After hysterectomy, what is the role of chemotherapy (concurrent/concomitant, sequential, sandwich, chemoradiation) in the management of early stage high risk endometrial cancer?

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After hysterectomy, what is the role of chemotherapy (concurrent/concomitant, sequential, sandwich, chemoradiation) in the management of early stage high risk endometrial cancer?

Endometrial cancer rates are increasing as obesity rates climb in developed countries such as Australia, where endometrial cancer is now the third commonest cancer affecting women.[1][2] It is predominantly diagnosed in post-menopausal women many of whom present early with bleeding and have stage 1 disease that is highly curable, with an overall long-term survival rate of 80%. However, once disease has spread to involve the deep myometrium, the uterine cervix or beyond (FIGO stage II and above), overall survival rates drop down to 65% and below. Standard post-operative therapy consists of radiotherapy which lowers the risk of local relapse but does not increase survival rates as most deaths occur due to the development of distant metastatic disease.

Although there is some evidence to suggest that adjuvant chemotherapy may be of value, the place of adjuvant chemotherapy remains controversial and as yet no large randomised trial has conclusively demonstrated an overall survival advantage if used in addition to radiotherapy. The relative paucity of high-quality evidence and lack of level 1 evidence means that opinions are divided and recommendations must be made with caution. In order to give women with this disease the best chance of survival it is important to consider all aspects of available evidence and present a balanced view.

In this section the term ‘adjuvant’ chemotherapy is used to refer to chemotherapy given after surgery that results in no visible macroscopic disease. The term adjuvant is not used for the treatment of residual macroscopic disease post surgery, or the treatment of stage IV disease.

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Identification of patients at higher risk of relapse

It is possible to identify a group of patients who are at high-risk of developing relapsed disease at distant sites after initial surgery, despite the use of standard adjuvant pelvic radiotherapy. Important prognostic features that are reflected in the FIGO surgical staging system include the depth of myometrial invasion, the grade of the tumour and the presence of pelvic or para-aortic lymph node involvement.[3][4][5] Lymphovascular space invasion has also been found to be a major prognostic factor which significantly and independently increases the risk of relapse, especially distant relapse.[6][7][8] The histological subtype of disease is also important. Serous and clear cell cancers, which comprise up to 10% and 5% of endometrial carcinomas, respectively, have an inferior prognosis due to aggressive growth and frequent presentation at a more advanced stage.[9]

The five year survival rates for endometrial cancer as a whole, based on the most recent FIGO data are shown in Table 1 below:

Table 1: 5 year overall survival for selected FIGO 2008 stages and grade of endometrial cancer*

Stage and grade Description 5 year overall survival (%)
Stage IB, grade 1 Tumour confined to the myometrium, with invasion equal to or more than half of the myometrium 91
Stage IB, grade 2 86
Stage IB, grade 3 75
 
Stage II, grade 1 Tumour invades the cervical stroma, but does not extend beyond the uterus 81
Stage II, grade 2 77
Stage II, grade 3 65
 
Stage IIIA, grade 1 Tumour invades the serosa of the corpus uteri and/or adnexae 83
Stage IIIA, grade 2 71
Stage IIIA, grade 3 45
 
Stage IIIB, grade 1 Vaginal and/or parametrial involvement 75
Stage IIIB, grade 2 45
Stage IIIB, grade 3 31
 
Stage IIIC, grade 1 Metastases to pelvic and/or para-aortic lymph nodes 67
Stage IIIC, grade 2 61
Stage IIIC, grade 3 51

* Based on the 26th volume of the FIGO annual report of the treatment of carcinoma of the corpus uteri[10]

What evidence exists regarding the role of chemotherapy?

Retrospective data

Multiple influential retrospective reports about the experience of using adjuvant chemotherapy have been published. Unfortunately the role of selection bias inherent in all of these retrospective studies is a major confounding variable making it impossible to provide high-quality recommendations for the treatment of women on the basis on these data. Some of the larger reports are described in the Appendix.

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Randomised controlled trials comparing the use of adjuvant chemotherapy alone with the use of adjuvant radiotherapy alone

Several prospective randomised trials involving adjuvant chemotherapy have been performed. Unfortunately, the results are not conclusive, with many of the studies being under powered and having significant variation in eligibility criteria as well as the nature of the control and intervention arms. Three trials have compared the use of adjuvant chemotherapy alone with the use of adjuvant radiotherapy alone.[11][12][13] Two of these trials, from Italy and Japan, showed no difference in survival outcomes between the two treatments, while the GOG122 study suggested a survival benefit from adjuvant chemotherapy in women with stage III and IV disease compared to the use of whole abdominal radiotherapy alone.[11][12][13] The full results of these trials are described in detail in the Appendix, and also summarised in Table 2.

Of note, the pelvic recurrence rate was high (up to 18%) in the chemotherapy alone arm of the GOG122 trial. However, this trial suggests that there is a role for chemotherapy in the treatment of women with advanced endometrial cancer, particularly those who are incompletely staged or have residual disease at the completion of surgery. However, the role of chemotherapy in the treatment of women with stage III disease and no macroscopic disease at the completion of surgery is uncertain given the negative results of the Italian trial in which two thirds of the patients had stage III disease.


Table 2: Randomised trials comparing adjuvant chemotherapy with adjuvant radiation treatment

Author Eligible patients Patient numbers Treatment arms 5year          PFS 5year OS Comments
GOG122

Randall et al[11]

Stage III-IV disease of any histology. Residual disease less than 2cm allowed 202

194

WAI

Cisplatin and doxorubicin x 6

38%

50%

P < 0.01

42%

55%

P < 0.01

Chemotherapy superior but associated with more toxicity

WAI not optimal RT

No clear benefit with serous histology

Italian study

Maggi et al[13]

 

FIGO 1988 stage IC grade 3, stage II grade 3 with > 50% myometrial invasion or stage III

 

Serous or clear cell excluded

166

174

Pelvic XRT

Cyclophosphamide, doxorubicin and cisplatin  x 5

63%

63%

P = ns

 

66%

69%

P = ns

No significant difference in survival outcomes.

Trend suggesting chemotherapy lowered distant relapse and XRT lowered local relapse

JGOG- 2033

Susumu et al[12]

FIGO 1988 stage IC – IIIC endometrioid endometrial cancer with > 50% myometrial invasion 193

192

Pelvic XRT

Cyclophosphamide, doxorubicin and cisplatin  x 3

83.5%

81.8%

P = ns

85.3%

86.7%

P = ns

No difference in survival outcomes. Post-hoc analysis suggested improved survival with chemotherapy in a ‘high-intermediate’ risk group but not in those with ‘high’ risk disease

Abbreviations: PFS – progression free survival, OS – overall survival, WAI – whole abdominal irradiation, XRT – Radiotherapy, ns – not significant

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Randomised controlled trials comparing sequential adjuvant chemotherapy and radiotherapy to adjuvant radiotherapy alone

Four trials have compared the use of pelvic radiotherapy alone with a combination of chemotherapy and pelvic radiotherapy treatment (table below).[14][15][16] None of these trials have demonstrated a statistically significant improvement in overall survival with the addition of adjuvant chemotherapy to radiotherapy. However, all of the trials are small and underpowered to detect an overall survival difference, with two trials (ILIADE-III and GOG 34) closing prematurely due to poor accrual. The full results of all of the individual trials are described in the Appendix.

Author and year of publication Eligible patients No Treatment arms 5year PFS 5 year OS
GOG 34

Morrow et al[14]

1990

Clinical stage I or II with ≥1 high risk factor 89

92

Pelvic RT

Pelvic RT followed by doxorubicin x 6

-
61%

66%

P = ns

Finnish trial

Kuoppala et al[15]

2008

FIGO 1988 stage IA-IB grade 3 or stage IC-IIIA of any grade 72

85

Split-course Pelvic RT

Sequential cisplatin, adriamycin, cyclophosphamide  x3 plus split-course pelvic RT

Median18mo

Median25mo

P = ns

84.7%

82.1%

P = ns

NSGO-EORTC

Hogberg etal[16]

2010

Stage I-III disease including serous and clear cell histology. No residual macroscopic disease 191

187

Pelvic RT

Pelvic RT with various types of chemotherapy x 4 before or after

72%

79%

P = 0.04

76%

83%

P = ns

ILIADE-III

Hogberg et al[16]

2010

FIGO 1988 stage IIB or III disease. Serous and clear cell histology excluded 76

80

Pelvic RT

Doxorubicin and cisplatin X3  followed by pelvic RT

61%

74%

P = ns

73%

78%

P = ns

Pooled  NSGO and ILIADE-3

Hogberg et al[16]

2010

As above 267

267

Pelvic XRT

Pelvic XRT plus chemotherapy

69%

78%

P = 0.009

75%

82%

P = ns

Split course Pelvic RT: 28Gy each separated by a pause of three weeks

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Combined analysis of MaNGO and NSGO/EORTC trials

The results of two trials ILIADE-III and NSGO-EORTC, which were individually underpowered, have been presented in a single combined publication with an analysis of pooled results.[16] Although the trend in both of these trials is for a benefit from the use of adjuvant chemotherapy, there was still a lack of an overall survival benefit in the pooled results. It is unclear if this has occurred because of lack of power or because not all of the very variable treatments used in the NSGO/EORTC trial have an equal effect, with most patients receiving older-style doxorubicin and cisplatin chemotherapy and the radiotherapy not being standardised. In subset analysis, there appeared to be similar treatment effects with regard to age, grade, stage, or whether or not a lymphadenectomy was performed. However, there was an apparent lack of benefit in patients with serous and clear cell carcinomas.

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Randomised controlled trial comparing two different adjuvant chemotherapy regimens post adjuvant radiotherapy

GOG184

The GOG184 study compared a primary endpoint of relapse-free survival using two different adjuvant chemotherapy regimens (cisplatin and doxorubicin versus cisplatin, doxorubicin and paclitaxel [TAP]) given to 522 eligible randomised patients.[17] Further details are described in the Appendix. After a median follow-up of 47 months these was no difference in the primary outcome of the relapse free survival rate between the two groups (62 versus 64%; p = 0.21), despite this regimen being more active in the setting of advanced endometrial cancer.[18] Survival data are not yet mature for final analysis; however the trial results so far would not support the use of TAP chemotherapy in the adjuvant setting given its significant toxicity.

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Data about which chemotherapy is most active in the adjuvant treatment of endometrial cancer

Limited data is available about what is the most active chemotherapy treatment in the adjuvant setting, as the trials described earlier have used a range of different regimens. Single-agent treatment does not appear to be effective. The trials that have suggested some benefit from the use of adjuvant chemotherapy have used cisplatin and doxorubicin, or also allowed platinum-containing doublets such as carboplatin plus paclitaxel.[16] Trials performed in the metastatic setting, including a meta-analysis, have determined that the addition of anthracyclines (e.g. doxorubicin) or taxanes (e.g. paclitaxel) to cisplatin increases the response rate, although leads to greater toxicity.[9][19] A randomised GOG trial comparing doxorubicin and cisplatin (AP) therapy with adriamycin, cisplatin and paclitaxel with filgrastim support (TAP) for women with measurable stage III, stage IV or recurrent endometrial carcinoma showed an improved response rate (57% versus 34%) and a significantly longer median survival of 15 versus12 months (58% versus 50% one-year survival) for TAP.[18] About half of the women in this trial had received prior radiotherapy to the pelvis. However the TAP regimen resulted in significantly increased neurotoxicity and may not be suitable for older patients.[18] Doxorubicin and paclitaxel is not superior to doxorubicin and cisplatin.[20] Carboplatin and paclitaxel therapy appears to be as effective and less toxic than AP or TAP, based on single arm studies, and may be more suitable for older patients.[21][22][23] A GOG trial addressing this question by comparing carboplatin and paclitaxel with TAP in metastatic disease has recently completed accrual.

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Data available about the role of chemo-radiation in adjuvant therapy

The rationale for the addition of concurrent platinum-based chemotherapy to adjuvant radiotherapy to the pelvis is based on the premise that it should further improve local control rates by sensitising tumour cells to the effects of irradiation. The approach of combining platinum-based chemotherapy with radiotherapy has proven to increase treatment efficacy in a number of tumour types including head and neck, esophageal and cervical carcinomas. Four pilot studies have indicated concurrent radiotherapy and chemotherapy to be tolerable in endometrial cancer.[24][25][26][27] A small (46 patients) RTOG phase II trial of concurrent radiotherapy and cisplatin (two courses), followed by four courses of cisplatin and paclitaxel for high risk or advanced stage endometrial carcinoma has confirmed the feasibility (98% completion rate) and acceptability of the regimen.[25] Surgery consisted of TAH-BSO with or without additional surgical staging. Patients were treated with pelvic RT (45 Gy in 1.8 Gy fractions) plus vaginal brachytherapy. Concurrent chemotherapy with cisplatin 50 mg/m2 was given on days 1 and 22. After RT completion, patients received four additional cycles of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2) at 28-day intervals. Two-year disease-free and overall survival rates were 83% and 90%. The two-year rates of pelvic, regional, and distant recurrence were 2%, 3%, and 17% respectively.

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Prospective data available about the adjuvant management of uterine papillary serous (UPSC) and clear cell carcinomas (CCC)

A number of small phase II prospective trials in women with UPSC and CCC have been reported. The role of whole abdominal radiotherapy (WART) was evaluated in the GOG 94 trial.[28] Five year progression free survival was relatively higher at 38%. The majority of recurrences were within the radiation field, which led the author to conclude that a combination of chemotherapy and radiotherapy may improve survival outcomes.

The Hoosier Oncology Group reported outcomes of a phase 2 study on 21 patients with stage I and II (pelvic and para-aortic node negative) UPSC and CC. Patients received intraperitoneal radioactive phosphorus ± vaginal brachytherapy. The treatment was extremely well tolerated, with minimal toxicity.[29] The study reported an overall two-year survival rate of 93.3% in the 17 patients who had undergone comprehensive surgical staging. There were two intraperitoneal and two vaginal recurrences (seen in patients who did not receive vaginal brachtherapy).

A prospective clinical trial by Fields and colleagues evaluated pelvic radiation treatment ‘sandwiched’ between six cycles of paclitaxel/platinum chemotherapy in 30 patients with stage I to IV UPSC and reported an overall survival of 75% for patients for stage I and II UPSC and 52% for advanced disease (stages III and IV) at two years.[30] Twelve of the 29 patients available for follow-up (41%) recurred despite this treatment, including 5 of the 16 patients (31%) with stage I disease.

A prospective Canadian cohort study by Lupe et al treated 43 patients with stage III (n=38) and stage IV (n=5) endometrial carcinoma with four cycles of adjuvant carboplatin and paclitaxel chemotherapy followed by pelvic radiotherapy (45Gy) and then another two cycles of chemotherapy.[31] The majority of patients had non-endometrioid histology with serous being the most common (49%). The regimen was feasible to deliver with 81% completing the six cycles of chemotherapy and a manageable rate of acute toxicity. However five patients (12%) experienced chronic grade 3 radiation toxicities. After a median follow-up of 30 months, 21 patients (49%) had recurred, mostly at distal sites, with the estimated three year disease-free and OS rates being 53% and 68% respectively. The small numbers prevented further analysis of the results by subtype. There have also been other single-arm reports of using this ‘sandwich’ approach to adjuvant therapy in endometrioid endometrial cancer.[32] However, the only randomised trial reported to date using this approach was negative.[15]

A phase II clinical trial from Australia, enrolled 31 patients with surgically staged Ib-IV UPSC who were treated with four cycles of adjuvant carboplatin (AUC 5) and paclitaxel 175 mg /m2 chemotherapy prior to receiving 50.5 Gy of external beam radiotherapy to the pelvis. The treatment was feasible to deliver and patients reported a stable quality of life with acceptable toxicity. After a median follow-up of 27 months, 13 of the 29 patients with stage 1-3 disease (44.8%) and both of the patients with stage 4 disease developed recurrent disease. The two year survival probabilities were 85.6% for patients with stage 1 or 2 disease and 68.8% for patients with stage 3 disease, and survival rates did not appear superior to a group of historical controls.[33]

Unfortunately, due to the small patient numbers in any one country, there have been no randomised trials that specifically evaluate the use of adjuvant therapy in UPSC and CC. However, this subgroup of patients have been included in some of the randomised trials described earlier on the basis that their disease is also chemo-sensitive and seems to have similar response rates to chemotherapy in the advanced disease setting.[9]

In both the NSGO/EORTC and GOG122 trials, it was not clear that patients with UPSC obtained any benefit from the use of adjuvant chemotherapy. In the NSGO/EORTC trial, patients with serous or clear cell histology made up 37% (n=140) of the trial population. In this subset neither PFS (72% versus 71%), cancer-specific survival (77% versus 78%), nor OS (85% versus 82%) was significantly improved by the addition of the chemotherapy treatment. This finding is similar to what was seen in the GOG122 trial, where the hazard ratio (HR) for death in the 83 women with serous carcinomas was slight above 1.0 in contrast to the HR of 0.48 favoring chemotherapy for the endometrioid cell types.

Although no firm conclusions can be drawn from these results due to small absolute numbers of patients, the trends do not suggest that the addition of adjuvant chemotherapy and/or radiotherapy improves the problem of a high relapse rate for women with UPSC and CC, and it is appropriate that these women are included in the ongoing randomised trials. In addition, it is imperative that alternative molecular targets are identified and pursued in adequately powered prospective trials in this group.

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Conclusion

The randomised trials reported to date show no clear overall survival benefit from the use of adjuvant chemotherapy for stage I – III endometrial cancer, with the exception of the GOG122 trial showing that systemic chemotherapy is superior to the use of a sub-optimal radiotherapy regimen. Hence, the value of adjuvant chemotherapy in the management of high-risk endometrial cancer remains uncertain and there is no group of patients with completely resected disease for whom a benefit is clearly demonstrated. Those with stage IV or gross residual disease after surgery do appear to benefit from chemotherapy.

It is likely that some combination of chemotherapy and radiotherapy will be needed to obtain a benefit in earlier stage patients. However, the best type of combination remains to be determined and much more attention needs to be given to the impact of treatment on patient quality of life. Given that many of the trials reported to date are significantly underpowered, with improvements in PFS being seen in some of the more recent studies, the ongoing appropriately powered adjuvant studies being run by the GOG and Gynecologic Cancer Intergroup need to be supported to reach their accrual targets.

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Evidence summary and recommendations

Evidence summary Level References
The use of adjuvant chemotherapy alone is not superior to the use of adjuvant pelvic radiotherapy alone in women with stage I - III cancers that have been completely resected with no residual macroscopic disease. II [12], [13]
The use of adjuvant chemotherapy plus radiotherapy may improve disease-free and cancer-specific survival compared to the use of adjuvant radiotherapy alone in women with completely resected high-risk stage I-III disease. The benefit is predominantly seen in endometrioid histology. This form of treatment has not been proven to improve overall survival and the impact on quality of life is unknown. II [15], [16]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with completely resected stage I-III high-risk disease can be counselled that the use of adjuvant chemotherapy in addition to radiotherapy may improve progression-free survival rates compared to the use of adjuvant radiotherapy alone, particularly if their histology is endometrioid.
There is no evidence that overall survival is improved. These patients should be encouraged to consider enrolment into clinical trials addressing this question.
B


Evidence summary Level References
Some retrospective series suggest that a combination of chemotherapy and radiotherapy may produce better outcomes than radiotherapy alone or no adjuvant treatment in women with UPSC or clear cell carcinomas. III-3 [34], [35], [36], [37], [38], [39], [40], [41]
Adjuvant chemotherapy and radiotherapy has been safely given in prospective single-arm studies, although recurrence rates remain high (up to 18%). IV [29], [30], [31], [33]
Subset analyses of randomised trials show no evidence of improved survival from the use of adjuvant chemotherapy in women with UPSC or clear cell carcinomas. III-3 [11], [16]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with uterine papillary serous cancer (UPSC) or clear cell (CC) uterine cancer should be counselled that there is only low level evidence that adjuvant chemotherapy may have any impact on survival.
D


Evidence summary Level References
The optimal sequence of sequential adjuvant chemotherapy and radiotherapy is unknown. Adjuvant chemotherapy can be safely given before or after radiotherapy. In the trial suggesting most benefit from sequential treatment, the majority of patients received chemotherapy after radiotherapy.
The most effective and reasonably-tolerated chemotherapy for advanced endometrial cancer appears to be a combination of cisplatin and doxorubicin, or carboplatin and paclitaxel.
II [15], [16]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients treated with sequential adjuvant chemotherapy and radiotherapy may receive the full course of chemotherapy either before or after radiotherapy, or given as part of a sandwich regimen.
Acceptable chemotherapy regimens include cisplatin and doxorubicin or carboplatin and paclitaxel.
C


Evidence summary Level References
The use of chemotherapy alone may improve overall survival compared to the use of radiotherapy alone in women with stage IV disease or stage III disease with residual tumour present at the completion of surgery.
The rates of pelvic relapse are high (up to 18%) if adjuvant chemotherapy alone is used.
II [11]
Evidence-based recommendationQuestion mark transparent.png Grade
The use of chemotherapy should be considered for patients with stage IV disease or those with stage III disease plus residual disease at the completion of surgery. Pelvic radiotherapy should also be considered to reduce the risk of pelvic relapse, except perhaps in patients with widespread distant disease.
B


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Appendix

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Supporting material

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