Extrafascial hysterectomy after concurrent chemoradiotherapy in locally advanced cervical adenocarcinoma

Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide, accounting for 11% of the total female cancer deaths [1]. Approximately 60% patients of cervical cancer are diagnosed with bulky or advanced diseases that are no longer candidates for primary radical surgery [2]. In the last decade, radiotherapy consisting of external beam radiation and intracavitary brachytherapy, in combination with concurrent platin-based chemotherapy has produced substantial improvement in overall survival (OS) and control of distant recurrence. Definitive concurrent chemoradiotherapy (CCRT) is the standard of care for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB2, IIA2, IIB, IIIA, IIIB, and IVA disease. Many squamous cell carcinoma (SCC) can even be cured by CCRT [3]. Despite these improvements in SCC practice, emerging evidences suggest adenocarcinoma (AC) may be more radio-resistant [3] and nearly 50% of cases still have residual disease (RD) after CCRT [4]. RD after primary CCRT is directly associated to local recurrence. Many researchers have showed a worse prognosis in AC compared with SCC with a 20% difference in OS, and this becomes more apparent as the stage increases [5].

Traditionally, cervical AC is treated similar to SCC. However, there is increasing evidence that AC behaves differently, with different epidemiology, patterns of spread and recurrence, prognostic factors, and response to radiation therapy (RT). In addition, by virtue of screening strategies and human papilloma virus vaccine, the proportion of cervical SCC has decreased. On the contrary, AC has increased to 20% to 25% [5]. Since CCRT for advanced cervical AC is unsatisfactory, a more aggressive therapy is in demand [6]. To evaluate RD and improve local control, adjuvant hysterectomy after radical standard CCRT was investigated since 2004 in Peking Union Medical College Hospital (PUMCH). In consideration of the difficulties in radical excision and retroperitoneal lymphadenectomy after radiation, and to minimize surgery-related complications and morbidity, extrafascial hysterectomy and bilateral salpingo-oophorectomy was performed in patients with advanced AC after CCRT. We conducted this study to determine whether patients received adjuvant hysterectomy have better prognosis than those only treated with a standard CCRT. We also analyzed the features of surgery after CCRT.

We conducted a retrospective study using PUMCH database from 2004 to 2014. This study method was approved by the PUMCH Review Board. Informed consent to chemo, RT and surgery was obtained from all patients in accordance to institutional requirements.

2. Treatment

All the patients received standard RT including external pelvic irradiation and brachytherapy in PUMCH. One course of neoadjuvant chemotherapy (NAC) was added if waiting time for CCRT was longer than 1 month. The radiation doses were dependent on tumor volume with external beam radiation of 40 to 58 Gy and brachytherapy of 30 to 48 Gy. Radiotherapy was completed within 8 weeks. Concurrent chemotherapy including weekly cisplatin (40 mg/m²), or weekly paclitaxel (75 mg/m²) for patients with impaired renal function (glomerular filtration rate <60 mL/min) that was not eligible for cisplatin chemotherapy. Clinical response of radiation was evaluated by imaging and pelvic examination one month after CCRT and cervical biopsy was performed if residue tumor was suspected. In the study group, all the patients received extrafascial hysterectomy and bilateral salpingo-oophorectomy at 10 to 12 weeks after CCRT completion. Vaginal margins, parametrium, lymphovascular space, and cervical stroma were microscopically verified. Any positive findings led to platin-based consolidation chemotherapy of 3 to 6 courses. Chemotherapy regimen included paclitaxel plus carboplatin (TC; T, 175 mg/m²; C, area under the curve=5) or paclitaxel plus cisplatin (TP; T, 175 mg/m²; P, 70 mg/m²) in 21-day schedule. Patients in standard care group also received no less than 3 courses of platin-based consolidation chemotherapy if any sign of residue disease after CCRT. Post-treatment surveillance was every 3 to 6 months for the first 2 years, and annually since the 3rd year (Fig. 1).

Fig. 1
Treatment flow diagram of adjuvant surgical therapy. BSO, bilateral salpingo-oophorectomy; CCRT, concurrent chemoradiotherapy; CR, complete remission; PF, cisplatin plus 5-fluorouracil; TC, paclitaxel plus carboplatin; TP, paclitaxel plus cisplatin.

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In this retrospective cohort, adjuvant hysterectomy after CCRT confers a more favorable prognosis (PFS, PFS at 3 years, and OS) over CCRT alone in LACAC with similar baseline tumor status. To our knowledge, this study is the first report of isolating AC subtype to analyses and showing significant improvement in survival outcomes for LACAC with combination approaches compared with current CCRT. To minimize the confounding by different stage distribution, stage IIB were stratified to be analyzed alone and a similar benefit from adjuvant hysterectomy was demonstrated.

A few previous studies have investigated the value of adjuvant hysterectomy after chemo-RT of locally advanced cervical cancer. Results are controversial. Sun et al. [7] showed an improvement of local disease control in patients with a partial pathologic response and enhanced survival. The study of Motton et al. [8] failed to demonstrate significant improvement of survival by completion surgery and early morbidity was higher after hysterectomy. Moreover, most studies have suggested an improvement in local control but failed to demonstrate an unequivocal benefit in survival [9, 10, 11]. However, major pathology type in these publications were SCC, of which chemoradiotherapy is thought to be efficient and beneficial in improving local disease control [12]. Unlike SCC, it has been demonstrated in several studies that AC are more radio-resistant, which is considered to be an important reason for the poor prognosis associated with AC [13]. Some studies suggest a higher recurrence rates after RT in ACs compared to SCC [14]. Therefore it is more reasonable to separate AC from general cervical cancer in evaluating the efficacy of completion surgery after CCRT separately. Despite the debate involving the clinical significance of completion hysterectomy in locally advanced cervical cancer, it is recognized as an effective approach in reduction of residue disease after CCRT.

RD is recognized as a significant prognostic factor [15] due to its relation to incomplete response to CCRT and future local relapse. Favero et al. [4] reported approximately 30% of the patients with complete clinical and radiologic response submitted to adjuvant hysterectomy had RD on histologic analysis of the specimen, and in 78% of these cases, histologic finding was AC, 50% of AC had pathologic residue disease. This was very similar to our results (47.0%), and the differences of recurrent pattern between the two groups also suggested that completion surgery is a rational method in control of regional and local recurrence. Variable factors may be associated with RD after radical CCRT have been reported in literature [16], however much remains controversial. Although initial tumor size was most relevant to RD, none of those potential risk factors analyzed in this AC series was statistically significant.

Nevertheless, except for seldom patients who were extremely insensitive to CCRT and had gross residue tumor, most patients achieved CR by extrafascial hysterectomy with clear surgical margin in vagina and parametrium. Thus, a less radical hysterectomy might be sufficient. On completion of RT, tissue fibrosis and vascular impairment increase difficulties and complications of surgery [15]. Avoiding radical hysterectomy greatly reduces procedure-related morbidity and postsurgery impairment [17]. In this cohort, we report no severe complication caused by postradiation surgery. Besides, we found that laparoscopic procedure is promising in postradiation hysterectomy with lower blood loss and expedites recovery. The value of laparoscopic surgery in gynecological cancer has been confirmed by several prospective trials [18]. In our opinion, in either laparotomy or laparoscopy, extrafascial hysterectomy is appropriate in local control of bulky or advanced AC after definitive CCRT without grossly residue disease.

Since the frequency of ovarian metastasis is higher in AC than in SCC (5.3% vs. 0.7%) [19], we provide bilateral salpingo-oophorectomy simultaneously. However, due to lack of randomized trial, the prognostic value from oophorectomy needs further investigation.

It is controversial to provide NAC before CCRT in the management of locally advanced cervix cancer. Some published articles which had proved the efficacy of NAC before CCRT [12, 20]. LACC patients in our center who received NAC were dependent on the waiting time for radiation, which was variable due to many social-economic reasons. In addition, the number of cases in this series was too small, that our data could not elucidate the efficacy of NAC in LACAC.

Our study has certain limitations. First, the cohort size is relatively small. Theoretically, randomized control trials could be less prone to bias; however, the only randomized trial in this scenario (GYNECO 02) was closed because of insufficient recruitment of participants who were in favor of completion surgery and refused to participate in the randomization [11]. Second, patients in this study were not randomly allocated to different arm at beginning. Although patients in this study were statistically similar for several known clinical factors between two groups, factors such as tumor stage, NAC before CCRT and some other prognostic or predictive factors may have been unevenly distributed. This is a shortage hardly evitable in retrospective studies. Third, the locally advanced stage includes a wide range of participants in FIGO IA2, IIA2, IIB, and III. Optimal patient selection needs further investigation. Since extrafascial hysterectomy is only capable at local control, we suggest this multimodality treatment should be specifically limited to those without distant metastasis. However, AC patients are associated with higher rate of lymph node metastasis [21]. In that case, previous study noted laparoscopic nodal staging before beginning of CCRT, although it would result in the execution of 2 surgical procedures and consequently, elevate morbidity [4].

In conclusion, our study demonstrates that adjuvant extrafascial hysterectomy and bilateral salpingo-oophorectomy after CCRT improves prognosis for patients with LACAC, compared with current standard of care. It is unknown whether adjuvant chemotherapy and laparoscopic nodal staging before CCRT will have impact on survival outcomes. Further studies are required to define optimal candidates and optimal scheme of this multimodality therapy.