Age at Diagnosis	57 Years	24–88 Years
Stage at diagnosis (FIGO 2014)	Ia	60 (56.1%)
	Ib	3 (2.8%)
	Ic (all)	34 (31.8%)
	Ic undetermined *	6 (5.6%)
	Ic1	12 (11.2%)
	Ic2	16 (15.0%)
	Ic3	0
	II	5 (4.7%)
	III	4 (3.7%)
	IV	1 (0.9%)
Primary surgical procedure	H+BSO+O+A	29 (27.1%)
	H+BSO	28 (26.2%)
	USO	25 (23.4%)
	BSO	18 (16.8%)
	H+BSO+O+A+LND	4 (3.7%)
	Ovarian cystectomy	2 (1.9%)
	Other	1 (0.9%)

* Ic undetermined = not able to classify by subtype. A = appendicectomy, BSO = bilateral salpingo-oophorectomy, H = hysterectomy, LND = lymphadenectomy, O = omentectomy, USO = unilateral salpingo-oophorectomy.

). Very few patients had complete surgical staging (hysterectomy, BSO, and omental biopsy/omentectomy (H+BSO+O)), due to the unexpected histological diagnosis; therefore, where this had not been performed, staging was based on available histology, imaging, and MDT opinion. Data on tumour markers, including inhibin and CA-125, were collected where available, but, unfortunately, this was not consistently available and, therefore, could not be analysed.

3.1. Primary Management

Of the total cohort, 61/107 (57.0%) underwent a hysterectomy and bilateral salpingo-oophorectomy (H+BSO), of whom just over half had staging procedures (33/61; 54.1%) with omentectomy and appendicectomy. Eighteen (18/107; 16.8%) underwent a BSO only, almost a quarter (25/107; 23.4%) had unilateral salpingo-oophorectomy (USO), and two (2/107; 1.9%) had an initial ovarian cystectomy followed by either a USO or BSO at a later date. One patient had a partial resection of an ovary. In total, 28 patients had a single ovary removed during their primary procedure. Seven of these (7/28; 25.0%) went on to have a completion surgery, and 21 (75%) did not. Of these 21 patients, 4/21 (19.0%) had previously had a contralateral oophorectomy, leaving 17 patients with a preserved ovary following primary treatment.

The primary operation was performed via laparotomy in 66/107 (61.7%), laparoscopically in 37/107 (34.6%), vaginally in 2/107 (1.9%), and not known in 2/107 (1.9%). The reason for the chosen operative route was not always described. Most (101/107; 94.4%) surgeries reported no macroscopic residual disease (NMRD) at the end of the primary procedure, with 4/107 (3.7% unknown and 1/107 (0.9%) reporting residual disease in the liver and lung. Of the 17 patients who had ovarian conservation, two (11.8%) were postmenopausal. Three (17.6%) patients with ovarian conservation had no residual disease at the time of surgery with normal imaging and opted for surveillance, one (5.8%) declined further surgery, and 13 (76.5%) wished to retain their fertility. In the pre-menopausal group, 3/15 women (20.0%) went on to have a successful pregnancy.

Twelve of the total 107 in the cohort were offered adjuvant therapy, of whom three declined. Nine (8.4%) women underwent adjuvant treatment: four radiotherapy, four chemotherapy, and one hormonal therapy. Of the 12 offered adjuvant treatment, one (11.1%) had stage 1a disease (with adjuvant treatment delivered primarily for a co-existing endometrial carcinosarcoma), four (44.4%) had stage 1c2 disease, and 4 (44.4%) had stage II or III disease. None of the patients in the fertility-sparing group had adjuvant treatment. In total, there were ten patients with stage II or higher disease, of whom six did not have adjuvant treatment, four declined, and two were not advised to have any following MDT review as there was no macroscopic residual disease recorded at surgery.

3.2. Recurrence

A quarter of patients (27/107; 25.2%) were diagnosed with recurrent AGCT. The median number of months from primary treatment to recurrence was 40 (range 2–247), with the overall median follow-up of 60 months. Patients with stage Ia disease had a median time to recurrence of 61.5 months (27–247 months), whereas all other stages had a median time to recurrence of 40 months (2–133 months) (see Figure 1a). A total of 52.3% (n = 56) of our patients had a follow-up time of more than 60 months (5 years). Recurrence rates in this group were 41.1% (23/56) with 9/23 (39.1%) experiencing their first recurrence after 5 years of follow-up.

The recurrence rate for those who had ovarian-conserving surgery was higher (6/17; 35.3%), and all recurrences in this group involved the residual ovary or fallopian tube (see Figure 1b). Four patients went on to have a second recurrence, and two had three or more recurrences. Of those who had surgical staging performed at the time of their primary diagnosis, 12/61 (19.67%) went on to develop recurrent disease. The median time to recurrence was 60 months (2–247 months) in the ovarian conservation group, compared to 40 months in the patients without ovarian conservation (12–171 months).

Table 2. Pattern of recurrences and characteristics of patients with recurrences.

		Number of Patients	p Value
Number of recurrences	1	27 (25.2%)
	2	15 (14.0%)
	3	9 (8.4%)
	4	3 (2.8%)
	5	2 (1.9%)
	6	2 (1.9%)
	7	1 (0.9%)
	8	1 (0.9%)
Stage	Ia	8/60 (13.3%)	p = 0.035
	Ib	1/3 (33.3%)
	Ic (all)	14/34 (41.2%)
	Ic undetermined	2/6 (33.3%)
	Ic1	5/12 (41.7%)
	Ic2	7/16 (43.8%)
	II	2/5 (40.0%)
	III	2/5 (40.0%)
Primary procedure	Ovarian cystectomy	2/2 (100%)	p < 0.001
	USO	10/25 (40.0%)
	BSO	2/18 (11.1%)
	H+BSO	4/28 (14.3%)
	H+BSO+O+A	8/29 (27.6%)
	H+BSO+O+A+LND	0/4
	Other	1/1 (100%)
Ovarian conservation	Yes	6/17 (35.3%)	p = 0.386
	No	21/90 (23.3%)
Route of surgery	Open	14/66 (21.1%)	p = 0.406
	Laparoscopic	12/37 (32.4%)
	Vaginal	0/2
Intra-operative surgical spill	Spillage	12/31 (38.7%)	p < 0.001
	No spillage	10/70 (14.3%)

A = appendicectomy, BSO = bilateral salpingo-oophorectomy, H = hysterectomy, LND = lymphadenectomy, O = omentectomy, USO = unilateral salpingo-oophorectomy.

shows the proportion of patients experiencing a recurrence by stage at primary diagnosis. A higher stage at diagnosis was associated with one or more recurrences (p = 0.035).

Documented spillage at time of surgery was associated with a higher risk of recurrence (12/31 (38.7%) compared with 10/70 (14.3%) with no evidence of cyst spillage (p < 0.001); Figure 1c). Spillage was more common in the laparoscopic group compared to the open group (17/37 (46.0%) versus 14/66 (21.2%, respectively)). Data on spillage/no spillage was incomplete or unclear for six of the 107 patients (5.6%). There was an association with the type of procedure and rate of recurrence (p = 0.0097), with higher rates of recurrence in the ovarian cystectomy and unilateral salpingo-oophorectomy groups.

Of the 27 patients who had a recurrence, 15/27 (55.6%) patients developed a second recurrence (

Table 3. Management of recurrence.

Number of Recurrences	1	2	3	4 or More
Patients with recurrence	27/107 (25.2%)	15/107 (14.0%)	9/107 (8.4%)	3/107 (2.8%)
Median time to recurrence (months)	40 (2–247)	26 (11–47)	17 (8–43)	15 (7–15)
Site of recurrence
Pelvis	16/27 (59.3%)	7/15 (46.7%)	2/9 (22.2%)	1/3 (33.3%)
Pelvis and other	7/27 (25.9%)	6/15 (40.0%)	3/9 (33.3%)	1/3 (33.3%)
Other	2/27 (14.8%)	2/15 (13.3%)	4/9 (44.4%)	1/3 (33.3%)
Management
surgery	17/27 (63.0%)	10/15 (66.7%)	5/9 (55.6%)	2/3 (66.7%)
Chemotherapy	1/27 (3.7%)	2/15 (13.3%)	0/9	0/3
Radiotherapy	1/27 (3.7%)	0/15	1/9 (11.1%)	0/3
Hormonal	2/27 (7.4%)	2/15 (13.3%)	1/9 (11.1%)	0/3
Surveillance	4/27 (14.8%)	0/15	1/9 (11.1%)	0/3
Best supportive care	2/27 (7.4%)	0/15	0/9	0/3
Other	0/27	1/15 (6.7%)	1/9 (11.1%)	1/3 (33.3%)
Adjuvant treatment post-surgery	5/17 (29.4%)	4/10 (40.0%)	3/5 (60.0%)	0/3
NMRD post-surgery	14/17 (82.4%)	8/10 (80.0%)	3/5 (60.0%)	1/2 (50.0%)
Surgical complications (stage III Clavien or greater)	1/17 (5.9%)	1/10 (10.0%)	0/5	0/5

NMRD = no macroscopic residual disease.

). The median age at diagnosis, in women who went on to develop recurrent disease, was 50 years (33–85 years) compared to 59 years (24–88 years) in the group without recurrent disease. Recurrence rates by route of primary surgery were not different, but this may be because the data are too small to reliably demonstrate a difference (recurrence in laparoscopic group = 12/37 (32.4%) versus 14/66 (21.0%) in the laparotomy group (p = 0.145)). There were only two patients who had vaginal surgery and neither have yet been diagnosed with recurrent disease.

Surgery was the most common management of recurrent AGCT; however, there was increasing use of a variety of adjuvant treatment modalities with further recurrences. There were shorter intervals and a higher likelihood of incomplete surgical cytoreduction and further recurrences. Table 3 provides information on the site and treatment for those with recurrent AGCT.

3.3. Surgical Complications

A total of 17 of the 107 (15.9%) women had peri-operative complications at primary surgery: 10 patients (9.35%) had Clavien I or II complications; 6 (5.61%) had Clavien III complications; and 1 (0.93%) had a Clavien IV complication. Clavien III complications included return to theatre for wound dehiscence, intra-abdominal haemorrhage, adhesional bowel obstruction, ureteric injury, and incisional hernia. The one Clavien stage IV complication was an intra-operative haemorrhage resulting in unplanned admission to critical care. All (n = 7) significant complications were following open procedures. There was one significant (Clavien III or greater) post-operative complication (Clavien III; intra-operative splenic injury) at first recurrence and one at the time of surgery for second recurrence (intra-operative vascular injury). There were no significant complications after surgical management of third and fourth recurrences. After surgical management of the fifth recurrence, there was one significant complication (intra-operative ureteric injury), and one patient had an intra-abdominal collection requiring drainage after surgery for a sixth recurrence.

3.4. Mortality

There were eleven deaths during the follow-up period (10.3% death rate; with median follow-up of 60 months (range 0–261 months), six due to progressive disease and five due to other causes. The median time from diagnosis to death was 64 months (16–187 months), and the median age of death was 81 years (69.5–85). Of the six women who died due to progressive disease, the median time to death from diagnosis was 84 months (16–187), and the median age at death was 79 years. Two of those who died from progressive AGCT had stage Ic disease at diagnosis (one had an ovarian cystectomy followed by a TAH+BSO in the immediate post-operative period, and the other had an USO with a history of contralateral oophorectomy), three had stage II disease, and one stage III disease (see Figure 2). Two of the six patients who died from AGCT had received adjuvant treatment after primary surgery (both stage II at diagnosis). None of the patients who had a residual ovary following primary surgical treatment (n = 17) have yet died, although 6/17 (35.29%) are currently undergoing active treatment for recurrent disease.

4. Discussion

This study provides a comprehensive description of the management of primary and recurrent AGCT in a large region of the UK. Outcomes in terms of progression-free, disease-specific and overall survival rates in our study group are similar to previously published data1,3. Our cohort of patients had similar estimated survival to the existing literature. This likely reflects the indolent growth and late recurrence of AGCT [18].

In the group who had ovarian conservation, a third developed a recurrence compared to just under a quarter in the group without ovarian conservation. Time to recurrence, however, was longer, with a median of 60 months compared with 40 months in the group without a retained ovary. Although this was not statistically significant, due to lack of statistical power, this raises the question of whether, when performing surgery with the intention of fertility preservation, there should be consideration of contralateral oophorectomy when the woman has completed her family and/or approaches the natural age of menopause. Informed consent is important, especially as all six women with a conserved ovary who had a recurrence did so within their remaining ovary, and only 20% of the pre-menopausal women in the ovarian conservation group went on to have a successful pregnancy. It was not possible to determine whether the low conception rate was due to choice or infertility. At present, there is no conclusive evidence to support a contralateral oophorectomy [19], and as an early menopause can have significant morbidity and mortality, a contralateral oophorectomy could be delayed until menopause. This requires careful counselling of risks and benefits, and if an ovary is conserved, long-term surveillance and reconsideration of completion surgery recommended at regular intervals is recommended, as recurrences can occur many years later. Additionally, there is currently no evidence that HRT is contraindicated in patients with an early-stage AGCT, and this option may be preferred by patients [20].

The safety of a laparoscopic approach has previously been demonstrated [5,12]. Our study showed a higher proportion of complications with open procedures 7/74 (9.5%) compared with laparoscopic surgery (1/39; 2.6%), although this is most likely due to confounding factors, such as age, volume of disease, etc., as those with a small tumour not thought to be malignant are more likely to have had more simple initial treatment. Recurrence rates may be higher in the minimal access group, although we have insufficient numbers to make any firm conclusions, and this may be affected by the higher rates of ovarian-conserving surgery performed laparoscopically in our cohort.

Tumour stage is an important prognostic factor in patients diagnosed with AGCT [21]. In our cohort, rates of recurrence were broadly similar from stage Ib to stage III, although numbers were small. Previous studies have suggested prognostic factors increase the likelihood of recurrence, including age and tumour rupture which are inconsistent between studies [22]. We demonstrated that cyst rupture or spillage was associated with an increased risk of recurrence. Similarly to our data, people with stage I disease receiving adjuvant treatment were more likely to have a recurrence [22], likely attributed to confounding risk factors, which were associated with recommendations for adjuvant treatment, not apparent in our data set. A strong pre-operative suspicion of AGCT might provide an opportunity to take steps to prevent spillage and consequently reduce recurrence risk.

Existing evidence supports cytoreductive surgery as first-line management of recurrence where possible, as macroscopic cytoreduction reduces rates of further recurrence and prolongs survival. With each repeated surgery, the complexity and rate of intra-operative complications are thought to increase [19]. The numbers who had further surgery in our study were too small to draw meaningful conclusions, but may suggest that careful decision-making around surgery can limit complications to acceptable levels. However, as the number of episodes of recurrence increases, the likelihood of achieving macroscopic cytoreduction decreases, and the extent of surgery becomes increasingly complex, often involving upper GI or colorectal procedures. Recently published guidance by the British Gynaecological Cancer Society (BGCS) reports that there is not sufficient evidence to recommend adjuvant chemotherapy in the management of AGCT, but there may be a role for aromatase inhibitors in managing advanced or recurrent disease not amenable to surgical excision [23].

In recent years, patient-initiated follow-up has replaced traditional hospital-based follow-up for some patients following a gynaecological malignancy. As people with AGCT may be amenable to further cytoreductive surgery, if they have low-volume, resectable disease at recurrence, they should be followed-up with tumour markers (inhibin and/or anti-mullerian hormone) for long durations to enable early identification of asymptomatic recurrent disease [24]. The European Society of Medical Oncology (ESMO) recommends lifelong follow-up due to the likelihood of later recurrence and increased risk of secondary malignancy, if managed with chemotherapy [10]. In patients undergoing fertility treatment on the background of AGCT, it is important to individualise their risk of recurrence and consider completion of surgery at a later date. Alternatively, lifelong follow-up with inhibin could be recommended.

Strengths and Limitations

The primary strength of this study is that it is one of only a few relatively large contemporary series of these rare tumours over multiple centres. It therefore reflects a typical clinical population, likely to be representative of management across the UK. There are several potential limitations. As a retrospective study, there is a high risk of selection bias, as patients are not assigned to a pre-determined management group. AGCTs are rare tumours and are commonly diagnosed incidentally. As in any retrospective study, there are missing data, and a few patients were lost to follow-up, although we were able to minimise this by collecting data from an entire region of the UK, and retention rates are good in this specific population. We were not able to consider the effect of variables such as tumour size, performance status and hormonal assays on survival outcomes, as these data were not consistently available.

Our study highlights the heterogeneity of management of patients with recurrent AGCT, particularly in the use of adjuvant treatment. Collaborative research, such as the RaNGO study [25], will hopefully improve data collection for people with AGCT and help further inform best practice. Surgical management of recurrent tumours depends on the resectability of the tumour (site of recurrence), tumour size, and the performance status of the patient. An overall prospective audit tool in patients with AGCT might help develop standardised recommendations for the management of recurrent AGCT.

5. Conclusions

In conclusion, this multicentre retrospective analysis provides information about outcomes for those with AGCT. There is insufficient evidence to definitively recommend completion of surgery once fertility is no longer required, and/or at the average age for menopause. However, there should be discussion of the risks and benefits of completion surgery versus ongoing surveillance to allow for personalised care and informed decision-making. Intra-operative cyst spillage appears to be associated with higher rates of recurrence, although this may be due to confounding factors. Management of recurrence is variable, and it is difficult to draw meaningful conclusions from retrospective, non-randomised data. However, surgery to try and achieve no macroscopic residual disease should be considered for those fit enough who have recurrent disease.