The aim of this case report is to provide a source of information regarding patients with Bulky stage 1B cervical cancer by focusing on optimum care and treatment pathway of a patient. The author aims to describe important scientific observations from clinical trials, and therefore provide insightful information to expand knowledge and new research already present.
Despite a ‘well established’ UK screening programme for detecting cervical pre-invasive disease there are still approximately 2,800 cases of cervical cancer per annum and 1,000 women still die from cervical cancer each year (Cancer research UK, 2003).
The case study focuses on a patient with squamous cell carcinoma of the cervix uteri (exocervix and endocervix), poorly differentiated and staged by FIGO staging system at IB2 N1 (appendix A).
The FIGO staging system (Appendix 1), is based on clinical evaluation (inspection, palpation, colposcopy), radiological examination of chest, kidneys, and skeleton, and endocervical curettage and biopsies. The FIGO staging recommendations were last revised in 1995.
Stage IB (T1b) includes all invasive tumours limited to cervix larger than stage 1A2 lesions. Stage T1b occult is no longer used. Stage IB lesions (confined to cervix) were subdivided into stage IB1 clinical lesions (?4cm in size) and stage IB2 lesions (>4cm in size). There were no changes in other stages, including the 1987 definitions of stages IA, IA1, and IA2 (FIGO, 1995).
Brady et al (1999) acknowledge squamous cell carcinoma of the uterine cervix originating at the squamous columnar junction (transformation zone) of the endocervical canal and portio of the cervix. This lesion is frequently associated with severe dysplasia and carcinoma in situ, which has the possibility of progressing to an invasive carcinoma in 10 to 20 years.
The malignant process breaks through the basement membrane of epithelium and invades the cervical stroma. If invasion was less than 3mm, the lesion was classified as microinvasive or superficially invasive (stage IA1) the probability of lymph node metastasis is about 1% (Bohm et al, 1976).
Perez et al (1998) suggested incidence of pelvic node metastases to be approximately 15% in stage IB, 25% to 30% in stage IIB, and 50% in stage IIIB disease.Incidence of para-aortic node metastases was found to be approximately 5% in stage IB, 19% in stage IIB, and 30% in stage IIIB disease.
Fagundes et al (1992) submitted the tumour may spread to adjacent vaginal fornices or to paracervical and parametrial tissues, with eventual direct invasion of bladder, rectum, or both. They advocated the most common metastatic sites as lungs (21%), para-aortic nodes (11%), mediastinal and supraclavicular lymph nodes, bones, and liver.
Literature review criteria:
The most recent form of literature available was published scientific articles in form of electronic journals. Literature found included, reviews on the subject of Cervical cancer and published clinical trials which demonstrated clinical benefits and subsequent evaluation. Journals were accessed via internet using PubMed and Science Direct databases. Papers were selected based on merit of abstract and relevant articles were extracted from reference lists.
Primary search terms:
‘Squamous cell carcinoma of cervix’
‘Cancer of the cervix’
Secondary search terms:
‘Poorly differentiated IB2 N1 Cervical cancer’
‘IB2 N1 Cervical Cancer’
‘Ovarian Transposition + Cervical Cancer’
‘Phase 1 trials +Cervical Cancer’
‘Treatment pathway + Cervical Cancer’
‘Supportive care + Cervical Cancer’
‘HPV + Cervical Cancer’
Most of the references used were less than eight years old, although older articles were reviewed to note development of treatment.
Patient case presentation
The patient case is of a twenty two year old women (gravida 0, para 0). She had no familial history of Cervical cancer or any other type. She consumes two units of alcohol per week and is an occasional smoker with a one pack per year history. She is currently employed and works thirty-six hour per week.
In November 2008, patient presented with an abnormal cytologic (Papanicolaou) smear test and some postcoital spotting. She denied any forms of vaginal discharge but remarked a feeling of heavy fatigue and pelvic pain.
A general physical examination of the patient was carried out with special attention to supraclavicular (nodal) areas, abdomen, and liver. A careful pelvic examination which included a bimanual palpation of the pelvis took place.
Following an abnormal smear test the patient was referred for a colposcopic examination, where high grade cervical dysplasia was discovered. The patient was consequently referred in October to her local hospital for a LLETZ (large loop excision of transformation zone of cervix) biopsy of cervix. Specimens obtained during this procedure identified an invasive, moderately differentiated squamous cell carcinoma of large cell keratinising type. Vascular invasion was not identified. The tumour was staged as IB+.
November 2008, contrast MRI of abdomen and pelvis completed, which concluded a large homogenous mass being seen arising from lower end of cervix extending slightly more to the right. Cervical canal was noted to appear preserved and the endometrium and rest of uterus appeared normal. There was suspicion of extension of tumour into the upper vaginal wall. A right sided simple ovarian cyst was noted, with a normal left ovary observed. A large lymph node was seen in the right pelvic sidewall highly suspicious of being metastatic. No Para- aortic lymphadenopathy noted. Concluding staging on MRI grounds was recorded as a Stage T2b, N2 cervical cancer.
Based on MRI findings, patient was referred for EUA (examination under anaesthesia) for consideration of trachelectomy, in November. Trachelectomy is a surgical removal of the uterine cervix. EUA recorded a large 5cm exophytic tumour and on looking around it on 360? no macroscopic infiltration into vagina was seen.In order to give better definition an endo-cervical coil MRI was performed in December 2008, which further confirmed a definitive 6cm exophytic cervical cancer and enlarged right pelvic lymph node. Due to this the patient was not an ideal candidate for a trachelectomy.
The patient was next referred for a EUA, cystoscopy, colonoscopy, sigmoidoscopy and biopsies. Procedure was uneventful. No vaginal or parametrial involvement were identified. Cystoscopy, sigmoidoscopy and colonoscopy were normal. This gave a concluding staging of Ib/2a.
The patient’s case was discussed within a MDT (multi-disciplinary team) meeting. Here it was decided that chemo-radiotherapy would be preferred treatment.
The patient’s main concern was preservation of fertility due to her young age. Due to the progression of disease and quick follow through from diagnosis to treatment, the patients family, patient and partner all became very distressed, and a referral was made to a specialist gynae – nurse, where information regarding treatment, prognosis and side effects could be explained and discussed again.
The oncologist referred patient to a fertility specialist in December 2008, to discuss possible options for fertility sparing prior to patient commencing radiotherapy and chemotherapy. From this meeting it was decided that the patient was to undergo ovarian transposition to exclude them from the radiation scatter effect from the proposed adjuvant radiotherapy. Within the same procedure in December, patient underwent a laparoscopic para-aortic node assessment, which subsequently defined the radiotherapy field. The results of the assessment were discussed within a MDT meeting whereby it was found that the frozen section of the suspicious right obturator node confirmed malignancy, although, the para-aortic lymphadenectomy was negative. Patients consent, height and weight were taken in order to calculate Cisplatin chemotherapy dosage needed for concomitant chemotherapy.
December 2008, patient proceeded to commencing radiotherapy prescribed at 50.4Gy in 28 fractions with a four field technique at 10MV. In addition to this she commenced her first concomitant chemotherapy of Cisplatin 40MG/M2 60MG, first of four cycles.
The patient was reviewed throughout her radiotherapy and chemotherapy and tolerated both well with minimum side effects. Subsequently the patient was consented for intrauterine and intravaginal high dose rate brachytherapy for February 2009.
The patient was noted to be down and depressed and very tearful and expressed concerns of not coping. The patient was referred to a CLIC/Sargent social worker for support and advice in January 2009.
Prior to first fraction of brachytherapy, patient underwent EUA. It showed a good regression of tumour, but was still bulky. A smit sleeve was inserted as well as intrauterine tube and ovoids. Patient was admitted for brachytherapy (16.5Gy to point A in three fractions) which proceeded without complication, patient was subsequently discharged. Following brachytherapy, an external beam pelvic side wall boost was performed at 5.4Gy in three fractions.
The patient was reviewed five weeks post treatment in March 2009. She noted slight bowel changes and noticed that she was leaking small amounts of urine. This was dismissed as radiotherapy related. The patient was given vaginal dilators and provided with instructions as well as an explanatory DVD. Patient relayed her fears of being re-infected by HPV. Patient was encouraged to talk with long partner regarding HPV testing. The patient also mentioned experiencing a few night sweats and hot flushes, actioning referral for an estradiol level, FSH and LH check.
April 2009, patient was given news that hormonal tests taken showed signs of menopause. Patient devastated as ovarian transposition was not successful. Patient referred for hormone replacement therapy. Three month follow up MRI scan and clinical examination revealed no sign of disease.
July 2009, three months post follow up, patient seen in clinic complaining of recurrent pain in right upper quadrant. Patient was on regular analgesics, but denied any per vagina bleeding or discharge. Bowels and micturation not working properly, denied it being associated with pain. Patient sent for CT scan of thorax, abdomen and pelvis in conjunction with FBC and U and E’s.
Results of patient scans discussed within an MDT in August 2009, where it showed recurrent disease in the transposed side ovary. The plan decided within MDT is to perform a diagnostic laparoscopy and removal of said ovary. Patient and family were extremely distressed and emotional on hearing this news.
Final pathology of biopsies taken laparoscopicaly in September 2009 confirmed malignancy in the right ovary. Following discussion at MDM, decision made to give the patient three cycles of Carboplatin and Taxol and reassess to see if surgical excision were possible. It was noted that peritoneal washings taken at time of biopsy were positive, which implies that peritoneal disease is elsewhere. Patient was consented for further chemotherapy and was distressed about possibility of hair loss due to chemotherapy. Patient was referred to MacMillan team for assessment of grant for financial assistance.
An interval CT scan was taken post 3rd cycle of chemotherapy in November 2009. This showed a response in disease with the mass having reduced slightly in size. Patient proceeded with a further two cycles of chemotherapy with G-CSF support (granulocyte-colony stimulating factor) a growth factor
that stimulates the bone marrow to produce more white blood cells.
After the patient had finished five cycles of Carboplatin and Taxol, patient was consented and referred for a laparotomy and exploration of lesser sac and paracolic gutter in December 2009. This showed evidence of metastatic disease in form of omentum nodules, which subsequently tested positive for metastases on frozen section. The tumour was found in right hepatic flexure and was fixed to the right para-colic gutter involving head of pancreas and infiltrating liver. From this discovery of metastatic disease, it was considered inappropriate to proceed with the proposed right hemicolectomy, cholecystectomy, resection of part of liver and excision of the Gerota’s fascia.
Patient and family were understandably very distressed about intra-operative findings. They were given a psychological support referral. Family were seen by a clinical psychologist, although the patient declined the appointment, but opted to speak to a CLIC Sargent social worker. Community palliative care team were to liaise and follow up with patient and family. The patient and family were additionally put in contact with a local hospice within their catchment
Based on findings the clinical oncologist felt that the Carboplatin and Taxol regime was ineffective in controlling disease progression and spread and was therefore stopped. In December 2009, next chemotherapy line suggested was Topotecan, although a request was made to consider the patient for a Phase 1 agent.
Due to patients increasing pain and problems with control the patient was not a suitable candidate for Phase 1 chemotherapy. Therefore patient was commenced on fives cycles of standard palliative chemotherapy Topotecan in January 2010.
Patient had extensive meetings and liaisons with social worker for young people. Macmillan nurse, from hospice arranged for home visits to assess pain medication. The patients ECOG performance was ranked as 1 (Appendix 2). Re-staging CT was performed which showed an increase in size of tumour with further encroachment onto liver, new malignant lesions were identified as well as more dilated bowel loops.
Patient completed intended cycles of Topotecan but was admitted for treatment of Sepsis with IV antibiotics in March 2010.
Subsequent CT scans in April 2010 displayed disease progression despite Topotecan. Patient commenced on Tamoxifen therapy due to her disease having some ER positivity.
Patient’s family were seen separately from patient, advised of patient’s prognosis to be less than 6 months. Patient’s mother raised concerns of patient expressing suicidal ideation. Macmillan nurse visited patient’s home.
May 2010, patients pain became difficult to control, home visit made by consultant in palliative medicine as patient became increasingly drowsy. Patient deteriorated rapidly and was commenced on the Liverpool Care Pathway.Marie curie nurse, present most evenings with patient at familial home.
June 2010, patient passed away with family around her.
Screening and HPV testing
Since first being introduced as a screening test for cervical cancer by Papanicolaou in 1927 (Papanicolaou, 1928), the cervico-vaginal smear test has proved to be one of the most cost effective test within medicine.The American Cancer society (1997) states that according to the National Cancer Institute, mortality rate from cervical cancer has dropped 70% over the last 70 years.
Currently only 30% of cervical cancers are screen detected, the majority of these cases occur in women who have never had a smear (PAP- Papanicolaou) test or regularly attend a screening programme. The patient discussed (patient A), was part of this statistic as she had never had a smear test due to the UK cervical screening age being 25. Patient A presented with symptoms aged 22. Standard practice within the UK is for women aged between 25 and 60 to be contacted every 3 to 5 years and asked to go for a cervical screening test. In patients A case, a smear test was only done due to other symptoms such as post coital bleeding.
An article in ‘The Times’ (2009) confirmed that new guidance will be issued to all GP’s and practice nurses to increase awareness and management of cervical cancer, but age at which women are screened will not be lowered to 20, announced by the department of health. This decision was finalised after a review by the Independent Advisory Committee on Cervical Screening (ACCS) which found that risks for women under 25 of false positive results and premature births outweighed benefit of identifying a “few extra cases”.
The ACCS found that treating women for abnormal cervical cell changes has been linked to an increased risk of premature birth. While women of all ages who are treated are more likely to give birth prematurely, benefits of screening older women outweigh this risk, the panel said.
One in three women under the age of 25 will have an abnormal result compared with one in fourteen for older women, the ACCS said, meaning that there are many false positives identifying abnormal changes in cells that often return to normal without treatment.
A study by Sasieni et al (2009) further confirmed the ACCS’s findings that cervical screening in women aged 20-34 is less effective than in older women. By studying the effect of screening in smaller age groups, Sasieni et al showed that efficacy of screening decreases with decreasing age, even within the age 20-34. On average, participation in the UK cervical screening programme by a woman aged 35-64 reduces her risk of cervical cancer over the next five years by 60-80% and her risk of advanced cervical cancer by about 90%. The benefit of screening for women aged 25-34 is more modest. Screening in women aged 20-24 has little or no impact on incidence of cervical cancer under the age of 30.
HPV is a factor being recognized as a major risk factor in pathogenesis of squamous cell carcinoma of cervix. Any woman who is sexually active is at risk of infection from human papillomavirus (HPV). Patient A was sexually active from aged 16. De Villiers et al (2004) identified Over 100 subtypes of HPV. A significant proportion of HPV disease is attributed to four subtypes; 6, 11, 16 and 18. HPV subtypes 16 and 18 cause approximately 70% of cervical cancer cases worldwide. HPV subtypes 6 and 11 infections are responsible for genital warts (Wiley et al, 2002).
Arbyn et al (2007) acknowledge that HPV is the major cause of nearly 100% of all cervix cancers. This finding rapidly led to the development of vaccines against common and aggressive virus strains causing cervix cancer, the HPV genotypes 16 and 18 (Harper et al, 2006).
According to Tornesello et al (2011), the role of HPVs in the etiology of cervical cancer precursor lesions and invasive carcinoma development has been well established. Bouvard et al (2009) found that at least 12 viral genotypes of alpha genus (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) have been found associated with a high relative risk of cervical cancer and labelled carcinogenic to humans. Although holding different prevalence rates, HPV types 16 and 18 were the most common viral types in invasive carcinoma of the uterine cervix worldwide (Li et al 2008).
Cheryl et al (2000) explain the HPV as replicating primarily within the proliferating basal cells of squamous epithelium. In order for the virus to infiltrate these cells, disturbance of the overlying epithelium must occur. Once present in the basal squamous cell, HPV early genes are expressed, which lead to viral replication and host cell duplication.
Previously no specific antiviral treatments existed for HPV-associated diseases, including genital warts, cervical, vaginal and vulval dysplasia as well as cervical cancer. The development of vaccines against HPV is an attractive strategy for both prevention and therapeutic intervention against genital tract HPV infections (Sherman et al, 1998).
Two HPV vaccines have been developed: Cervarix® (GlaxoSmithKline, London, UK) a bivalent HPV (types 16, 18) vaccine and Gardasil® (Merck & Co., Whitehouse Station, NJ), a quadrivalent HPV (types 6, 11, 16, 18) vaccine. Both are prophylactic vaccines that have been shown to be effective in young women prior to HPV exposure. Following advice of the Joint Committee on Vaccination and Immunisation (JCV I) the Government and Department of Health (DOH, 2007) have introduced HPV vaccines for girls aged 12 to 13 years of age, starting from September 2008 (Garland et al, 2007). This was implemented three months after Patient A’s diagnosis.
Cricca et al 2006 recognised an increased interest being focused on HPV detection in cervical lesions. They subsequently reported that detections of HPV DNA in the absence of cytological abnormalities may indicate persistent high-grade squamous lesions which may have been missed by PAP screening within the follow up of CIN3 – cervical intraepithelial neoplasia (severe dysplasia, carcinoma in situ- Dysplastic cells extend into the upper third and may occupy the full thickness of the epithelium) treated patients.
A study carried out by Silvana et al (2007) found HPV testing significantly predicts disease clearance or persistence, in comparison to PAP smear whose results did not register any statistical significance. The study further suggested that after treatment women should be followed up at 6-month intervals, for a minimum of 2 years with both PAP and HPV testing being carried out.
Patient A only received HPV testing after her abnormal smear test was analysed. Introducing routine HPV testing as part of screening process every three years could have had a marked impact on her prognosis.
Patient A’s initial main concern was preservation of fertility and a referral was made by the clinical oncologist for her to see a fertility specialist to seek advice. In women who preservation of fertility is anticipated, an alternative to simple/radical hysterectomy is a radical trachelectomy. This process requires vaginal resection of cervix, upper 1 to2 cm of vaginal cuff and medial portions of cardinal and uterosacral ligaments. The cervix is transected at lower uterine segment and a prophylactic cerclage is placed at time of surgery .
Landoni et al (1997) argue that for early stage disease, surgery conserves ovarian function and avoids effects of early menopause. They further propose that less shortening and fibrosis of vagina occurs compared to radical radiotherapy which gives better results in terms of residual sexual function. Surgery was thought to be the preferred treatment option in young women excluding the presence of any contraindications. Patient A fell into the young woman classification and initially had no contraindications to surgery. Relative risks and benefits of different surgical management approaches should be thoroughly discussed with the patient on an individual basis (Shepherd, 2009). Patient A had a thorough consent process prior to each surgical procedure and was put in contact with a specialist gynaecological nurse to answer any further questions.
Patient A presented with a 5cm exophytic tumour. She undertook a radical trachelectomy, although research suggests that it does not appear to increase rate of recurrence, provided tumour diameter is no greater than 2cm (Landoni et al, 2005). Safety of radical trachelectomy in women with lesions that are greater than 2cm in diameter is not known as the majority of reported cases of radical trachelectomy have been in women with tumours less than 2cm in diameter. A recent prospective multicentre study by Renaud et al (2004) of radical trachelectomy combined with laparoscopic pelvic lymphadenectomy reported three recurrences in 100 treated patients (FIGO IA1, IA2, and IB1).
NICE (national institute for clinical excellence) guidelines (2010) state, that women requesting fertility conservation should be offered radical trachelectomy and pelvic lymph node dissection, providing tumour diameter is less than 2cm and no lymphatic-vascular space invasion is present. As established within the case notes, Patients A tumour presented at 5cms, which means guidelines were not properly followed.
In addition to trachelectomy patient A underwent ovarian transposition. Preservation of ovarian function is an important concern in premenopausal cancer patients whose treatments include external beam radiation to pelvic structures that incorporate ovaries applicable to patient A. Ovarian transposition was developed to displace ovaries from their normal anatomic position and away from direct radiation, with goal of maintaining long-term ovarian function. Ovarian transposition is seen as 40-50% successful (Shepherd, 2009).
Techniques for ovarian transposition using a laparoscopic approach depend on radiation field size and location. Tinga et al (1999) have described transposition of ovaries in a fixed position behind uterus (to lie beneath an external midline block) as well as a superior transposition to level of iliac crest. They contend that the disadvantage of midline oophoropexy (surgical fixation or suspension of an ovary) is a higher level of internal radiation scatter, as the area is generally surrounded by in-field radiation. Morice et al (1998) reported a series of 24 patients who underwent ovarian transposition to paracolic gutters, before radiation for gynecologic malignancies. Authors concluded that this procedure was a safe and effective method of preserving ovarian function. Complications in both of these reports were rare. The fact of Patients A recurrence being at sight of transposition was noted as extremely rare and was the first case experienced by the clinical oncologist. No literature was found outlining risks of recurrence of cervical cancer with ovarian transposition. It could be noted that perhaps Patient A’s size of tumour was too large for radical fertility sparing surgery.
Patient A and her family experienced a great deal of distress during the care pathway. In 1983 Derogatis et al acknowledged cervical cancer as having a significant psychological and psychosocial impact on the individual and felt it was important to develop strategies to deal with this.
Fallowfield et al (2001) recognise psychological distress as being common in patients with all forms of cancer and advocate it as remaining undetected. Regardless of socio-demographic characteristics or clinical characteristics, the well-being of patients with cervical cancer changes during the course of their disease (Greimel et al, 2000). A study by Greimel et al (2000) of 119 patients’ newly diagnosed gynaecological cancer evaluated psychological well-being and functions of daily living before surgery, three months after surgery and one year after surgery.
Greimel et al (2000) noted a decline in psychological well-being and functions of daily living scores at three months after surgery. After one year there was a significant improvement in psychological well-being and no significant difference in functions of daily living compared to before surgery. Greimel (2000) recognised that in patients treated with surgery, level of psychological distress may be related to extent of surgery.
The multidisciplinary team (MDT) should routinely screen for presence of psychological distress and be aware of risk factors for very high levels of psychological distress from point of diagnosis onwards (including during follow-up review phases) (Fallowfield et al, 2001). The MDT team involved with patient A routinely screened her psychological well-being and monitored it closely due to the young age of the patient. Patient A had regular contact with a support group and social worker for young patients in a similar circumstance. She was able to discuss matters which she was unable to share with her family and partner, such as body image and sexuality issues.
As illustrated by Fallowfield et al (2001), many of psychological, physical and practical challenges facing women with cervical cancer are common to all cancer patients. These include, coping with shock of diagnosis, pain, nausea, fatigue and disfigurement from surgery as well as treatment worries over practical issues such as travel costs and loss of income. These above challenges were all experienced by Patient A. MDT supported the patient through these challenges. There is evidence that providing psychological and practical support may have a positive effect on patients’ well-being (Slevin et al, 1996). Evidence identified in relation to support needs of cancer patients was from small heterogeneous studies such as Walker et al (1999) and types of help offered are very varied. No studies found were specific to patients with cervical cancer but were comparable to cervical cancer population. Interventions included structured psychological support, relaxation techniques, orientation programmes and general psychological support. The interventions reduced anxiety levels and improved quality of life.There are many national and local support services, for example, voluntary agencies, clinical nurse specialists, liaison psychiatry, clinical psychologists, local support groups, drop-in centres and day centres. These support services may offer complementary therapy services, such as yoga, aromatherapy and reiki. Reflexology was undertaken by patient A which, was offered by one of these support services.
NICE guidelines (2010) state that “Patients with cervical cancer should be offered psychological support at time of diagnosis and at intervals throughout their management. Information about local support services should be made available to patients. Carers, families and dependants should be made aware of support available including local and national organisations. Multidisciplinary teams across healthcare settings should have agreed protocols for offering support for carers, families and dependants of patients with cervical cancer.” These guidelines were adhered to in the treatment of patient A.
Near the end of Patients’ A life, a MDT decision was made to commence the Liverpool Care Pathway. Over past few years a major drive has been underway to ensure that all dying patients, and their relatives and carers receive a high standard of care in the last hours and days of their life. The Liverpool Care Pathway for the Dying Patient (LCP) is a key programme within the palliative care pathway for a patient.
LCP was recognised as a model of best practice in the NHS Beacon Programme (2001). It was recommended in NICE guidance on supportive and palliative care for patients with cancer (2004) as a mechanism for identifying and addressing the needs of dying patients. It was recommended in the Our Health, Our Care, Our Say white paper 2006 as a tool that should be rolled out across the country. It is recommended in the End of Life Care Strategy DH 2008.
Optimal management of cervical cancer involves a multidisciplinary team as demonstrated in Patients A case. The challenge for the team is to individualise treatment. As cervical cancer commonly occurs between ages of 30 and 45, this includes offering women with early disease the option of having fertility conserving surgery, where appropriate. Patient A did not fall into common age group for occurrence of cervical cancer. Patient A presented aged 22. For those such as Patient A, with intermediate or advanced disease, aim is to minimise treatment side effects without compromising outcome.
Chemotherapy and Trials
Within the last ten years concomitant chemoradiation has been the standard of care for advanced cervical cancer. Patient A received Cisplatin with radiotherapy followed by Adjuvant Topotecan. Varying proposals have been made that to control occult metastatic disease adjuvant chemotherapy after chemoradiation will improve outcome.
In 2009 Duenas-Gonzalez et al described results of a phase III randomized trial which compared chemoradiation with gemcitabine and cisplatin followed by adjuvant gemcitabine and cisplatin for two additional cycles VS chemoradiation with cisplatin in women with stage IIA to IVA cervical cancer. Results showed a significant survival benefit for patients receiving chemoradiation plus adjuvant chemotherapy, the results concluded a 3 year survival of 74% in the chemoradiation plus chemotherapy arm against 65% in the chemoradiation arm. In order to confirm these results future trials are imperative, Kitchener et al (2010) aim to randomise women receiving chemoradiaiton after radical hysterectomy to four additional cycles of carboplatin and paclitaxel or no additional therapy.
Chemotherapy is recognised as a standard treatment for women with late stage disease and those with recurrence not eligible for chemoradiation or surgery applicable to patient A. Monk et al (2009) published results of a phase III trial which compared 4 platinum containing doublets. Patients were randomised to receive cisplatin combined with either paclitaxel (the reference arm), vinorelbine, gemcitabine or topotecan. The results showed that progression free survival and response rates were similar in all four arms. Cisplatin with paclitaxel was found to have the best toxicity profile with quality of life similar across the four arms
Angiogenisis is the formation of new blood vessels that grow into the tumour, giving it nutrients and oxygen to assist its growth. As with other cancers the role of anti-angiogenic targeted agents are of interest and importance in the treatment of cervical cancer. A phase II trial of bevacizumab in women with persistent or recurrent cervical cancer concluded a median progression free and an average overall survival range 3.4 – 7.3 months thus showing favoribilty within cervical cancer (Monk et al, 2009). Leading from the results of this trial Kitchener et al (2010) constructed a phase III trial where women are randomised to one of four arms using bevacizumab with cisplatin/paclitaxel or topotecan/paclitaxel.
Monk et al (2010) identified Pazopanib as a second anti-angiogenic agent usuable within the cervical cancer patient population. This agent is known as an oral tyrosine kinase inhibitor which targets the vascular endothelial growth factor receptor. It was found that patients treated with pazopanib had a median overall survival of 50.7 weeks.
Patient A received topotecan as a single adjuvant agent, if combined with an anti-angiogenic agent such as bevacizumab or pazopanib she may have had a prolonged life expectancy. Funding, costing and PCT approval may have been a barrier to access.
Patients A case is a sad case. The patient underwent ovarian transposition in order to preserve fertility but unfortunately the disease recurred at this site. Perhaps if the transposition was not undertaken then she may have still been alive. Ultimately it was the patient’s choice and due to the patients young age fertility preservation was very much applicable and supported by the clinician.
There is a lot of controversy surrounding the topic of lowering the age of PAP smear testing and the standardisation of HPV testing as routine. If patient A had had regular smear tests and HPV testing as research has proved beneficial her disease may have been identified earlier and put through radical treatment.
The availability of anti angiogenic has not yet been standardised by some PCTs, patients A access to chemo drugs such as pazopanib may have prolonged her life further.
Throughout the past years there have been many advances and discoveries in the prevention and treatment of cervical cancer, Within the next five years there are many other advcances and technologies that will possibly impact the management of this common indiscriminatory disease. Active areas of research that can change the management and practice include the use of PET/CT imaging to guide therapy and PET or high-field MRI to monitor response to treatment, combined use of hyperthermia and radiation therapy to treat locally advanced disease and the role of intensity modulated radiotherapy.
FIGO staging of cervical carcinomas
Stage I is carcinoma strictly confined to the cervix; extension to the uterine corpus should be disregarded. The diagnosis of both Stages IA1 and IA2 should be based on microscopic examination of removed tissue, preferably a cone, which must include the entire lesion.
Invasive cancer identified only microscopically. Invasion is limited to measured stromal invasion with a maximum depth of 5 mm and no wider than 7 mm.
Stage IA1: Measured invasion of the stroma no greater than 3 mm in depth and no wider than 7 mm diameter.
Stage IA2: Measured invasion of stroma greater than 3 mm but no greater than 5 mm in depth and no wider than 7 mm in diameter.
Clinical lesions confined to the cervix or preclinical lesions greater than Stage IA. All gross lesions even with superficial invasion are Stage IB cancers.
Stage IB1: Clinical lesions no greater than 4 cm in size.
Stage IB2: Clinical lesions greater than 4 cm in size.
Stage II is carcinoma that extends beyond the cervix, but does not extend into the pelvic wall. The carcinoma involves the vagina, but not as far as the lower third.
No obvious parametrial involvement. Involvement of up to, upper two thirds of the vagina.
Obvious parametrial involvement, but not into the pelvic sidewall.
Stage III is carcinoma that has extended into the pelvic sidewall. On rectal examination, there is no cancer-free space between the tumour and the pelvic sidewall. The tumour involves the lower third of the vagina. All cases with hydronephrosis or a non-functioning kidney are Stage III cancers.
No extension into the pelvic sidewall but involvement of the lower third of the vagina.
Stage IIIB: Extension into the pelvic sidewall or hydronephrosis or non-functioning kidney.
Stage IV is carcinoma that has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
Stage IVA: Spread of the tumour into adjacent pelvic organs.
Stage IVB: Spread to distant organs.
Source: TNM Classification of malignant tumours. L. Sobin and Ch. Wittekind (eds.),
UICC Internation Union against Cancer, Geneva, Switzerland, pp155-157; 6th ed. 2002
ECOG Performance Status
These scales and criteria are used by doctors and researchers to assess how a patient’s disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
ECOG PERFORMANCE STATUS
0Fully active, able to carry on all pre-disease performance without restriction
1Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
As published in Am. J. Clin. Oncol. :Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982
Cancer Research UK. (2003) UK Cervical Cancer incidence statistics [online]. Available from http://info.cancerresearchuk.org/cancerstats/types/cervix/incidence/Information Services Division. Cervix Uteri (ICD-9 180; ICD-10 C53). (Accessed 16th February 2011)
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