Metastatic gynaecological cancer

Introduction

Awareness of genital tract malignancies, in particular of cervical cancer, has recently increased due to affected celebrities and main characters in popular TV-dramas. Despite that, it remains an unfortunate fact that women most in need of screening are those least likely to attend.¹ Hence we still find women with cervical cancer presenting at a late stage.

Ovarian cancer, in contrast, has no valid screening test. Vague and late symptoms often lead to a delayed presentation with symptomatic metastases. As a result, ovarian cancer has the highest mortality rate amongst genital tract cancers. In 2008, 6,537 women were newly diagnosed with and 4,373 women died of ovarian cancer in the UK.²

Endometrial cancer is on the rise with increasing numbers of patients affected by obesity and diabetes. It is now the most common of the gynaecological cancers but the death rate has fallen steadily due to its early presentation and improved diagnostic pathways. Nevertheless, these patients with multiple co-morbidities pose a particular surgical dilemma and often need to be referred to the medical oncologist for palliative chemoradiation rather than being suitable for surgery with curative intent. Thus, metastatic gynaecological cancer remains a clinical challenge and mortality rates have not dramatically improved in the last two decades. This article aims to highlight some of the particular problems with each individual gynaecological cancer.

Cervical cancer

In 2007, 2,828 new cases of cervical cancer were diagnosed in the UK, of which 702 were under the age of 35. The life-time risk of women in the UK to develop cervical cancer is 1:136.³

Cervical cancer can spread by direct invasion, lymphatic permeation, and haematogenous dissemination. Cervical cancer can involve all pelvic lymph nodes, especially the obturator nodes. Haematogenous spread commonly occurs to the lung, liver and bones, although any site in the body may be affected. Staging detects the extent of the disease. It is the basis for choosing the optimal treatment and for cervical cancer is undertaken clinically involving an examination under anaesthetic, a cystoscopy and a sigmoidoscopy. Staging is also assisted by further imaging to detect parametrial and pelvic lymphnode involvement. Magnetic resonance imaging (MRI) demonstrates parametrial invasion whereas positron emission tomography (PET) has now super-ceded computerised tomography (CT) scans as they are far more accurate in detecting lymphnode involvement and distant metastases. In principal, treatment can involve surgery or radiotherapy. Surgery is preferred for small tumours with limited spread when complete removal of the tumour seems achievable with clear excision margins. Radiotherapy is given as internal radiotherapy (also called Brachytherapy) and/or external beam radiotherapy (EBRT) and is the treatment of choice for large tumours with parametrial and extensive pelvic and para-aortic lymphnode involvement. Chemotherapy (mostly Cisplatin) is increasingly used in combination with radiotherapy particularly when distant metastases are present and has shown to decrease death rates significantly.⁴

Patients with recurrent or metastatic cervical cancer are commonly symptomatic and may experience pain, anorexia, weight loss, vaginal bleeding, cachexia and dyspnoea amongst other symptoms. Treatment of recurrent disease depends on treatment mode of primary therapy and the site of disease recurrence. If disease recurs after treatment with primary pelvic radiotherapy in the pelvis, some form of pelvic exenteration can be considered as treatment. Radical hysterectomy may be an option for a select group with persistent or recurrent disease after treatment with primary radiotherapy. Pulmonary metastases following primary radical hysterectomy has been reported in 6.4% of patients with negative nodes and 11.3% of patients with positive pelvic nodes. When lung is the only site of recurrence a 46% survival rate can be achieved with surgical resection and chemotherapy.⁵

Figure 1: Malignant pleural effusion right lung

Vaginal cancer

One to two percent of all gynaecological cancers are vaginal carcinomas. The majority are squamous-cell carcinomas. Metastases found with 25% of tumours that have reached a size of 2cm.⁶ Direct spread occurs to neighbouring organs and lymphatic invasion leads to pelvic and para-aortic lymphnode involvement. Distant metastases are more likely with increasing tumour volume. Hysteroscopy to exclude cervical or endometrial cancer may be helpful as vaginal cancer is rare and vaginal deposits are more likely to be secondary rather than primary.

Treatment for advanced disease involves chemoradiation or radiotherapy alone. Surgery is only an option when the tumour is small and located near the cervix.

Figure 2: Large complex ovarian cyst on CT scan likely representing ovarian cancer

Ovarian cancer

Epithelial ovarian cancer is the fourth commonest malignancy in women, with more than 50% occurring in women older than 65 years of age.⁷ Prognosis is usually poor due to a late presentation. Sixty-five percent present with stage three or four.⁶ Symptoms are often vague including abdominal bloating and swelling, constipation, pain and occasionally vaginal bleeding. Ovarian cancer (see Figure 2) spreads via shedding into the peritoneal cavity, lymphatically to pelvic and para-aortic nodes. Trans-diaphragmatic spread into the pleura is common and haematogenic spread occurs into liver (Figure 3a and 3b), spleen, lungs and rarely brain.

Figure 3a: Focal liver metastases in CT scan

Figure 3b: Focal liver metastases in CT scan

The prognosis of epithelial ovarian cancer is significantly influenced by the tumour residual following first surgery. Primary cytoreductive surgery aims to remove all local cancer and if possible all metastatic disease. Supra-radical surgery may involve resection of large and small bowel, a splenectomy, resection of disease from the diaphragm and liver metastases. Primary surgery is followed by adjuvant platinum-based chemotherapy.

Neoadjuvant Chemotherapy (often Cisplatin/Paclitaxel) is used for primary inoperable malignancies with ascites, peritoneal disease, lymphnode involvement and upper abdominal disease when an optimal debulking (<1cm residual disease) seems not possible to be achieved with primary surgery. If there is a good response the multidisciplinary team might decide to continue with intermittent debulking surgery (IDS). Response to chemotherapy is usually effective with disappearance of ascites in 90% and complete remission in 30%.⁶ IDS is followed by a further three cycles of chemotherapy.

If tumour growth continues during platinum-based chemotherapy or is recurring within two years of first treatment, second line treatment options need to be considered. For late recurrences the first chemotherapy regime can be used again. Second-line options include Topotecan, Etoposide, Doxorubicin and possibly intraperitoneal installation of Cisplatin.⁸

Endometrial cancer

Endometrial cancer accounts for six to ten percent of all female cancers.⁹ It is most common between 55-60 years of age. Myometrial invasion leads to lympho-vascular space and pelvic and para-aortic lymphnode involvement. Distant spread occurs to vagina, lungs, liver, bone and occasionally brain. Cure with distant spread is not possible and individual management plans consider the performance status and age of the patient. Treatment of pelvic disease consists of surgery (Hysterectomy and bilateral salpingo-oophorectomy, omentectomy and pelvic/para-aortic lymphnode sampling). Bulky local disease is treated with a combination of internal Brachytherapy and EBRT. High dose progestogens (Medroxyprogesterone acetate, MPA) is useful with distant disease (particularly lung). MPA and palliative radiotherapy may be helpful for symptomatic relief and reduction of vaginal bleeding. No standard chemotherapy programme for distant disease is available, but combinations of Cisplatin, Doxorubicin and Paclitaxel have shown an increase in overall survival.

In recurrent endometrial cancer serum Carcino-Antigen 125(CA125) levels are usually elevated particularly if the recurrence is intraperitoneal.¹⁰ Isolated vaginal recurrences are the most amenable to therapy with curative intent. High dose brachytherapy and EBRT may be useful to achieve loco-regional control. Systemic recurrences may be treated with surgery followed by chemotherapy and/or hormonal therapy. Patients with a long disease free interval (>2years) and isolated recurrence in the lungs, liver or lymphnodes should be considered for surgical resection as long as the patient is surgically fit and resection is technically feasible.

Uterine sarcomas

Uterine sarcomas (Rhabdomyosarcomas and stromal sarcomas) and malignant mixed muellerian tumours (MMMT, with mixed epithelial and sarcomatous components) are rare and amount to 1-5% of all uterine cancers. They may be discovered due to a rapidly expanding uterine mass or present with vaginal bleeding or discharge. The mainstay of treatment is surgical as they are not particularly sensitive to radiotherapy and only have a limited response to chemotherapy.

Table 1: Selected metastatic gynaecological cancers and their prognosis depending on extent of disease.

Vulval cancer

Vulval carcinoma amounts to 4% of all genital cancers in women. Most tumours are relatively small and are amenable to surgery. Spread is principally lymphatic and direct to neighbouring organs. Twenty-five percent of patients present with lymphnode involvement (i.e. stage three or more).¹¹ Blood-borne spread is late and its risk rises with increasing tumour size. Large tumours with inguinal nodes are treated with chemoradiation. This can be combined with surgery to gain local control of disease and for palliation. Urinary or bowel diversion may need to be considered.

Five-year survival rates are mainly influenced by lymphnode involvement. This is 90% at best with negative lymph nodes, but falls to 45% with inguinal node involvement and drops to 25% with positive pelvic lymph nodes.¹²

Choriocarcinoma

Choriocarcinoma is reserved for the malignant end of the spectrum within gestational trophoblastic neoplasia (GTN). Most choriocarcinomas occur in the uterus, but occasionally arise in the ovary. Choriocarcinoma invades the decidua, breaks into blood vessels and causes distant metastases to lungs and sometimes brain.

Metastases may present with haemoptysis, jaundice or red/blue-coloured nodules in vulva/vagina. Signs include an enlarged uterus with a snowstorm picture on ultrasound and a massively raised HCG (Human Chorionic Gonadotrophin) level. Metastases are found on X-ray/ CT.

Methotrexate is the treatment of choice for low risk choriocarcinoma (destructive hydatidiform mole, non-metastasising Choriocarcinoma and low risk metastasising Chorioncarcinoma). High risk metastasising Choriocarcinoma is treated with combination chemotherapy. Overall, the prognosis is very good with a 90-95% survival rate even with lung metastases. However, metastases to liver and brain are often incurable.

These tumours require to be registered with the Trophoblastic Service in the UK in either Charing Cross Hospital, London; Western General, Sheffield and Ninewells Hospital, Dundee.

Palliative care and pain management

Systemic symptoms are common with advanced disease. Gastrointestinal problems may occur in the form of bowel obstruction requiring surgical resection or a colostomy. Constipation can be related to opioid analgesia and regular laxatives may be helpful. Oral candidiasis is a frequent side effect during chemotherapy, but usually responds to oral antifungal preparations. Severe hiccups can be eased with anti-emetics or sedative preparations. A nephrostomy and ante- or retrograde ureteric stenting may be necessary for ureteric obstruction or fistulae. Infiltration of the vascular system may lead to ischaemic pain and venous thrombosis. Lymphatic involvement causes lymphoedema distal to the disease process and can affect 5-10% of women with vulval cancer particularly if groin radiotherapy is used.

Pain in advanced cancer can occur for various reasons. Gynaecological malignancies may infiltrate the lumbo-sacral plexus or damage may occur with radiotherapy and surgery. Consequently, patients may develop neuropathic pain in the lower back, pelvis, lower limbs and perineum as well as motor and sensory deficits. Additionally, chemotherapy can cause peripheral neuropathy. Pain is managed using the WHO pain ladder regime. Patches delivering strong opioids are particularly helpful. In neuropathic pain the use of Amitriptyline or Gabapentin may be required. If pain is difficult to manage then liaison with a Pain Management Team is advised. The General Practitioner (GP) is also crucial to the care of the patient as they act as the palliative care provider for the patient at home and liaise with members of the palliative care team.

Conclusion

Five-year survival rates for all genital tract cancers per stage have improved over the last 20-30 years, most significantly perhaps for ovarian cancer in stage one.¹³ However, very few patients with ovarian cancer present with early stage disease. Thus, the overall prognosis has not changed noticeably in recent years. Increasing public awareness of the importance of non-specific symptoms has started a trend for earlier presentation within the primary health care centres. This increases the pressure on the General Practitioner to select the right patients for an urgent referral process. Naturally, an increase in the workload within the secondary care centres in the National Health Service will follow, but whether this will aid a rise in the rates of early diagnosis will have to be seen. Nevertheless, a closer cooperation between primary and secondary health care should be encouraged perhaps including in-depth case reviews to learn from patients who present late.

References

1. Smith JR and Barron BA. Fast Facts-Gynaecological Oncology.Oxford: Health Press Limited.1998.
2. www.info.cancerresearchuk.org/cancerstats/types/ovary/mortality site visited 15/02/2012
3. www.cervicalcancer.org/statistics.html site visited 15/02/2012
4. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Eng J Med. 1999 Apr 15;340(15):1144-53.
5. Shiromizu K, Kasamatsu T, Takahashi M, Kikuchi A, Yoshinari T, Matsuzawa M. A clinicopathological study of postoperative pulmonary metastasis of uterine cervical carcinomas. J Obstet Gynaecol Res. 1999 Aug;25(4):245-249
6. Goerke K, Steller J., Valet A. Klinikleitfaden Gynaekologie Geburtshilfe. Muenchen-Jena: Urban&Fischer.2000.
7. www.cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional, site visited 14/02/2012
8. Markman M and Bookman MA. Second-Line Treatment of Ovarian Cancer. The Oncologist. Feb 2000;5(1):26-35
9. www.cancer.gov/cancertopics/pdq/treatment/endometrial /HealthProfessional, site visited 20/02/12
10. Lo SS, Kho US, Cheng DK, Ng TY, Wong LC, Ngan HY. Role of serial tumour markers in the surveillance for recurrence in endometrial cancer. Cancer Detect Prev. 1999;23(5)397-400.
11. Beller U et al. Carcinoma of the vulva. Int. J. Gynaecol Obstet.2003;83(1):7-26
12. www.cancer.gov/cancertopics/pdq/treatment/vulvar/HealthProfessional, National Cancer Institute publication, site visited 10/02/2012
13. www.cancerhelp.cancerresearchuk.org/type/ovarian-cancer/treatment/statistics-and-outlook-for-ovarian-cancer published by Anglia Cancer Network, 2004-2008, site visited 14/02/2012
14. www.cancerhelp.cancerresearchuk.org/type/womb-cancer/treatment/statistics-and-outlook-for-womb-cancer, site visited 14/02/2012
15. www.cancerhelp.cancerresearchuk.org/type/cervical-cancer/treatment/statistics-and-outlook-for-cervical-cancer, site visited 14/02/2012
16. www.who.int/cancer/palliative/definition/en/ site visited 10/02/2012

Articles