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Cervical Cancer

Chapter 17 – Gynaecological Cancer in the Senior Patient

The staging of cervical cancer is clinically based on the Fédération Internationale de Gynécologie Obstétrique (FIGO) staging system. The squamous carcinomas account for 80% of all cases and are declining due to the screening. Adenocarcinomas account for 15% of cases, but the incidence has almost doubled during the last 20 years despite screening.

The diagnosis is made by a (cone) biopsy. The average age of a women with cervical cancer is between 35 and 45. The 2008 FIGO staging system is used.

Among other rare types of cervical cancer are neuroendocrine small cell carcinomas of the cervix. The treatment of these carcinomas should conform to those of small cell lung cancer.

Stage 0 Cervical Cancer

This is carcinoma in situ. The five-year survival rate is 100%. Treatment could be conisation (preferable) or hysterectomy. One can opt for the latter if the patient has other gynaecological problems.

Stage I Cervical Cancer

This is cancer strictly confined to the cervix, and it can be divided into IA and IB. The five-year survival is about 80%. Surgery for these patients is the preferred approach. However, if the patient is unfit for surgery, one can opt for concomitant chemoradiation or radiotherapy alone.

Stage IA1
This stage includes tumours with stromal invasion of 3 mm in depth and horizontal extension of 7 mm. Adenocarcinomas and adenosquamous carcinomas should be treated in the same way as squamous carcinomas.

  • If there is no lymphovascular space invasion (LVSI), the preferred treatment is conisation or type 1 hysterectomy if there are associated (benign) problems. There is no indication for node dissection (lymph node metastasis rate is <0.5%) or ovariectomy.
  • If there is LVSI, the preferable treatment in elderly women is a type 1 or 2 hysterectomy with pelvic node dissection. A node dissection is indicated since the lymph node metastasis rate is up to 4.7%. There is no indication for an ovariectomy. An alternative to a hysterectomy could be a conisation or modified radical trachelectomy for younger patients who wish to preserve fertility.

Stage IA2
This stage includes tumours with a stromal invasion of >3 mm and 5 mm in depth and horizontal extension of 7 mm.

  • If there is no LVSI, the rate of lymph node metastasis is up to 3.4%. The treatment could be conisation or a type 1 hysterectomy or, alternatively, a radical trachelectomy or a type 2 hysterectomy. All procedures should be combined with a pelvic (laparoscopy/laparotomy) lymph node dissection. There is no indication for an ovariectomy.
  • If there is LVSI, the rate of lymph node metastasis is up to 11.1%. The treatment options are radical trachelectomy with pelvic lymph node dissection or a type 2 hysterectomy with pelvic node dissection. There is no indication for an ovariectomy.

Stage IB1
This is a clinically visible lesion up to 4.0 cm in greatest dimension.

  • One should opt for a radical hysterectomy. The operation should always be combined with a bilateral pelvic lymphadenectomy. Alternatively, a radical trachelectomy, either vaginal or abdominal, can be performed. The radical trachelectomy should ideally be reserved for patients with a well-differentiated tumour of less than 2 cm in size and no evidence of LVSI. Depending on final pathology (presence of LVSI, depth of cervical invasion and tumour size) the patient may or may not require postoperative radiation therapy or chemoradiation therapy.
  • Another approach is definitive concomitant chemoradiation therapy.

Stage IB2
This is a clinically visible lesion >4.0 cm. The treatment can be a type 2 or 3 radical hysterectomy with bilateral pelvic and para-aortic lymph node dissection or concomitant chemoradiation.

Primary concomitant chemoradiation [cisplatin 40 mg/m2/week intravenously during radiotherapy (six weeks)] is equally effective as primary radical surgery for disease-free and overall survival. Treatment choice is based on the features of the tumour, the treatment-related morbidity, condition, and wishes of the patient. One should try to avoid the combination of chemoradiation and radical surgery to reduce therapy-related morbidity.

Patients with lymph node metastasis or positive tumour margins should receive adjuvant concomitant chemoradiation. Ideally, surgery should be performed on patients without lymph node involvement. Sentinel node biopsy may be ideal to tailor the treatment. The technique is feasible, but its sensitivity and specificity are unclear at the moment. Studies are ongoing to evaluate the value of sentinel node biopsy in patients with cervical cancer. Until the results are known, sentinel node biopsy cannot be considered as the standard approach for patients with cervical cancer.

Stage II

Tumour extends beyond the cervix but not to the pelvic sidewall nor to the lower third of the vagina. The five-year survival is 60%.

Stage II is subdivided into the following:

  • IIA tumour: no parametrial involvement
  • IIA1: clinical lesion ≤4.0 cm
  • IIA2: clinical visible lesions >4.0 cm Treatment in the same way as stage IB
  • IIB tumour: with obvious parametrial involvement

Treatment: concomitant chemoradiation is the preferred approach.

Stage III

The tumour extends to the pelvic sidewall and/or the lower one-third of the vagina and/or causes hydronephrosis or a nonfunctioning kidney. Overall survival is 30%.

Stage III is subdivided into the following:

  • IIIA: Tumour involves lower third of the vagina, with no extension to the pelvic wall.
  • IIIB: Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney.

The preferred treatment is concomitant chemoradiation.

Stage IV

Tumour extends beyond the true pelvis or involves (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a patient to be allotted to stage IV. Overall survival is 5%.

It is subdivided into the following:

  • IVA: spread of growth to adjacent organs. Standard treatment is concomitant chemoradiation. If there are fistula or if it is only localised disease with no signs of disease outside the pelvis, one can opt for pelvic exenteration. However, this leads to a high morbidity, and careful staging is of utmost importance.
  • IVB: spread to distant organs. Treatment is palliative and consists of chemotherapy. Chemotherapy (e.g., cisplatin, carboplatin, paclitaxel, or topotecan) can give a response in up to 30% of patients. In a new study, bevacizumab has also been shown to be effective in combination with chemotherapy (paclitaxel and cisplatin).

Bevacizumab

Bevacizumab is approved by the European Medicines Agency (EMA) and the Food and Drug Administration of the United States (FDA).  The EMA has approved the drug for first line treatment of patients with stages III and IV epithelial ovarian, fallopian-tube, or primary peritoneal cancer, in combination with carboplatin and gemcitabine in first recurrence of platinum-sensitive epithelial-ovarian, fallopian-tube or primary peritoneal cancer with no prior therapy with bevacizumab and in combination with paclitaxel and cisplatin, or paclitaxel and topotecan, in patients who cannot receive platinum therapy.  In ovarian cancer, the FDA approval is for platinum resistant disease only.  The approvals were based on progression free survival data with improvements of 2-4 months.  This must be weighed versus the known increased toxicity of bevacizumab in older patients including arterial thromboembolic events, hypertension and perforation.  It is also approved for the treatment of patients with persistent, recurrent, or metastatic carcinoma of the cervix. 

BRCA

BRCA mutation is a mutation in either of the BRCA1 or BRCA2 genes.  They are tumor suppressor genes in which harmful Mutations can lead to an increase of ovarian cancer, primarily high grade serous carcinoma.  Testing for these mutations has become an integral part of care of these patients.  The detection of these genes is helpful in screening for other disorders, particularly breast cancer in the patient, siblings, children and other relatives.  This can include decisions regarding risk-reducing surgery and chemoprevention. 

Olaparib is a targeted therapy approved by both the FDA and EMA.  The oral drug is an inhibitor of PARP (poly ADP ribose polymerase), which is involved in DNA repair.   The FDA has approved it for germline BRCA-mutated advanced ovarian cancer after three or more lines of chemotherapy.  The EMA approval in BRCA-mutated patients   includes maintenance therapy of high grade serous ovarian cancer and patients who have recurrent disease after platinum based therapy where the response was ≥6 months.

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