Diagnosis and Treatment of Early Invasive Cervical Cancer – FIGO stage 1A1-1B1

1. Introduction

Cervical cancer is a gynecologic malignancy that if detected early can often be treated and cured. Existing cervical cancer screening programs, including testing for high-risk human papillomavirus and cervical cytology, results in most cases in North America are being diagnosed at these early stages. Women with disease limited to the uterus, are defined as having early-stage cervical cancer.

The Swedish cervical cancer screening program performed an audit demonstrating that women diagnosed with cervical cancer who participated in the screening program based on recommendations were diagnosed at stages IA or IB (30% and 52%, respectively); whereas approximately 50% of patients who were not part of the screening program were mostly diagnosed at FIGO stage II or higher.

In the United States, the Centers for Disease Control reported an unadjusted death rate of 10.2 per 100,000 for White women and 18.0 for non-White women (age-adjusted mortality not reported) in 1950. Newer reports in 2012 demonstrated the age-adjusted mortality had dropped to 2.1 for White women, 3.7 for Black women, 2.7 for Hispanic women and 2.43 overall.

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2. Staging

Cervical cancer is clinically staged. The FIGO 2009 cervical cancer staging is listed in Table I.

Table I.
Stage Description
IA1 Microscopicinvasive carcinoma. Measured stromal invasionof ≤3.0 mm in depth and extension of ≤7.0 mm
IA2 Measured stromal invasionof >3.0 mm and not >5.0 mm with an extension of not >7.0 mm
IB1 Lesion limited to thecervix.Clinically visible lesion≤4.0 cm in greatest dimension

3. Treatment

Generally, early stage invasive cervical cancer is treated surgically. However, the choice of therapy depends not only on the stage of a patient’s disease, but various prognostic factors. These include size of tumor, the presence of lymphovascular space invasion, deep cervical stromal invasion, parametrial involvement, or positive surgical margins. These prognostic factors play an important role in determining prognosis and the need for adjuvant therapy.

For microscopic stage IA1 lesions without lymphovascular invasion (LVSI) and no evidence of intermediate or high-risk features, an extrafascial hysterectomy (class 1) may be performed as definitive treatment. If preservation of fertility is desired, then a cone biopsy may be performed, and observation would be appropriate if negative cone biopsy margins were identified.

Stage IA2 lesions can be treated with a modified radical hysterectomy (class II) and pelvic lymphadenectomy with or without para-aortic lymph node dissection. If patients are not suitable surgical candidates brachytherapy and pelvic radiotherapy can be used to treat these lesions.

When preservation of fertility is desired, radical trachelectomy with either robotic or laparoscopic pelvic lymphadenectomy may be performed. Studies have shown that there does not appear to be a higher risk of recurrence, although there is an associated higher risk of preterm birth.

For stage IB1 lesions, radical hysterectomy (class III) and pelvic lymphadenectomy with tailored post-operative adjuvant therapy is recommended. Alternatively, concurrent cisplatin-based chemotherapy, pelvic radiotherapy and brachytherapy may be used to treat these types of lesions. However, equal cure rates have been obtained with primary radiation therapy as with surgical treatment.

4. Prognostic Factors

Gynecologic Oncology Group (GOG) study 49 investigated risk factors for nodal metastasis. Factors investigated include depth of tumor invasion, parametrial involvement, lymphovascular space invasion, tumor grade and gross versus occult primary tumor involvement. After multivariate analysis, study findings demonstrated that lymphovascular space invasion, depth of tumor invasion, parametrial involvement and age were independent risk factors.

Of the risk factors investigated, some were shown to be more important than others. For example, high risk factors are lymph node metastases, parametrial involvement and positive resection margins. On the other hand, intermediate risk factors include deep stromal invasion, large tumor size and lymphovascular space invasion. (See Table II.)

Table II.
IntermediateRisk Factors HighRisk Factors
Deepstromal invasion Lymphnode metastasis
Largetumor size Parametrialinvolvement
Lymphovascularspace invasion Positivetumor resection margin

GOG 71 was a randomized clinical trial comparing extrafascial hysterectomy to observation in bulky (>4 cm) stage IB cancers following definitive radiation therapy (RT). It showed bulky tumors benefited from extrafascial hysterectomy and the combined approach (RT + surgery) provided greater local control, but there was no survival advantage.

GOG 92 (6) investigated the role of adjuvant radiation therapy after surgical debulking. Stage IB cervical cancer patients who had prior radical hysterectomy with pelvic lymphadenectomy and negative lymph nodes along with two or more of the following: deep stromal invasion, capillary lymphatic space involvement or tumor size greater than or equal to 4 cm were included in the study. The radiation therapy arm demonstrated a statistically significant (46%) reduction in risk of recurrence (HR = 0.54, 90% CI [CI] 0.35-0.81, p=0.007) compared to the control arm. However, improvement in overall survival (OS) with radiation therapy did not meet statistical significance (HR = 0.70, 90%CI = 0.45-1.05, p=0.074). See Figure 1. and Figure 2.

Figure 1.

Progression free survival (PFS) by treatment group. 30 Radiation therapy (RT) patients and 49 Observed (OBS) patients recurred or died. RT significantly increased PFS (p=0.009).

Figure 2.

Survival by treatment group (p=0.074). 27 RT patients and 40 OBS patients died. Beyond 6 years, only four disease-related deaths (2 RT, 2 OBS) occurred. Therefore, the convergence of the curves is a result of other causes.

Although pelvic RT continues to be a standard therapy of early invasive and locally advanced cervical cancers, treatment results are still suboptimal. Multiple GOG trials have looked at the possibility of enhancing irradiation with chemotherapy. GOG 4 investigated affects of hydroxyurea (HU) with RT on more locally advanced stages (Stage IIIB and IVA). This showed an improved in progression free survival (PFS) and OS that enabled HU to be a standard comparison with new therapeutic approaches. GOG 56 did show significant results (p=0.006) when HU was compared with Misonidazole and concurrent pelvic RT.

GOG 26 demonstrated cisplatin to be the agent of choice for advanced or recurrent cervical cancers. This was then extended to early invasive cervical cancer treatment. GOG 120 demonstrated a tolerable dose schedule of cisplatin+RT that could possibly be applied to stage IA-IB.

Many intergroup trials compared cisplatin with either 5FU or HU with concurrent RT, such as GOG 85, 123 and 109. However GOG 109 had the largest contribution to the GOG. This study assessed Stage IA2, IB and IIA cervical cancer patients who were treated surgically with radical hysterectomy and pelvic lymphadenectomy; with findings of positive pelvic lymph nodes, positive resection margins or parametrial involvement. The two arms of the study were radiation therapy alone versus radiation therapy with concurrent cisplatin chemotherapy.

The PFS and OS showed significant results in the RT+ Chemotherapy treatment (CT) arm. Projected PFS at 4 years was 63% for the RT arm and 80% for the RT+CT arm. Projected overall survival at 4 years was 71% for the RT arm and 81% for the RT+CT arm. A follow-up study was performed and the sub-group analysis investigated the role of various prognostic factors, such as tumor size, depth of invasion, LVSI, margin status, parametrial involvement and nodal status. Study results demonstrated that age, histologic type and tumor grade were not prognostic within either treatment group, but that the benefit of CT was similar in both arms.

However, tumor size and lymph node metastases were noted to be significant prognostic factors. Benefit from the addition of CT was most evident when tumor was greater than 2 cm (p=0.17 for size under 2 cm, p=0.009 for size greater than 2 cm). When tumor size was greater than 2 cm, the addition of CT results in 19% improvement in 5-year survival. It was postulated that size might be surrogate for predicting risk of nodal metastases. In regards to lymph node metastases, patients did worse in the RT only group if there were two or more pelvic nodal metastases, or if the tumor was greater than 2 cm. The benefit of CT in patients with 2+ lymph nodes was demonstrated by an estimated 20% improvement in 5-year survival (p=0.006). See Figure 3., Figure 4. and Figure 5.

Figure 3.

Survival of women with tumors greater than 2cm by treatment arm

Figure 4.

Survival of women with one nodal metastasis by treatment arm.

Figure 5.

Survival of women with more than two nodal metastases by treatment arm.

The GOG 0263 is an ongoing randomized phase III trial whose goal is to investigate whether or not there would be an improvement in 3-year recurrence-free interval in post-operative stage I-IIA cervical cancer patients with intermediate risk factors by addition of weekly cisplatin CT to RT. Intermediate risk factors are defined as deep stromal invasion, large tumor size and LVSI. The rationale for this this study was that patients with intermediate factors have been shown to have a 30% recurrence rate, similar to those patients with one high risk factor. Patients in this study must have negative lymph nodes, parametrial involvement, or positive resection margins. For patients with positive lymphovascular space invasion (LVSI), one of the following must be present: deep 1/3 penetration, middle 1/3 penetration, clinical tumor greater than or equal to 2 cm, or superficial 1/3 penetration, clinical tumor greater than or equal to 5 cm. For those with negative LVSI involvement, the tumor must involve the middle or deep third penetration, or the clinical tumor must be greater than or equal to 4 cm.

Adjuvant Trials

The GOG continues to investigate the effect of adjuvant chemotherapy in order to standardize treatments for early invasive cervical cancer.

GOG 0724 continues to recruit participates by investigating post operative stage IA2, IB or IIA cervical cancer patients with high risk features (positive pelvic nodes, parametrial involvement, positive para-aortic nodes), who have completely resected tumors (PET/CT negative). Patients receive concurrent weekly cisplatin and RT +/- brachytherapy, or concurrent weekly cisplatin and RT +/- brachytherapy followed by carboplatin and paclitaxel.

This study will evaluate the addition of systemic adjuvant therapy with paclitaxel and carboplatin following radical surgery and chemoradiation in early stage; while assessing high-risk patients for the reduction in recurrence risk and improvement in disease-free survival and overall survival.

GOG 9926 is an ongoing Phase I trial that aims to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of adjuvant carboplatin and paclitaxel chemotherapy following concurrent weekly cisplatin chemotherapy and extended field radiation in women with newly diagnosed stage IB-IVA cervical cancer, with confirmed positive para-aortic nodes, by PET/CT scan, fine needle biopsy, extra peritoneal biopsy, laparoscopic biopsy or lymphadenectomy. Patients are designated receive cisplatin with concurrent daily RT followed by brachytherapy. After the completion of chemoradiation, patients receive adjuvant +carboplatin.

GOG 9929 is another ongoing Phase 1 trial that continues to recruit women with Stage IB2/IIA with positive para-aortic lymph nodes or stages IIB/IIIB/IVA with positive pelvic and/or para-aortic lymph nodes. Nodal status was confirmed by PET/CT scan, fine needle biopsy, extra peritoneal biopsy, laparoscopic biopsy or lymphadenectomy. The study aims to maximize the MTD and DLT of adjuvant ipilimumab following concurrent weekly cisplatin and extended field radiation followed by intracavitary brachytherapy.

GOG 0278, ConCerv and SHAPE are three ongoing studies evaluating less radical surgery. GOG 0278 is an interventional study assessing the impact of non-radical surgery on bladder, bowel and sexual function and examining the incidence and severity of lymphedema after non-radical surgery. Patients with Stage 1A1 with LVSI invasion and IA2-IB1 cervical cancer undergo either extrafascial hysterectomy or cone biopsy with pelvic lymphadenectomy depending on fertility desire. Patients enrolled are given a pre-operative and post-operative survey on bladder, bowel and sexual function. Follow-up includes 4-6 weeks post procedure, every 3 months for the first year, then every 6 months for 2 years.

5. Summary

Treatments for early stage invasive cervical carcinomas have shown to yield equivalent oncologic outcome. Further evaluation and discussion are needed to help patients determine their best option for care.

For stage IA1 lesions, cone biopsy with negative margins or an extrafascial hysterectomy may be performed. Stage IA2 lesions may be treated with modified radical hysterectomy and pelvic lymphadenectomy with or without para-aortic lymph node dissection. Radiation therapy may be used as the primary treatment modality if patients are not suitable surgical candidates. Trachelectomy with laparoscopic or pelvic lymphadenectomy may be performed if preservation of fertility is desired.

Radical hysterectomy and pelvic lymphadenectomy with tailored post-operative adjuvant therapy is recommended for stage IB1 lesions. Concurrent cisplatin-based chemotherapy, pelvic radiotherapy and brachytherapy are alternative forms of treatment that have shown to have similar cure rates compared to surgery.

Women with stage IB cervical cancer and negative lymph nodes with high risk features (2 cm or more of deep stromal invasion, capillary lymphatic space involvement, or tumor size >4 cm) the addition of adjuvant radiation therapy after surgical debulking has shown a decreased incidence of local recurrence with little or no effect on overall survival.

Concurrent cisplatin chemotherapy with radiation therapy was found to result in higher overall survival rates in stage IA2, IB and IIA cervical cancer patients who demonstrated positive pelvic lymph nodes, positive resection margins or parametrial involvement after radical hysterectomy with pelvic lymphadenectomy.

Ongoing studies include those investigating the potential benefits of radiation with concurrent cisplatin chemotherapy for post-operative stage I-IIA cervical cancer patients with intermediate risk factors (deep stromal invasion, large tumor size and LVSI). The effects of adjuvant chemotherapy for post operative stage IA2, IB, or IIA cervical cancer patients with high-risk features (positive pelvic nodes, parametrial involvement, positive para-aortic nodes) are also being investigated in ongoing clinical trials.

6. Conclusion

With established cervical cancer screening programs in North America, invasive cervical cancers are usually diagnosed at early stages (stage IA1-IB1), and are often adequately treated. However there seems to be a variation in practice, minimal high quality evidence in order to base decisions or counsel patients adequately. Currently we are missing a standardized treatment for woman with locally invasive cervical cancers especially those with high risk factors. If preservation of future fertility is desired for stage IA1 and IA2 invasive cervical carcinoma patients, fertility sparing procedures, such as cone biopsy or trachelectomy with either laparoscopic or robotic pelvic lymphadenectomy may be performed. Adjuvant radiation therapy may reduce the risk of cancer recurrence in patients with intermediate risk factors. On the other hand, concurrent cisplatin chemotherapy and radiation therapy results in higher overall survival for post-operative patients with high risk factors. Further knowledge from ongoing clinical trials aim to achieve not only the best oncologic outcome but also with the least invasive treatments.

7. What is the evidence for specific management and treatment recommendations?

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