Treatment of Documented Liver Metastasis from Cervical Cancer with High Dose of Chemoradiation

Introduction

Cervical cancer was the fourth most common cancer in women, with ∼530,000 new cases in 2012, representing 7.9% of all female cancers. The number of deaths was 2 per 100,000 in Western Asia. ¹ Thirteen percent of cervical cancer patients are diagnosed at advanced stages. The 5-year survival rate for metastatic cervical cancer is 16.5%, compared to 91.5% for localized cervical cancer. ² Patients who have distant metastatic disease are considered for palliation only. Interpretation of the available literature is difficult, because most studies have included patients with both metastatic and recurrent disease. Currently, the median survival time is only 8–13 months. ² Hematogenous dissemination is relatively unusual, and half of these patients died within 6 months.

The most common sites are lungs and bones. Patients with liver metastases represent only 1.2%–2.2% of cases, ³ and most of these cases are diagnosed by marked elevations in liver-function tests and imaging findings. At present, there are too few studies to draw any conclusions about treatment and survival time of patients who have cervical cancer with liver metastases. This report describes a case of cervical cancer with liver metastases, in which a patient had complete remission for 16 years after laparoscopic staging and treatment with combined high-dose chemoradiotherapy. However, she subsequently suffered from severe radiation cystitis that was complicated with urinary bladder rupture, and she died of sepsis.

Case

A 56-year-old, gravida 5, para 3 female presented with postcoital bleeding. She had a large cervical tumor that extended to the right pelvic wall and the upper vagina, as noted in a pelvic examination. Multiple biopsies of the cervix and vagina were performed. The clinical diagnosis was possibly International Federation of Gynecology and Obstetrics–stage IIIb squamous-cell cervical carcinoma. The patient's liver and renal function tests were within normal limits. She had a serum level of squamous-cell carcinoma–antigen (SCCA) of 44.7 ng/mL (normal value: <2.0 ng/mL). Magnetic resonance imaging (MRI) was performed and it showed the cervical tumor invading the uterine body, upper half of the vagina, right parametrium, right pelvic wall, and posterior wall of the bladder. There was also a similar extension of the cervical tumor without any metastasis to the liver, lungs, and bones. Computed tomography (CT) scanning showed no lymphnode involvement. Cystoscopy revealed no bladder invasion. Intravenous pyelography revealed delayed function of her right kidney due to invasion of the tumor in the distal part of the urethra.

Laparoscopic staging was performed in order to confirm the extent of cancer and determine further management with radiotherapy. A liver biopsy and lymphnode dissections were performed because of an incidental finding of multiple, whitish, small liver nodules in both anatomical lobes. The histopathologic report revealed that all sites of the lymph nodes were negative, but there was metastatic squamous-cell carcinoma of the liver (Fig. 1).

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FIG. 1.

Histopathology of a primary tumor and liver metastases. (A) Hematoxylin and eosin (H&E) staining at magnification × 40 of the primary cervical squamous-cell carcinoma. (B) H&E staining at magnification × 40 of the liver biopsy. Metastatic squamous-cell carcinoma was observed.

The chemoradiotherapy, cisplatin-based multiagents, as radiosensitizing agents, were administered concurrently with radiotherapy. Radiotherapy was given as 10 MV X-ray to the whole pelvic area for 4400 cGy/22 Fr; then, the field was reduced to the true pelvis with AP-PA for 1400 cGy/7 Fr. A total of 5800 cGy/29 Fr. Intracavity brachytherapy (IC) was given with Ir-192 for 430 cGy to point A × 6 courses. Chemotherapeutic regimens during radiotherapy included 50 mg/m² of cisplatin, 1mg/m² of vincristine, and 25 mg/ m² of bleomycin every 3 weeks for 3 courses, with postradiation adjuvant chemotherapy, 3-weekly 50 mg/m² of cisplatin, 6 mg/m² of mitomycin, and 1000 mg/m² of 5-fluorouracil for 3 courses.

Results

Fortunately, the serum tumor marker (SCCA) was within normal range after chemotherapy. The cervix and liver were unremarkable on CT scanning.

The patient had regular follow-ups with cytologic (Papanicolaou) smear, tumor marker (SCCA) once every 3 months and annual imaging. She had remained in complete remission for sixteen years after completion of therapy. After that, she developed an infection as the result of a spontaneous rupture of her bladder that was associated with radiation cystitis. She then developed sepsis and died.

Discussion

This report described a case of cervical cancer with liver metastases. The patient had a complete response following treatment with combined high dose chemoradiation. Liver metastases from cervical cancer have been seen rarely, being reported in 1.2%–2% of cases. ³ Kim et al. reported that only 5% of cases developed an isolated hepatic metastasis alone without extrahepatic disease, whereas the remaining 95% of cases developed uncontrolled locoregional disease. ⁴ Multiple lesions with various sizes of liver lesions occurred in 80% of these patients, whereas solitary lesions confined to single lobes were observed only in 20% of cases. There were 55% percent of metastatic lesions occurring in both hepatic lobes, and the remaining lesion was confined to a single lobe.^2,4

The patient in the current report presented with multiple small nodules in both liver lobes, which comprised a common pattern of hepatic involvement. However, the pattern of liver metastasis, including the number of lesions and distribution of metastases, was not associated with any known survival rate. Hepatic metastases are almost always accompanied by uncontrolled regional disease or extrahepatic metastases; therefore, the survival prognosis might be determined by uncontrolled primary disease or could present with concomitantly extrahepatic disease.

Most cases of liver metastases were detected by clinical or radiologic examination, and were proven by fine-needle aspiration biopsy. In the current case, the liver metastases were diagnosed as a result of an incidental finding during laparoscopic surgical staging. Thus, this patient's cancer was upstaged to IVB. It has been demonstrated that surgical staging has been associated with a very low complication rate and a significant upstaging rate without any delay in primary treatment. Staging laparoscopy has provided additional valuable information about lymph-node, peritoneum, and parametrium involvement in some difficult cases.^5,6 Moreover, it has been found that surgical staging was more accurate than CT and MRI for evaluating liver metastases, resulting in potential modifications in treatment planning. Laparoscopic staging has been recommended as a safe procedure prior to chemoradiation for patients with locally advanced cervical cancer. Nevertheless, the positive effect of surgical staging on prognosis of patients with advanced cervical cancer has not been shown.^5,7

Until now, there has been no standard treatment for patients with metastatic cervical cancer because of its heterogeneous manifestations. Articles mostly mention patients with both primary and metastatic or recurrent diseases in many studies because of the lack of enrolled patients with first-diagnosed metastatic cervical cancer. Cervical cancer at stage IVB is not usually considered curable. The aim of treatment is to slow progression of the tumor and control the patient's symptoms. Treatment options include radiation and systemic chemotherapy or best supportive care. Most chemotherapy regimens are cisplatin-based combinations. The addition of bevacizumab may be considered. One study, conducted by Zighelboim et al., focused only on the outcomes in 24 patients with stage IVB cervical cancer treated with irradiation in combination with aggressive chemotherapy. ⁸ There were only 3 cases (12.5%) of patients diagnosed with liver metastases. All of these patients underwent external-beam radiotherapy (EBRT) and 19/24 patients underwent additional brachytherapy. Twenty patients (83%) received radiosensitizing cisplatin with their radiation treatments. This cohort showed survival rates of 44% and 22% at 3 and 5 years, respectively. ⁸ These percentages exceeded other studies that reported 5-year survival rates for metastatic cervical cancer ranging from 14% to 16%.^2,8,9 Interpretation of the survival data from other literature was difficult because most studies had included patients with both primary metastatic and recurrent disease.

Despite her initially excellent response to the aggressive treatment she received, the current patient suffered and died from late toxicity of her bladder after radiation. At present, radiation techniques have evolved dramatically over the past 2 decades. Conventional radiation that this patient was given has been superseded by newer EBRT techniques, such as intensity-modulated radiation therapy, image-guided radiation therapy, and positron-emission tomography–computed tomography-guided radiation. These techniques can be achieved with optimal sparing of normal tissue without compromising the doses to targeted areas. ¹⁰

Conclusions

This report demonstrated that laparoscopic surgical staging was safe and was associated with significant upstaging. The treatment of metastatic cervical cancer is mainly palliative, but optimal management might result in survival improvement as well. This current case showed that use of combined high-dose chemoradiotherapy in a patient with stage IVB cervical cancer could prolong disease-free interval and improve the patient's survival outcome. Innovation in chemotherapy and radiation therapy could decrease long-term morbidity as well as improving survival rates and quality of life.