Case Conference January 25th 2017

25-Jan-2017, Divisi Ginekologi Onkologi RSCM

CASE CONFERENCE

January 25^th, 2017

Mrs. X

Central Recurrent Endometrial Cancer stage IB grade 1 (Intermediate risk)

 

Case Description:

Patient had no current clinical complain came with Pap’s smear result of adenocarcinoma. Patient had her operation (hysterectomy and bilateral salphingoooforectomies) on March 17^th, 2016. She had post menopausal bleeding before the operation. Her PA result from operation was endometrioid adenocarcinoma well differentiated (infiltrated up to half of myometrium). She was advised to have radiotherapy but then refused to have the therapy for her personal reason. She had her routine checkups with Pap’s smear every 3 months. The second Pap’s smear result (Oct 17^th, 2016) was adenocarcinoma. Then, she was referred to our hospital by her gyn-oncologist with local recurrent of endometrial carcinoma post surgical staging. On physical examination (Dec 13^th, 2016), mass was seen on the vaginal punctum. Biopsy was done and the result was adenocarcinoma endometrioid well differentiated (same as the previous PA result), probably recurrent. Review slides from the previous operation was adenocarcinoma endometrium type endometrioid well differentiated, infiltrated until more than half of myometrium.

 

Physical examination on January 7^th, 2017:

General status:

CM. BP: 140/90mmHg, HR: 80 bpm, RR: 20x/m, T:36^oC, Height 147cm, Weight 63kg

Head: Pale conjungtiva (-/-)

Neck: lymph nodes (-/-)

Axilla: lymph nodes (-/-)

Thorax: symmetry shape and movement of hemithorax

Cardia: no murmur, no gallop

Abd: flat, no palpable mass

 

Extremity: inguinal lymph nodes (-/-)

 

PA results from biopsy, January 6^th, 2017

 

Adenocarcinoma endometrioid well differentiated (same as the orevious PA result). Note: probably recurrence.

Discussion

 

The patient was considered to be endometrial cancer intermediate risk after the operation. Generally speaking, this The stage I intermediate-risk group includes patients with grade 1 or 2 adenocarcinoma with more than 50% invasion or grade 3 tumours with superficial invasion and the presence of extensive lymph vascular space invasion in the uterine specimen.

 

French Clinical Guidelines 2011

The therapeutic strategy is determined by the risk of recurrence, which is defined by stage, histological type, and grade according to the classification above. The recommended adjuvant therapy from CPG which was published by Querleau on 2011 for the intermediate risk endometrial cancer is postoperative high-dose rate BT. It is recommended instead of EBRT and CT is not recommended.

ESMO-ESTRO-ESGO 2014

Patients considered intermediate risk in the current classification were included in the large randomised trials evaluating the role of adjuvant RT in early-stage endometrial cancer. In these trials, patients were randomised after total hysterectomy with bilateral salpingoophorectomy to pelvic EBRT or observation after surgery.  All three trials and a meta-analysis by Kong  et.a. reported that EBRT reduced the risk of pelvic recurrence by threefold (from 14% to 4%), but did not lead to an OS benefit and came at the cost of increased risk of (predominantly gastrointestinal) toxicity.

 In contrast to the Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-1 trial, surgical staging lymphadenectomy was mandatory in the Gynecologic Oncology Group (GOG)-99 trial, showing that for node-negative disease, EBRT still reduced the risk of recurrence. This risk reduction was mainly caused by prevention of local (vaginal) recurrence. Both PORTEC-1 and GOG-99 defined a subgroup of patients who derived the greatest benefit of adjuvant EBRT, a so-called high-intermediate-risk group. In the PORTEC-1 trial, the definition of risk groups was based on risk factors for locoregional recurrence (age >60 years, deep (≥50%) myometrial invasion, grade 3), with high-inter- mediate-risk patients defined as having two of three of these risk factors. In this subgroup, the 5-year risk of locoregional recurrence was 20% for observation versus 5% for adjuvant RT, and only in this subgroup was the risk of relapse deemed high enough to consider adjuvant RT.

 In the GOG99 trial, the definition of risk groups was based on risk factors for overall recurrence identified in previous GOG studies, with high-intermediate-risk patients defined as: age <50 years and one risk factor, age 50–70 years and two risk factors and age >70 and all three risk factors. Similar results were found in the ASTEC trial, which reported a lower risk of vaginal and pelvic relapse in the no-EBRT group (7% versus 4% in the EBRT arm). In the ASTEC trial, vaginal brachytherapy was allowed in both study arms, and more than 50% of patients in the observation arm received vaginal brachytherapy.

Since adjuvant RT does not improve OS and combined EBRT and brachytherapy for recurrent disease is associated with a high chance of complete remission, not performing routine adjuvant RT is also an option.  However, combined EBRTand brachytherapy for recurrent disease is associated with a higher rate of side effects compared with adjuvant vaginal brachytherapy alone. The recommendations are:

Recommendation 8.2: In patients with intermediate risk endometrial cancer (stage I endometrioid, grade 1 or 2, >50% myometrial invasion, LVSI negative):

1.    Adjuvant brachytherapy is recommended to decrease vaginal recurrence

        Level of evidence: I

        Strength of recommendation: B

2.    No adjuvant treatment is an option, especially for patients aged >60 years

        Level of evidence: II

        Strength of recommendation: C

        Consensus: 100% yes (37 voters)

 

UptoDate:  Adjuvant treatment of intermediate-risk endometrial cancer (2014)

Intermediate-risk patients are defined by cancer confined to the uterus and invading the myometrium (stage IA or stage IB) or cancer that demonstrates occult cervical stromal invasion (stage II). These groups have a higher risk of recurrence than do patients, whose tumors are confined to the endometrium. Women with endometrial cancer can be considered to have low intermediate-risk and high intermediate-risk based on certain pathologic criteria. The GOG defines high intermediate-risk based on age and any of three pathologic factors: the presence of deep myometrial invasion, grade 2 or 3 histology, or the presence of lymphovascular space invasion (LVSI). Women have high intermediate-risk disease if they are: ≥70 years with one risk factor, age 50 to 69 years with two risk factors, or age ≥18 years with all three risk factors. In the GOG 99 trial, two-thirds of all recurrences were in women who met these pathologic criteria. In contrast, the PORTEC-1 trial defines high intermediate-risk by two of three clinicopathologic factors present: age >60 years, outer half myometrial invasion, and grade 3 histology. In the PORTEC-1 trial, women who underwent observation had a higher rate of relapse in the pelvis if these criteria were met.

For women with high intermediate-risk disease, we suggest RT rather than observation. RT can reduce the risk of a local recurrence, although it does not appear to improve OS. In a 2012 meta-analysis Cochrane Database that evaluated the role of adjuvant RT among women with stage I endometrial cancer, there was no significant difference in OS (HR 0.88, 95% CI 0.63-1.22) or endometrial cancer-specific survival (HR 0.80, 95% CI 0.54-1.18). However, the benefit of adjuvant RT for lowering the risk of a local recurrence was demonstrated in GOG-99. Pelvic RT resulted in a reduction in the risk of a local recurrence compared with observation (2 versus 9 percent, HR 0.42, 90% CI 0.21-0.83). Despite this, there was no statistically significant reduction in the risk of death (HR 0.73, 90% CI 0.43-1.26), although the study was not powered sufficiently for this endpoint.

Radiation therapy can be administered as vaginal brachytherapy (VBT), pelvic RT, and in specialized centers, using intensity-modulated RT (IMRT). We recommend vaginal brachytherapy for the treatment of women with high intermediate-risk endometrial cancer. While pelvic RT decreases the risk of a local recurrence, it is associated with more toxicity, including long-term urinary and bowel symptoms. VBT alone for most patients with high intermediate-risk endometrial cancer is preferable because it results in equivalent locoregional recurrence rates compared with pelvic RT and has a more favorable toxicity profile. In the PORTEC-2 trial, 427 women with high intermediate-risk disease were randomly assigned treatment with VBT or pelvic RT. At 45 months, there were no statistically significant differences between VBT and pelvic RT in terms of locoregional recurrence rate (5 versus 3 percent for VBT and pelvic RT, respectively), distant metastases (8 versus 6 percent, respectively), and five-year disease-free survival (83 versus 78 percent, respectively) and OS (85 versus 80 percent, respectively)

Of note, VBT was associated with a significantly lower rate of treatment-related diarrhea and other bowel symptoms (13 versus 54 percent, respectively). Vaginal cuff brachytherapy is typically accomplished using high dose rate (HDR) therapy with an iridium-192 source, but also can be delivered using a low dose rate (LDR). Treatment is initiated three to six weeks following surgery, although some experts prefer to wait up to nine weeks to reduce the risk of vaginal cuff dehiscence. VBT consists of three to five fractions given once or twice weekly on an outpatient basis.

 

PORTEC-2 trial (2010)

This trial included women with endometrial cancer stage I or IIA with features of high-intermediate risk. There were 427 patients who were randomly assigned to either pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6–5.9) for VBT and 1.6% (0.5–4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17–3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8–9.6) for VBT and 2.1% (0.8–5.8) for EBRT (HR 2.08, 0.71–6.09; p=0·17). 1·5% (0.5–4.5) versus 0·5% (0.1–3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32–29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1–13.4] vs 5.7% [3.3–9.9]; HR 1.32, 0·63–2·74; p=0·46). We recorded no differences in overall survival (84.8% [95% CI 79.3–90.3] vs 79.6% [71.2–88.0]; HR 1.17, 0.69–1.98; p=0.57) or disease-free survival (82·7% [76.9–88.6] vs 78.1% [69.7–86.5]; HR 1.09, 0.66–1.78;

p=0.74). VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk.

 

Conclusion

In the first encounter of this patient, she was endometrial cancer stage IB grade 1 (intermediate risk) post TAH-BSO. Adjuvan radiotherapy is the preferable treatment after operation, which can be done by brachytherapy in order to have less toxicity. 

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