Adenocarcinoma is the second most prevalent histological type of cervical cancer: the incidence of invasive cervical adenocarcinoma has dramatically increased over the past few decades, accounting at present for about 25% of all invasive cervical cancers.1,2 Moreover, it has been reported that these tumors are associated with a worse prognosis due to their precocious tendency to metastasize to lymph nodes and their less sensitivity to radiotherapy. The Gynecologic Oncology Group’s 5 randomized trials accruing almost 2000 patients with cervical cancer have stated concomitant chemoradiation therapy (CCRT) as the standard treatment of locally advanced cervical cancer. In the recent years, neoadjuvant chemotherapy (NACT) followed by surgery has attained great interest in the treatment of locally advanced cervical cancer. In 1999, the National Cancer Institute Alert strongly supported its use in all patients with uterine cervical cancer; accordingly, a meta-analysis carried out by the Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Meta-analysis Collaboration group3–7 suggested a highly significant reduction in the risk of death for NACT followed by surgery, compared with radiotherapy alone, for stage IB2–IIB patients in particular.
The rationales for the use of NACT are several. Tumor size reduction may facilitate subsequent local therapy, both for radiotherapy and surgery, transforming inoperable tumors into radically resectable ones. Furthermore, it treats also the micrometastatic dissemination of disease, preventing a significant proportion of relapses.8 Cisplatin has been established to be the most effective cytotoxic drug against cervical carcinoma,9 and many cisplatinum-based combinations have been investigated.10,11 Until now, few of these randomized studies have included patients with cervical adenocarcinoma; therefore, most of our knowledge on the treatment of this disease comes from studies in which the majority of the patients had squamous histotype comprising adenocarcinoma, on average, 10% of those cases. Moreover, only a few of the studies report separate outcomes in detail for adenocarcinoma, and no prospective study has focused solely on the treatment of adenocarcinoma. As a result, our understanding of the natural history and optimal management of adenocarcinoma of the cervix is limited, and the poorer outcome of this tumor calls for new therapeutic strategies particularly in locally advanced disease.
This phase II trial was designed to evaluate the toxicity and activity of NACT with cisplatin-adriamycin-paclitaxel (TAP) in patients with locally advanced cervical adenocarcinoma (LACA). This chemotherapy combination has been reported to be active in several previously reported cervical cancer series.12–14
MATERIALS AND METHODS
Patients with newly diagnosed invasive FIGO (International Federation of Gynecology and Obstetrics) stage IB2–IIB cervical adenocarcinoma were entered into this study. All patients signed written informed consent to receive the proposed treatment, and institutional review board approval was obtained. The eligibility criteria were as follows: age 75 years or younger; performance status 2 or less; adequate bone marrow function (white blood cell count ≥3000 m3, platelets ≥100,000/µL, hemoglobin ≥9 g/L); and normal renal and liver functions (creatinine ≥1.5 mg/dL, bilirubin ≤2 mg/dL, AST (aspartate transaminase) and ALT (alanine transaminase) <1.5× upper normal limit), no active infections. The pretreatment workup included clinical examination, chest radiography, abdominopelvic magnetic resonance imaging, and electrocardiography.
The schedule of chemotherapy was as follows: cisplatin 70 mg/mq during 30 minutes, adriamycin 45 mg/mq bolus, and 3-hour paclitaxel 150 mg/mq intravenously day 1 every 21 days for 3 cycles. All patients received appropriate antiemetic prophylaxis. Two weeks after the end of the last cycle of chemotherapy, patients were evaluated for the objective response and operability, based on a second magnetic resonance imaging, chest radiography, and clinical examination. Clinical response was defined according to RECIST (Response Evaluation Criteria In Solid Tumors) version1.1 criteria as follows: a complete response (CR) indicated the disappearance of all measurable disease; a partial response (PR) was a 30% or greater reduction in the sum of the largest diameters of all the measurable lesions with no appearance of new lesions; stable disease (SD) was defined as a reduction less than 30% or an increase less than 20% in the sum of the largest diameters of all the measurable lesions; and progressive disease (PD) was a 20% or greater increase in sum of the largest diameters of all the measurable lesions. Toxicity assessment was performed according to World Health Organization criteria version 4.0. In case of white blood cell count of less than 3000/µL, neutrophil count less than 1500/dL, and/or platelets less than 100,000/µL, treatment was postponed by 1 week. If white blood cell count was less than 1000/µL, neutrophil count less than 500/dL, and/or platelets less than 50,000/µL for a period longer than 5 days, the drug doses were reduced by 20% in the next cycle. Granulocyte colony-stimulating factor was administered at a dose of 5 µg/kg subcutaneously daily in cases of grade 4 neutropenia. Four weeks after the end of chemotherapy, the patients in clinical response underwent type III nerve-sparing radical hysterectomy and systematic pelvic and para-aortic lymphadenectomy when indicated. The surgical specimens were carefully examined to assess the following parameters: no residual tumor (pCR), residual disease with less than 3-mm stromal invasion (pR1), residual disease with more than 3-mm stromal invasion (pR2), parametrial involvement, vaginal involvement, lymph node involvement, and lymphovascular space involvement. Pathological response was defined according to the TNM classification. Patients with residual tumors in surgical specimens were referred to additional chemotherapy (if peritoneal disease was detected during surgery and/or para-aortic nodes were positive) or radiation (if 2 of 3 of the following criteria were present: stromal infiltration >50%, grade 3 tumor, and/or lymphovascular space involvement) or chemoradiation therapy (if surgical margins, lymph nodes, or parametrial tissue was positive). After completion of the entire treatment plan, the patients were evaluated every 3 months for the first year and every 6 months thereafter.
All analyses were done on an intention-to-treat basis. Overall survival (OS) was defined as the time from the start of chemotherapy until death. Progression-free survival (PFS) was measured from the start of chemotherapy to the time of relapse or disease progression. Survival was calculated according to the method of Kaplan and Meier. Statistical analysis was carried out using SOLO (BMDP Statistical Software, Los Angeles, CA).
Between April 2003 and August 2010, 30 patients with newly diagnosed invasive FIGO stage IB2–IIB cervical adenocarcinoma admitted to the National Cancer Institute of Milan were entered into this study. The baseline characteristics of enrolled patients are summarized in Table 1. Nine cases were represented by FIGO stage IB2 tumors (30%), whereas the remaining 21 (70%) were stage IIB tumors: the prevalent histotype was adenocarcinoma (80%), whereas the others were represented by serous (13.3%), clear cell (3.3%), and mucinous (3.3%) tumors, respectively. Eight patients (26.7%) presented with enlarged suspicious positive lymph nodes at the pretreatment workup: in 5 patients (62.5%), only pelvic lymph nodes were involved, whereas in the remaining 3 cases also the para-aortic nodes were suspicious (37.5%).
A total of 90 cycles of chemotherapy were administered with a median of 3 cycles for patients; 2 dose reductions due to G4 neutropenia were performed, whereas no cycle delays due to toxicity were registered. There were no treatment-related deaths. All patients were assessable for toxicity (Table 2). Hematologic toxicity was the most relevant: in particular, grade 3–4 leukopenia and grade 3–4 neutropenia, the most common adverse events registered, occurred in 6 (20%) and 17 (56.7%) patients, respectively; no grade 3 anemia and thrombocytopenia were encountered, and no case of febrile neutropenia was registered. Nonhematologic toxicity was generally mild, except for gastrointestinal toxicity; grade 3 nausea and vomiting occurred in 7 patients (39%). Alopecia affected 100% of patients. Grade 2 or higher neurotoxicity was described in 5 patients (16.7%).
After completion of chemotherapy, clinical response was achieved in 24 patients (80%) with 14 CRs (46.6%) and 10 PRs (33.3%); 6 patients (20%) reported an SD, whereas no PD was registered. All the patients were defined eligible for surgery and underwent type III nerve-sparing radical hysterectomy, including bilateral pelvic lymphadenectomy and para-aortic lymphadenectomy when positive pelvic lymph nodes were detected, or when pretreatment workup indicated suspicious para-aortic nodes, and were assessable for pathological responses (Table 3). Objective pathological responses were as follows: 3 patients (10%) achieved a pCR, 6 patients (20%) achieved a pR1, whereas in the remaining 21 patients (70%) a macroscopic (> 3 mm; pR2) residual disease was detected. Lymph node involvement was noted in 33.3% (n = 10) of patients (all the 8 patients with suspicious lymph nodes at staging workup had confirmed positive nodes at pathological evaluation, and in 2 additional patients, micrometastases were detected in pelvic nodes). In most patients, only pelvic lymph nodes were involved (7 patients, 70%), whereas in 2 patients (20%) both pelvic and para-aortic lymph nodes were positive, and in 1 patient only para-aortic lymph nodes were metastatic (10%). Lymphovascular space involvement was detected in 22 patients (73.3%); metastatic disease in vagina and parametrium was present in 8 (26.7%) and 5 patients (16.7%), respectively, and 4 patients (13.3%) presented with positive surgical margins. In 1 patient, positive pelvic peritoneal nodes were detected. Complications related to radical surgery were mild and manageable, including wound infections in 1 patient (3.3%), lymphocyst in 3 patients (10%), and temporary (<20 days) bladder atony in 3 patients (10%); no additional complications such as bowel or vascular or urinary injuries were observed. Eighteen patients (60%) received adjuvant treatment: 7 (38.9%) received adjuvant chemotherapy according to the same scheme used in the neoadjuvant setting, whereas 11 (61.1%) were treated with adjuvant radio with or without concomitant chemotherapy. Overall, there were 9 recurrences (30%), including locoregional recurrence in 4 cases (44.4%), distant recurrence in 3 patients (33.3%), and both local and distant recurrences in the remaining 2 patients (22.2%). Risk factors for recurrence were stage (22.2% of stage I patients recurred vs 28.6% of stage II patients P = 0.72), positive lymph nodes (9 of 10 patients with positive nodes experienced recurrent disease), peritoneal disease, parametrial (60% of patients recurred), vagina (37.5% of patient recurred), and LVSI involvement (27.3% of patients recurred). Finally, positive margins (2 of 4 patients with positive margins recurred) and pathological response to treatment (16.7% of pR1 patients vs 38.1% of pR2 patients recurred P = 0.32) greatly impacted on the occurrence of recurrent disease. The recurrences were treated with radical surgery in 2 patients (22.2%), salvage chemotherapy in 4 patients (44.4%) and CCRT in the remaining 3 patients (33.3%,). After a median follow-up of 45 months (range, 8–98 months), the median PFS was 37 months (range, 1–98 months), and the median OS was 48.1 months (range, 9–101+ months); 5-year PFS and OS were 70.3% and 89.9%, respectively (Figs. 1 and 2). Quite surprisingly, no difference was seen in PFS or OS according to pathological responses or stage of disease at diagnosis (Table 4).
Until now, concomitant chemoradiotherapy is considered the standard treatment for locally advanced cervical cancer. Nevertheless, NACT followed by surgery has attained great interest. While expecting the results of the European Organization for Research and Treatment of Cancer 55994 trial comparing NACT followed by surgery versus concomitant chemoradiotherapy, the first option may represent an alternative to standard treatment in stage IB2–IIB tumors. The treatment of women with advanced cervical adenocarcinoma is still challenging: these patients exhibit poorer outcome with respect to squamous cervical cancer patients possibly because of their greater lymphatic spread and their less sensitivity to radiation therapy.15 A recent report showed the 5-year survival rates for stages I, II, III, and IV cervical adenocarcinoma to be 79%, 37%, 20%, and less than 9%, respectively.16 Moreover, pelvic failure with or without systemic components and the frequent involvement of the peritoneum at diagnosis emphasize the need to test new systemic treatment alternatives to improve survival in patients with LACA.
The activity of TAP combination in cervical adenocarcinoma has recently been described by Kimura et al,17 which reported 42% response rate, 8 months’ median PFS, and 13 months’ median OS in the salvage treatment of a population of 19 heavily pretreated cervical cancer patients.
The successful use of NACT has also been reported in another Italian study where patients with LACA were given platinum-based combinations for 2 or 3 cycles, followed by surgery18; the 5-year survival of 88% provided evidence of the chemosensitivity of cervical adenocarcinoma and supports the successful strategy of chemosurgical approach.
Our data suggest that the combination of TAP in the setting of NACT for the management of LACA is a safe and feasible treatment, with a clinical overall response rate of 80% enabling up to 100% of patients susceptible to radical surgery at the conclusion of 3 cycles, at the cost of a mild and acceptable overall toxicity. Even though a direct comparison across heterogeneous phase II studies should be taken with caution, the pathological complete and optimal (pCR + pR1) response rates of 10% and 30%, respectively, registered in our population fit well with what was previously reported in other series of squamous cervical carcinoma with NACT regimens burdened with a heavier toxicity19 and even better with respect to what was recently reported in smaller series of cervical adenocarcinoma with the same neoadjuvant combination chemotherapy.14 These figures are also in line with what was reported for definitive CCRT in patients with cervical adenocarcinoma.20–21 Quite surprisingly and not in accordance to what was previously reported by other authors,19 our data do not sustain that the pathological response to NACT is a strong and potent predictor of survival, but this may be possibly related to the small number of patients, which further reduces when stratified according to the pathological response. The impact of pathological response on recurrence rate seems to support this issue.
Shibata et al22 reported their experience in a population of 25 LACA treated with neoadjuvant CCRT and radical surgery. In a population of patients with more advanced disease (16% were represented by FIGO stages IIIB and IV), the authors registered a 52% optimal pathological response, although a 31.5% of disease persistence in the lymph nodes was detected. Moreover, the prize of the chemoradiation-surgical strategy was very high: intraoperative complications (visceral injuries) were registered in 16% of patients, clinically significant blood loss in 31% of patients, early postoperative complications (bladder atony, pelvic abscess, and lymphocyst) in 42%, and hematologic and non hematologic grades 3 to 4 toxicities in 60% and 42% of patients, respectively. Poujade et al23 in a population of 52 LACA patients treated with CCRT and surgery identified several predictive factors of absence of response to CCRT, suggesting that in presence of menopausal status, parametrial invasion, lymphovascular space involvement, and mucinous subtype patients should be oriented versus alternative treatments. To further ameliorate the clinical outcome of the disease, Tang et al24 reported their experience of CCRT and adjuvant chemotherapy versus CCRT alone in the largest randomized trial ever published on cervical adenocarcinoma. From 1998 to 2007, 880 patients with clinical FIGO stages IIB–IVA cervical adenocarcinoma were randomized to receive either CCRT or chemoradiation followed by 3 cycles of paclitaxel (135 mg/m2)–cisplatin (75 mg/m2) chemotherapy. At a median follow-up of 60 months, patients who received chemoradiation with adjuvant chemotherapy showed a significantly longer disease-free and cumulative survival (60.4% vs 71.4%). Patients who received CCRT alone had significantly more distant metastasis and pelvic failure than those in the experimental arm, which paid on the contrary the prize of a significant increase in hematologic and non hematologic toxicities.
This strategy, although extremely interesting, is lacking the possibility of evaluating the pathological response to neoadjuvant treatment on the surgical specimen and does not allow the pathological evaluation of lymph nodes status, which remain the most important prognostic indicator of survival, 2 aspects that should be taken into account to select which patients need adjuvant treatments avoiding to others the toxicity of unnecessary chemotherapy. The 31.5% of positive nodes after neoadjuvant chemoradiation and our 33.3% of lymph node metastasis after NACT raise the question of the relative inefficacy of both strategies on retroperitoneum. The presence of positive nodes has recently been confirmed as an independent prognostic factor before neoadjuvant chemoradiation, and given the high rate of persistence of disease after both the neoadjuvant options, patients with locally advanced disease should be counseled about the opportunity to receive a surgical staging of the retroperitoneum to better tailor the subsequent treatment.25 Probably in case of positive lymph nodes, CCRT with adjuvant chemotherapy could be the preferred option sparing the toxicity of the multimodality approach (NACT plus surgery plus CCRT treatment) to a subset of patients. On the contrary, if positive lymph nodes are detected at staging workup, NACT followed by radical surgery may represent a completely different and valuable treatment strategy allowing surgical radicality to most patients at a lower morbidity cost and with a better quality of life with respect to CCRT.26 Moreover, in our series, 60% of patients received radiation therapy as adjuvant postsurgical treatment, and this combined treatment may have potentially contributed to the survival benefit gained by the whole strategy. In addition, radiation therapy was administered as primary treatment in 3 of 9 recurrences, thus making this strategy appropriate and potentially curative for 33.3% of patients experiencing recurrent disease in contrast to what usually happens after exclusive chemoradiation when only demolitive surgery or palliative chemotherapy can be offered.
In conclusion, specific treatment strategies tailored to adenocarcinoma have not yet emerged, and the optimal management of adenocarcinoma of the cervix continues to be a subject of debate among clinicians. Neoadjuvant chemotherapy with TAP combination seems to be a feasible and moderately toxic strategy for the treatment of LACA, and these promising results warranted to be confirmed in a multicenter prospective study on a larger number of patients. The high percentage of lymph nodes involvement both after neoadjuvant chemotherapy and chemoradiation underlines the unmet need of alternative strategies to clear out the retroperitoneum.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Cervical cancer adenocarcinoma; Neoadjuvant chemotherapy; Surgery