- Email: [email protected]
Invasive cervical cancer
ARTICLE IN PRESS Current Obstetrics & Gynaecology (2004) 14, 200–206
www.elsevier.com/cuog
Invasive cervical cancer Richard W. Todda,*, Mahmood Shafib a
Gynaecological Oncology, Birmingham Women’s NHS Trust, Birmingham, UK Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, UK
b
KEYWORDS Cervical carcinoma
Summary Although relatively rare in developed countries, on a worldwide scale, cervical cancer remains the second most common malignancy to affect women. It is now clear that human papillomavirus infection is implicated in more than 95% of cases of cervical cancer. Early detection of cervical cancer and its precursors, using cytology-based screening, has led to a dramatic reduction in the incidence of, and deaths from, the disease in some developed countries. For early-stage disease, surgery forms the mainstay of treatment. In some cases, radical surgery may be avoided, particularly in early-stage disease, with the possibility of fertility conservation when desired. Minimal access surgery has contributed to this more conservative approach. For more advanced disease, combined chemotherapy and radiotherapy has emerged as being more effective than either treatment alone. Recently, efforts have been made to develop both therapeutic and prophylactic vaccines for use in the prevention and treatment of cervical cancer and precancer. & 2004 Elsevier Ltd. All rights reserved.
Introduction Cervical cancer remains a major global health issue. Each year, approximately 470 000 new cases of invasive cervical cancer are diagnosed, many in an advanced stage. As many as 250 000 deaths occur worldwide. While the UK and other developed countries have seen both the incidence of, and deaths from, cervical cancer fall in recent years, the same can not be said of less developed countries. Up to 80% of all cervical cancers will occur in less developed regions of the world, and in India, cervical cancer is the most common cause of death in women aged between 20 and 40 years. Since the introduction of the National Health Service Cervical Screening Programme in 1998, the UK has experienced a 40% reduction in the incidence of cervical cancer. For the first time ever, the number of deaths from cervical cancer in *Corresponding author. Department of Obstetrics, Gynaecology, Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, UK. Tel.: þ 44-121-472-1377; fax: þ 44-121-627-2667. E-mail address: [email protected] (R.W. Todd).
England fell to less than 1000 in 2002 (Fig. 1). Cervical screening is thought to prevent approximately 1300 deaths/year. Since more has been learnt about the role of human papillomaviruses (HPVs) in the development of cervical cancer, much effort has been directed at developing ways to prevent the development of the disease using immunological techniques. In the future, advances in chemotherapy, radiotherapy and the development of therapeutic vaccines may result in a diminishing role for surgery in the treatment of this disease.
Aetiology It has long been recognized that sexual activity is inextricably linked with the development of cervical cancer and its precursor, cervical intra-epithelial neoplasia (CIN). Early coitarche (age 16 years or younger) and a history of multiple sexual partners have been shown to be risk factors. Since the early work of Rigoni–Stern in the first half of the 19th
0268-0890/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2004.02.005
ARTICLE IN PRESS Invasive cervical cancer
201
Cervical intra-epithelial neoplasia
14
Rate per 100000
12 10 8 6 4 2 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Incidence
Mortality
Figure 1 Cervical cancer, incidence and mortality 1993–2002 (England).
century, the search has been on for a possible sexually transmitted agent. Over the last decade, it has become clear that HPV is the main aetiological agent responsible. HPVs are double-stranded DNA viruses that exhibit epithelial specificity. Over 200 different types and subtypes have been identified on the basis of their DNA sequences. Some of these viruses have been shown to have a predilection for genital mucosa, and within that group, certain oncogenic types can be identified. The so-called high-risk types include HPVs 16, 18, 31, 33 and 45. By using detection methods such as polymerase chain reaction, HPV DNA can be detected in 99% of cervical cancers. However, although HPV is the most common sexually transmitted disease, only a tiny proportion of those infected will go on to develop cancer. Therefore, other factors must be involved. Clearance and avoidance of HPV infection relies on a competent immune response. An efficient cellmediated immune response is probably crucial for the clearance of HPV infection, while the humoral component may be important in preventing reinfection. Therefore, anything compromising the immunity of an individual can be expected to result in increased risk of HPV-related disease. Smoking, through the effect of carcinogens and the interference with cervical antigen-presenting cells, has been shown to increase the relative risk of developing cervical cancer up to two-fold. Similarly, generalized immunosuppression, either as a result of drugs or human immunodeficiency virus, results in an increased risk of CIN and cancer. More recently, prolonged use of the oral contraceptive pill has been linked with up to a four-fold increase in risk for cervical cancer in women who are HPV-DNA positive.
The term ‘CIN’ was introduced by Richart in 1965 and was described as a spectrum of intra-epithelial abnormalities ranging from mild dysplasia to carcinoma in situ. These lesions affect the full thickness of the epithelium and are graded 1–3 depending on features such as loss of differentiation, abnormal nuclei and presence of abnormal mitotic figures. It is now recognized that the socalled low-grade CIN (CIN 1) will often regress spontaneously whereas high-grade CIN (CIN 2/3) has the potential to progress to frank malignancy in up to 30% of cases. The detection and potential treatment of CIN forms the basis of the cervical screening programme which relies on cervical cytology to detect dyskaryotic cells, thus alerting the medical practitioner to the possible presence of CIN or worse. Secondary screening with colposcopy allows identification of any lesions, which can then be treated if necessary. In the 10 years following the introduction of an organized screening programme that concentrated on adequate coverage of the target population, the incidence of cervical cancer fell by 42% in England and Wales. The development of liquid-based cytology has the potential to reduce the rate of inadequate smears as well as improving efficiency and laboratory productivity.
Diagnosis of cervical cancer Symptoms and signs A proportion of early-stage cervical cancers are asymptomatic and will be detected at colposcopy following abnormal cervical cytology. In other cases, abnormal vaginal bleeding may be the presenting symptom. Intermenstrual and postcoital bleeding are typical. An offensive, watery, blood-stained discharge may result in some cases. In more advanced disease, symptoms may arise due to local effects of tumour on surrounding structures. For instance, lymphatic obstruction may result in lymphoedema of the lower limbs, or hydronephrosis and loin pain in the case of a blocked ureter. Pelvic pain and sciatic pain have both been described when there is nerve involvement. Where bladder involvement occurs, haematuria, frequency and incontinence may occur. Rectal bleeding and tenesmus may result following rectal involvement.
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R.W. Todd, M. Shafi
Staging of cervical cancer The staging of cervical cancer is clinical and is shown in Table 1. The role of staging is to ascertain the extent of disease, allowing patients to be counselled and appropriate treatment to be planned. Underestimating the extent of disease may lead to the need for adjuvant therapy following surgery. Ideally, one treatment modality should be the goal in order to reduce morbidity.
Clinical examination In the past, examination under anaesthesia (EUA) was performed routinely when staging cervical cancer. Nowadays, some practitioners may feel EUA is unnecessary, particularly if examination in the clinic is satisfactory. Additional imaging may be sufficient, thus avoiding EUA. Clinical examination should include a careful assessment of the abdomen, in particular looking for hepatomegaly, hydronephrosis and lymphadenopathy. Bimanual vaginal examination is then performed. Of importance is the size and mobility of the cervix and uterus, as well as any suggestion of spread into surrounding tissues. Combined vaginal and rectal
Table 1
examination will also allow assessment of the uterosacral ligaments and further assessment of the parametria. EUA allows all of the above to be performed, usually more thoroughly than if the patient was awake. It also allows cystoscopy and sigmoidoscopy to be performed if there is suspicion of involvement of either bladder or bowel. Urine should be sent for cytology. EUA also permits further biopsies of the cervix or vagina to be taken if necessary. Clinical examination, although vital, has been shown to underestimate the extent of disease in up to 40% of cases. Therefore, other methods may be employed to obtain additional information.
Radiology If one studies the FIGO staging (Table 1), it can be seen that assessment of the renal tract is critical in defining Stage IIIb disease. In the past, an intravenous urogram was commonly performed, although some centres now rely on either computerized tomography (CT) or magnetic resonance imaging (MRI). These latter tools also allow assessment of the liver and para-aortic and pelvic lymph nodes as well as studying local spread of the disease. MRI has
Staging of cervical cancer (FIGO, 1994).
Stage
Features
I Ia Ia1
Carcinoma strictly confined to the cervix (extension to the corpus should be disregarded) Preclinical carcinoma of the cervix, i.e. diagnosed by microscopy Minimal microscopically evident stromal invasion o3 mm in depth and a horizontal spread p7 mm Lesions with a depth of invasion 43 mm and no more than 5 mm, and horizontal spread p7 mm Clinical lesions confined to the cervix or preclinical lesions greater than Stage Ia Clinical lesions o4 cm in diameter Clinical lesions X4 cm in diameter
Ia2 Ib Ib1 Ib2 II IIa IIb III
IIIa IIIb IV IVa IVb
The carcinoma extends beyond the cervix, but has not extended on to the pelvic wall; the carcinoma involves the vagina but not as far as the lower third No obvious parametrial involvement Obvious parametrial involvement The carcinoma has extended on to the pelvic wall. On rectal examination, there is no cancer-free space between the tumour and the pelvic wall; the tumour involves the lower third of the vagina; all cases with a hydronephrosis or non-functioning kidney should be included unless they are known to be due to another cause No extension to the pelvic wall, but involvement of the lower third of the vagina Extension onto the pelvic wall or hydronephrosis or non-functioning kidney The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum Spread of the growth to adjacent organs Spread to distant organs
ARTICLE IN PRESS Invasive cervical cancer
203
been shown to be superior to clinical examination and CT when determining tumour extent, particularly regarding parametrial involvement. MRI findings agree with the surgical and pathological findings in 70–90% of cases. MRI allows enlarged lymph nodes to be detected in up to 80% of cases, although sensitivity and specificity is reduced as distinguishing reactive inflammatory nodes from metastatic disease can be difficult. Positron emission tomography (PET) has emerged as a tool that may be useful in detecting recurrent disease, particularly after radiotherapy. Some studies have shown PET to have greater sensitivity than either MRI or CT in detecting lymph node metastases.
small cell or neuro-endocrine tumours, are associated with a poor prognosis.
Prognostic factors
Management
Patient factors
The management of be determined on a preferably in a cancer individualized, taking a account:
Cervical cancer has a bimodal distribution. It has previously been suggested that women in the younger (o40 years) age group have a worse prognosis. Data are conflicting, with some authors reporting a worse prognosis in this group, others reporting a better prognosis and others reporting no difference. Social status, race and parity are unrelated to outcome when compared stage for stage. Cervical cancer presenting at an early-stage in pregnancy is not associated with a worse outcome compared with the non-pregnant individual.
Tumour factors Stage at presentation is the strongest predictor of prognosis in cervical cancer, with survival times falling as stage increases (Table 2). This is due to the fact that as tumour stage increases, so does the tumour volume and, with that, the likelihood of lymphatic and vascular involvement increases. Lymphovascular space (LVS) involvement has been shown to correlate with the risk of lymph node metastases. In one series looking at Stage 1a2 tumours, LVS involvement increased the rate of node positivity from 3.2% to 16.1%. It can be seen (Table 2) that in the presence of positive nodes, 5year survival is reduced. The histology of the tumour can have a bearing on prognosis. It has been suggested that adenocarcinomas of the cervix have a worse prognosis than their squamous counterparts when compared stage for stage, although the data on this matter are conflicting. Certain rarer tumour types, such as
Table 2 Five-year survival (%) by stage and node status.
* * * * * *
Stage
Number
All cases
Node-positive cases
1b IIa IIb III IVa
6511 2433 2533 2598 1518
80.1 62.6 55.5 37.9 10.5
67.3 48.4 42.7 30.0 7.0
cervical cancer should multidisciplinary level, centre, and should be number of factors into
age of the patient; co-morbidities; stage and volume of the tumour; desire for fertility; patient choice; and tumour type.
Treatment modalities include surgery, radiotherapy and chemotherapy, either singly or in combination.
Early-stage disease Stage 1a1 disease Stage 1a1 lesions have a depth of invasion of less than 3 mm and are diagnosed on histology. The prognosis for Stage 1a1 disease is excellent with 5year survival rates of 495% described. The risk of lymph node metastasis is of the order of 0.5%. Thus, either local treatment in the form of a local excision or simple hysterectomy should suffice. It is important that excision margins on a cone biopsy are clear of any invasive or preinvasive disease. If not, repeat excision can be performed to obtain clear margins. Should other gynaecological conditions such as menorrhagia be a feature, or if desired by the patient, simple hysterectomy may be chosen.
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R.W. Todd, M. Shafi
Stage 1a2 disease In Stage 1a2 disease, the depth of invasion is between 3 and 5 mm and disease is subclinical with the diagnosis being made on histology. The management of Stage 1a2 carcinomas has changed over recent years with a trend away from radical treatments. Regardless of the radicality, death rates and recurrence rates are low in this group. Of importance is the risk of lymph node metastasis, which is approximately 7% in these cases. The optimal treatment has yet to be defined and should be managed on an individual basis. Treatments for the local lesion range from cone biopsy through simple hysterectomy to radical hysterectomy. With all of these, the lymph node status also needs to be addressed. Since many of these lesions will occur in young women with a desire to retain their fertility, there has been a trend towards fertility-sparing surgery. Thus, if fertility is desired, the local lesion can be managed with simple excision by cone biopsy to achieve clear margins. The lymph nodes can then be assessed either extraperitoneally or laparoscopically. In the event of lymph node metastases, adjuvant treatment can be offered.
Stage 1b1/2a disease It has been recognized for some time that the outcomes for Stage 1b/2a disease are similar whether treated by radical surgery or radiotherapy. A large randomized study compared radiotherapy with surgery in 343 patients with Stage 1b or 2a disease. It was shown that 5-year survival was similar in both groups (83% and 74%, respectively). The main differences related to morbidity. A significant number of women in the surgery arm went on to have adjuvant radiotherapy for adverse
Table 3
features. Even taking this into account, surgery was associated with greater morbidity, although these complications could be more easily corrected. Radiotherapy may be associated with ovarian failure, bowel and bladder disturbance and vaginal stenosis. In the above study, patients with bulky Stage 1b tumours (44 cm) were more likely to receive adjuvant radiotherapy. Therefore, it would appear that if one can be confident that complete removal of tumour can be achieved with positive margins, particularly in women who desire ovarian function, primary surgery may be preferable. In order to avoid the extra morbidity associated with dual treatment modalities, in the case of bulky Stage 1b2 tumours or Stage 2a disease where adequate excision cannot be assured and risk of metastatic disease is higher, or if ovarian and sexual function is no longer an issue, primary treatment with chemoradiotherapy should be considered. If considering surgery, one needs to consider which technique is to be employed. Central to the surgical management of most cancers is the ability to remove the primary lesion with an adequate margin of normal tissue to ensure complete resection. When considering cervical carcinomas, it is immediately apparent that this may be complicated by local anatomy. Since the bladder lies anterior to the cervix and the rectum lies posterior, it is clear that there is little scope in extending these margins beyond a certain limit. Laterally, however, there is far more scope to extend the amount of tissue removed. This forms the basis of the Piver–Rutledge Class 3 hysterectomy (Table 3). This procedure removes the central lesion along with parametrial and vaginal tissue. The uterine artery is ligated and divided at its origin, and the ureter is traced along its path to the point at which it enters the bladder. The uterosa-
Piver–Rutledge classification of extended hysterectomy for the management of cervical carcinoma.
Class 1
Extrafascial hysterectomy. Ensures removal of all cervical tissue
Class 2
Modified radical hysterectomy. Removal of the medial half of the cardinal and uterosacral ligaments. Uterine vessels divided medial to the ureter
Class 3
Classical Wertheim–Meig’s radical hysterectomy. Wide radical excision of the parametrial and paravaginal tissues. Ureter is dissected down to the bladder. Uterosacrals divided at their origin, the cardinals divided at the pelvic sidewall
Class 4
More radical. The ureter is dissected from the pubovesical ligament, the superior vesical artery is sacrificed and 75% of the vagina is removed
Class 5
Extended radical hysterectomy that may involve resection of bowel, bladder or ureter
ARTICLE IN PRESS Invasive cervical cancer
cral ligaments are divided at their origin and the cardinal ligaments are divided at the pelvic sidewall. Additionally, the external iliac vessels are cleared of lymphatics from the point of the bifurcation of the common iliacs and the obturator fossa is explored and cleared in a similar fashion. This procedure would be regarded as the ‘gold standard’ procedure. In reality, many practitioners would perform the Class 2 procedure since the little evidence that there is would suggest no advantage of the Class 3 procedure over the Class 2 procedure. For Stage 1b2 and 2a tumours, the likelihood of needing adjuvant radiotherapy after surgery is high. Therefore, Stage 1b1 tumours are probably best suited to the above surgical approach. When considering surgery, one should not forget the associated morbidity. Both bladder and bowel dysfunction are well described following radical hysterectomy. Vesico- or ureterovaginal fistulas may result either as a result of direct surgical injury or indirectly due to devascularization. In addition, lymphadenectomy may result in pelvic lymphocyst formation. Effects on sexual function are poorly researched, although there is good evidence that radical surgery results in loss of vulval sensation as well as altered vaginal lubrication and, in some cases, vaginal shortening and loss of elasticity.
Fertility-sparing surgery Since many patients with cervical cancer are young, techniques have been developed that may allow conservation of fertility. This has been facilitated by the advent of minimal access surgery for pelvic lymphadenectomy. Radical trachelectomy involves excision of the majority of the cervix, the upper vagina and the proximal cardinal ligaments. This is performed through a vaginal approach. Often it is preceded by a laparascopic pelvic lymphadenectomy. If the nodes are negative, one can proceed with the trachelectomy. It is necessary to insert a cervical suture at the same time since cervical incompetence is almost inevitable. These procedures are, at present, best regarded as experimental although experience is growing rapidly. When counselling patients for this procedure, it should be made clear that long-term follow-up data on large numbers of patients are not yet available and that premature delivery may result in up to 60% of cases despite cervical cerclage.
205
Advanced disease Surgery has very little role in the management of Stages IIb, III and IV disease. Previously, radiotherapy alone would have formed the mainstay of treatment. More recently, it has become clear that combined chemotherapy and radiotherapy confer a survival advantage. Cisplatin is the chemotherapy of choice and appears to be most effective when given alongside radiotherapy, possibly by sensitizing cells to radiotherapy. A large meta-analysis of 19 studies was published in 2001. As with most meta-analyses, trials included differed in size, design, schedules and agents used to treat. However, the conclusions drawn suggested a survival advantage, reduction in the incidence of local recurrence and a significant reduction in the incidence of distant metastases. Of note is that in the combined arms of all trials, acute toxicity was increased.
Relapsed disease The 5-year survival for patients with recurrent disease is less than 5%. Occasionally, if a recurrence is central and there is no evidence of distant spread, an exenterative procedure may be considered. This should be carefully planned by a multidisciplinary team, including colorectal and urological surgeons, since it may be necessary to remove the bladder (anterior exenteration), rectum (posterior exenteration) or both bladder and rectum (total exenteration). Input from both a psychiatrist and clinical psychologist is also vital in determining which patients are less likely to cope with the procedure and also in providing psychological support before and after. Patients who have undergone these procedures, particularly total exenteration, have been shown to be at a higher risk of suicide. Cisplatin may have a role in palliating symptoms in relapsed cases, although response rates may only be 30%. Since nearly all patients relapsing will have been exposed to radiotherapy, chemotherapy is less likely to be effective due to radiation-induced ischaemia. Re-irradiation rarely has a role in treating relapse. It was previously thought that further exposure to radiotherapy was possible if a significant time period had passed since the first exposure. Salvage percentages of between 10% and 25% were described. In reality, those cases where a ‘success’ was seen were likely to have received an inadequate dose at the outset. Nowa-
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days, with more modern sophisticated radiotherapy techniques, this situation is unlikely to occur. Reirradiation has been shown to result in major complications in at least 50% of cases.
Follow-up The strategy for following-up patients treated for cervical cancer will vary from centre to centre. This reflects the lack of evidence to back up any one strategy. Certainly, the use of vault smears is questionable since the sensitivity and specificity has been shown to be poor, particularly following radiotherapy. In reality, the follow-up will vary depending on local service provision and the wishes of the patient. Any follow-up should be based on history and clinical examination. Imaging should only be performed if there is clinical suspicion of recurrence.
R.W. Todd, M. Shafi
developed world, the same cannot be said of the developing world. Improved treatments, particularly in relation to chemoradiotherapy, have also led to improved survival in the developed world. More work is needed to develop and identify those strategies that will allow a similar reduction to occur in the developing world.
Practice points
*
*
*
*
The future *
The future will almost certainly see developments in the use of vaccines for both prevention and treatment of cervical cancer. The results of a randomized double-blind study looking at vaccination against HPV 16 in over 2300 young women were published in 2002. After a median of 17 months follow-up, the vaccine was shown to have an efficacy of 100% when looking at prevention of persistent genital HPV 16 infection. Clearly, these results are exciting and further work is needed. The main questions still to be answered are who to vaccinate, when, how often, which viruses to vaccinate against and what will be the effect on the incidence of cervical cancer and precancer? Work is also ongoing looking at therapeutic vaccines directed against HPV proteins, particularly the E6 and E7 proteins which are expressed by transformed cells. This could be of value in treating either CIN or cancer. Initial trials have yielded disappointing results and more work is needed. Finally, trials are ongoing to investigate the role of chemoradiotherapy, particularly in relation to studying different cytotoxic agents and treatment regimens.
Conclusions Cervical cancer continues to represent a major global health challenge. While screening for CIN has led to a fall in the incidence of the disease in the
Accurate staging of cervical cancer is critical in planning appropriate treatment. Staging is clinical and additional information may be obtained through the use of appropriate imaging. Early-stage disease is usually dealt with surgically. Fertility-sparing surgery may be possible in some cases. Combined chemoradiotherapy is more effective than either modality alone in the treatment of advanced disease. The prognosis for relapsed disease is poor, with a 5-year survival of approximately 5%.
Further reading Bernardini M, Barrett J, Seaward G, Covens A. Pregnancy outcomes in patients after radical trachelectomy. Am J Obstet Gynecol 2003;189:1378–82. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358:781–6. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217–26. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645–51. Landoni, F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib–IIa cervical cancer. Lancet 1997;350:535–40. Shepherd JH, Mould T, Oram DH. Radical trachelectomy in earlystage carcinoma of the cervix: outcome as judged by recurrence and fertility rates. Br J Obstetr Gynaecol 2001;108:882–5. Stanley M. Genital human papillomavirus infectionsFcurrent and prospective therapies. J Natl Cancer Inst Monogr 2003;31:117–24 [Chapter 17]. Van Geene P, Tidy JA. Prognostic factors in cervical cancer. In: Luesley DM, Barrasso R, editors. Cancer and Pre-cancer of the Cervix. Lippincott-Raven Publishers, Cambridge, UK, 1998. p. 275–95.
www.elsevier.com/cuog
Invasive cervical cancer Richard W. Todda,*, Mahmood Shafib a
Gynaecological Oncology, Birmingham Women’s NHS Trust, Birmingham, UK Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, UK
b
KEYWORDS Cervical carcinoma
Summary Although relatively rare in developed countries, on a worldwide scale, cervical cancer remains the second most common malignancy to affect women. It is now clear that human papillomavirus infection is implicated in more than 95% of cases of cervical cancer. Early detection of cervical cancer and its precursors, using cytology-based screening, has led to a dramatic reduction in the incidence of, and deaths from, the disease in some developed countries. For early-stage disease, surgery forms the mainstay of treatment. In some cases, radical surgery may be avoided, particularly in early-stage disease, with the possibility of fertility conservation when desired. Minimal access surgery has contributed to this more conservative approach. For more advanced disease, combined chemotherapy and radiotherapy has emerged as being more effective than either treatment alone. Recently, efforts have been made to develop both therapeutic and prophylactic vaccines for use in the prevention and treatment of cervical cancer and precancer. & 2004 Elsevier Ltd. All rights reserved.
Introduction Cervical cancer remains a major global health issue. Each year, approximately 470 000 new cases of invasive cervical cancer are diagnosed, many in an advanced stage. As many as 250 000 deaths occur worldwide. While the UK and other developed countries have seen both the incidence of, and deaths from, cervical cancer fall in recent years, the same can not be said of less developed countries. Up to 80% of all cervical cancers will occur in less developed regions of the world, and in India, cervical cancer is the most common cause of death in women aged between 20 and 40 years. Since the introduction of the National Health Service Cervical Screening Programme in 1998, the UK has experienced a 40% reduction in the incidence of cervical cancer. For the first time ever, the number of deaths from cervical cancer in *Corresponding author. Department of Obstetrics, Gynaecology, Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, UK. Tel.: þ 44-121-472-1377; fax: þ 44-121-627-2667. E-mail address: [email protected] (R.W. Todd).
England fell to less than 1000 in 2002 (Fig. 1). Cervical screening is thought to prevent approximately 1300 deaths/year. Since more has been learnt about the role of human papillomaviruses (HPVs) in the development of cervical cancer, much effort has been directed at developing ways to prevent the development of the disease using immunological techniques. In the future, advances in chemotherapy, radiotherapy and the development of therapeutic vaccines may result in a diminishing role for surgery in the treatment of this disease.
Aetiology It has long been recognized that sexual activity is inextricably linked with the development of cervical cancer and its precursor, cervical intra-epithelial neoplasia (CIN). Early coitarche (age 16 years or younger) and a history of multiple sexual partners have been shown to be risk factors. Since the early work of Rigoni–Stern in the first half of the 19th
0268-0890/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2004.02.005
ARTICLE IN PRESS Invasive cervical cancer
201
Cervical intra-epithelial neoplasia
14
Rate per 100000
12 10 8 6 4 2 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Incidence
Mortality
Figure 1 Cervical cancer, incidence and mortality 1993–2002 (England).
century, the search has been on for a possible sexually transmitted agent. Over the last decade, it has become clear that HPV is the main aetiological agent responsible. HPVs are double-stranded DNA viruses that exhibit epithelial specificity. Over 200 different types and subtypes have been identified on the basis of their DNA sequences. Some of these viruses have been shown to have a predilection for genital mucosa, and within that group, certain oncogenic types can be identified. The so-called high-risk types include HPVs 16, 18, 31, 33 and 45. By using detection methods such as polymerase chain reaction, HPV DNA can be detected in 99% of cervical cancers. However, although HPV is the most common sexually transmitted disease, only a tiny proportion of those infected will go on to develop cancer. Therefore, other factors must be involved. Clearance and avoidance of HPV infection relies on a competent immune response. An efficient cellmediated immune response is probably crucial for the clearance of HPV infection, while the humoral component may be important in preventing reinfection. Therefore, anything compromising the immunity of an individual can be expected to result in increased risk of HPV-related disease. Smoking, through the effect of carcinogens and the interference with cervical antigen-presenting cells, has been shown to increase the relative risk of developing cervical cancer up to two-fold. Similarly, generalized immunosuppression, either as a result of drugs or human immunodeficiency virus, results in an increased risk of CIN and cancer. More recently, prolonged use of the oral contraceptive pill has been linked with up to a four-fold increase in risk for cervical cancer in women who are HPV-DNA positive.
The term ‘CIN’ was introduced by Richart in 1965 and was described as a spectrum of intra-epithelial abnormalities ranging from mild dysplasia to carcinoma in situ. These lesions affect the full thickness of the epithelium and are graded 1–3 depending on features such as loss of differentiation, abnormal nuclei and presence of abnormal mitotic figures. It is now recognized that the socalled low-grade CIN (CIN 1) will often regress spontaneously whereas high-grade CIN (CIN 2/3) has the potential to progress to frank malignancy in up to 30% of cases. The detection and potential treatment of CIN forms the basis of the cervical screening programme which relies on cervical cytology to detect dyskaryotic cells, thus alerting the medical practitioner to the possible presence of CIN or worse. Secondary screening with colposcopy allows identification of any lesions, which can then be treated if necessary. In the 10 years following the introduction of an organized screening programme that concentrated on adequate coverage of the target population, the incidence of cervical cancer fell by 42% in England and Wales. The development of liquid-based cytology has the potential to reduce the rate of inadequate smears as well as improving efficiency and laboratory productivity.
Diagnosis of cervical cancer Symptoms and signs A proportion of early-stage cervical cancers are asymptomatic and will be detected at colposcopy following abnormal cervical cytology. In other cases, abnormal vaginal bleeding may be the presenting symptom. Intermenstrual and postcoital bleeding are typical. An offensive, watery, blood-stained discharge may result in some cases. In more advanced disease, symptoms may arise due to local effects of tumour on surrounding structures. For instance, lymphatic obstruction may result in lymphoedema of the lower limbs, or hydronephrosis and loin pain in the case of a blocked ureter. Pelvic pain and sciatic pain have both been described when there is nerve involvement. Where bladder involvement occurs, haematuria, frequency and incontinence may occur. Rectal bleeding and tenesmus may result following rectal involvement.
ARTICLE IN PRESS 202
R.W. Todd, M. Shafi
Staging of cervical cancer The staging of cervical cancer is clinical and is shown in Table 1. The role of staging is to ascertain the extent of disease, allowing patients to be counselled and appropriate treatment to be planned. Underestimating the extent of disease may lead to the need for adjuvant therapy following surgery. Ideally, one treatment modality should be the goal in order to reduce morbidity.
Clinical examination In the past, examination under anaesthesia (EUA) was performed routinely when staging cervical cancer. Nowadays, some practitioners may feel EUA is unnecessary, particularly if examination in the clinic is satisfactory. Additional imaging may be sufficient, thus avoiding EUA. Clinical examination should include a careful assessment of the abdomen, in particular looking for hepatomegaly, hydronephrosis and lymphadenopathy. Bimanual vaginal examination is then performed. Of importance is the size and mobility of the cervix and uterus, as well as any suggestion of spread into surrounding tissues. Combined vaginal and rectal
Table 1
examination will also allow assessment of the uterosacral ligaments and further assessment of the parametria. EUA allows all of the above to be performed, usually more thoroughly than if the patient was awake. It also allows cystoscopy and sigmoidoscopy to be performed if there is suspicion of involvement of either bladder or bowel. Urine should be sent for cytology. EUA also permits further biopsies of the cervix or vagina to be taken if necessary. Clinical examination, although vital, has been shown to underestimate the extent of disease in up to 40% of cases. Therefore, other methods may be employed to obtain additional information.
Radiology If one studies the FIGO staging (Table 1), it can be seen that assessment of the renal tract is critical in defining Stage IIIb disease. In the past, an intravenous urogram was commonly performed, although some centres now rely on either computerized tomography (CT) or magnetic resonance imaging (MRI). These latter tools also allow assessment of the liver and para-aortic and pelvic lymph nodes as well as studying local spread of the disease. MRI has
Staging of cervical cancer (FIGO, 1994).
Stage
Features
I Ia Ia1
Carcinoma strictly confined to the cervix (extension to the corpus should be disregarded) Preclinical carcinoma of the cervix, i.e. diagnosed by microscopy Minimal microscopically evident stromal invasion o3 mm in depth and a horizontal spread p7 mm Lesions with a depth of invasion 43 mm and no more than 5 mm, and horizontal spread p7 mm Clinical lesions confined to the cervix or preclinical lesions greater than Stage Ia Clinical lesions o4 cm in diameter Clinical lesions X4 cm in diameter
Ia2 Ib Ib1 Ib2 II IIa IIb III
IIIa IIIb IV IVa IVb
The carcinoma extends beyond the cervix, but has not extended on to the pelvic wall; the carcinoma involves the vagina but not as far as the lower third No obvious parametrial involvement Obvious parametrial involvement The carcinoma has extended on to the pelvic wall. On rectal examination, there is no cancer-free space between the tumour and the pelvic wall; the tumour involves the lower third of the vagina; all cases with a hydronephrosis or non-functioning kidney should be included unless they are known to be due to another cause No extension to the pelvic wall, but involvement of the lower third of the vagina Extension onto the pelvic wall or hydronephrosis or non-functioning kidney The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum Spread of the growth to adjacent organs Spread to distant organs
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been shown to be superior to clinical examination and CT when determining tumour extent, particularly regarding parametrial involvement. MRI findings agree with the surgical and pathological findings in 70–90% of cases. MRI allows enlarged lymph nodes to be detected in up to 80% of cases, although sensitivity and specificity is reduced as distinguishing reactive inflammatory nodes from metastatic disease can be difficult. Positron emission tomography (PET) has emerged as a tool that may be useful in detecting recurrent disease, particularly after radiotherapy. Some studies have shown PET to have greater sensitivity than either MRI or CT in detecting lymph node metastases.
small cell or neuro-endocrine tumours, are associated with a poor prognosis.
Prognostic factors
Management
Patient factors
The management of be determined on a preferably in a cancer individualized, taking a account:
Cervical cancer has a bimodal distribution. It has previously been suggested that women in the younger (o40 years) age group have a worse prognosis. Data are conflicting, with some authors reporting a worse prognosis in this group, others reporting a better prognosis and others reporting no difference. Social status, race and parity are unrelated to outcome when compared stage for stage. Cervical cancer presenting at an early-stage in pregnancy is not associated with a worse outcome compared with the non-pregnant individual.
Tumour factors Stage at presentation is the strongest predictor of prognosis in cervical cancer, with survival times falling as stage increases (Table 2). This is due to the fact that as tumour stage increases, so does the tumour volume and, with that, the likelihood of lymphatic and vascular involvement increases. Lymphovascular space (LVS) involvement has been shown to correlate with the risk of lymph node metastases. In one series looking at Stage 1a2 tumours, LVS involvement increased the rate of node positivity from 3.2% to 16.1%. It can be seen (Table 2) that in the presence of positive nodes, 5year survival is reduced. The histology of the tumour can have a bearing on prognosis. It has been suggested that adenocarcinomas of the cervix have a worse prognosis than their squamous counterparts when compared stage for stage, although the data on this matter are conflicting. Certain rarer tumour types, such as
Table 2 Five-year survival (%) by stage and node status.
* * * * * *
Stage
Number
All cases
Node-positive cases
1b IIa IIb III IVa
6511 2433 2533 2598 1518
80.1 62.6 55.5 37.9 10.5
67.3 48.4 42.7 30.0 7.0
cervical cancer should multidisciplinary level, centre, and should be number of factors into
age of the patient; co-morbidities; stage and volume of the tumour; desire for fertility; patient choice; and tumour type.
Treatment modalities include surgery, radiotherapy and chemotherapy, either singly or in combination.
Early-stage disease Stage 1a1 disease Stage 1a1 lesions have a depth of invasion of less than 3 mm and are diagnosed on histology. The prognosis for Stage 1a1 disease is excellent with 5year survival rates of 495% described. The risk of lymph node metastasis is of the order of 0.5%. Thus, either local treatment in the form of a local excision or simple hysterectomy should suffice. It is important that excision margins on a cone biopsy are clear of any invasive or preinvasive disease. If not, repeat excision can be performed to obtain clear margins. Should other gynaecological conditions such as menorrhagia be a feature, or if desired by the patient, simple hysterectomy may be chosen.
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Stage 1a2 disease In Stage 1a2 disease, the depth of invasion is between 3 and 5 mm and disease is subclinical with the diagnosis being made on histology. The management of Stage 1a2 carcinomas has changed over recent years with a trend away from radical treatments. Regardless of the radicality, death rates and recurrence rates are low in this group. Of importance is the risk of lymph node metastasis, which is approximately 7% in these cases. The optimal treatment has yet to be defined and should be managed on an individual basis. Treatments for the local lesion range from cone biopsy through simple hysterectomy to radical hysterectomy. With all of these, the lymph node status also needs to be addressed. Since many of these lesions will occur in young women with a desire to retain their fertility, there has been a trend towards fertility-sparing surgery. Thus, if fertility is desired, the local lesion can be managed with simple excision by cone biopsy to achieve clear margins. The lymph nodes can then be assessed either extraperitoneally or laparoscopically. In the event of lymph node metastases, adjuvant treatment can be offered.
Stage 1b1/2a disease It has been recognized for some time that the outcomes for Stage 1b/2a disease are similar whether treated by radical surgery or radiotherapy. A large randomized study compared radiotherapy with surgery in 343 patients with Stage 1b or 2a disease. It was shown that 5-year survival was similar in both groups (83% and 74%, respectively). The main differences related to morbidity. A significant number of women in the surgery arm went on to have adjuvant radiotherapy for adverse
Table 3
features. Even taking this into account, surgery was associated with greater morbidity, although these complications could be more easily corrected. Radiotherapy may be associated with ovarian failure, bowel and bladder disturbance and vaginal stenosis. In the above study, patients with bulky Stage 1b tumours (44 cm) were more likely to receive adjuvant radiotherapy. Therefore, it would appear that if one can be confident that complete removal of tumour can be achieved with positive margins, particularly in women who desire ovarian function, primary surgery may be preferable. In order to avoid the extra morbidity associated with dual treatment modalities, in the case of bulky Stage 1b2 tumours or Stage 2a disease where adequate excision cannot be assured and risk of metastatic disease is higher, or if ovarian and sexual function is no longer an issue, primary treatment with chemoradiotherapy should be considered. If considering surgery, one needs to consider which technique is to be employed. Central to the surgical management of most cancers is the ability to remove the primary lesion with an adequate margin of normal tissue to ensure complete resection. When considering cervical carcinomas, it is immediately apparent that this may be complicated by local anatomy. Since the bladder lies anterior to the cervix and the rectum lies posterior, it is clear that there is little scope in extending these margins beyond a certain limit. Laterally, however, there is far more scope to extend the amount of tissue removed. This forms the basis of the Piver–Rutledge Class 3 hysterectomy (Table 3). This procedure removes the central lesion along with parametrial and vaginal tissue. The uterine artery is ligated and divided at its origin, and the ureter is traced along its path to the point at which it enters the bladder. The uterosa-
Piver–Rutledge classification of extended hysterectomy for the management of cervical carcinoma.
Class 1
Extrafascial hysterectomy. Ensures removal of all cervical tissue
Class 2
Modified radical hysterectomy. Removal of the medial half of the cardinal and uterosacral ligaments. Uterine vessels divided medial to the ureter
Class 3
Classical Wertheim–Meig’s radical hysterectomy. Wide radical excision of the parametrial and paravaginal tissues. Ureter is dissected down to the bladder. Uterosacrals divided at their origin, the cardinals divided at the pelvic sidewall
Class 4
More radical. The ureter is dissected from the pubovesical ligament, the superior vesical artery is sacrificed and 75% of the vagina is removed
Class 5
Extended radical hysterectomy that may involve resection of bowel, bladder or ureter
ARTICLE IN PRESS Invasive cervical cancer
cral ligaments are divided at their origin and the cardinal ligaments are divided at the pelvic sidewall. Additionally, the external iliac vessels are cleared of lymphatics from the point of the bifurcation of the common iliacs and the obturator fossa is explored and cleared in a similar fashion. This procedure would be regarded as the ‘gold standard’ procedure. In reality, many practitioners would perform the Class 2 procedure since the little evidence that there is would suggest no advantage of the Class 3 procedure over the Class 2 procedure. For Stage 1b2 and 2a tumours, the likelihood of needing adjuvant radiotherapy after surgery is high. Therefore, Stage 1b1 tumours are probably best suited to the above surgical approach. When considering surgery, one should not forget the associated morbidity. Both bladder and bowel dysfunction are well described following radical hysterectomy. Vesico- or ureterovaginal fistulas may result either as a result of direct surgical injury or indirectly due to devascularization. In addition, lymphadenectomy may result in pelvic lymphocyst formation. Effects on sexual function are poorly researched, although there is good evidence that radical surgery results in loss of vulval sensation as well as altered vaginal lubrication and, in some cases, vaginal shortening and loss of elasticity.
Fertility-sparing surgery Since many patients with cervical cancer are young, techniques have been developed that may allow conservation of fertility. This has been facilitated by the advent of minimal access surgery for pelvic lymphadenectomy. Radical trachelectomy involves excision of the majority of the cervix, the upper vagina and the proximal cardinal ligaments. This is performed through a vaginal approach. Often it is preceded by a laparascopic pelvic lymphadenectomy. If the nodes are negative, one can proceed with the trachelectomy. It is necessary to insert a cervical suture at the same time since cervical incompetence is almost inevitable. These procedures are, at present, best regarded as experimental although experience is growing rapidly. When counselling patients for this procedure, it should be made clear that long-term follow-up data on large numbers of patients are not yet available and that premature delivery may result in up to 60% of cases despite cervical cerclage.
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Advanced disease Surgery has very little role in the management of Stages IIb, III and IV disease. Previously, radiotherapy alone would have formed the mainstay of treatment. More recently, it has become clear that combined chemotherapy and radiotherapy confer a survival advantage. Cisplatin is the chemotherapy of choice and appears to be most effective when given alongside radiotherapy, possibly by sensitizing cells to radiotherapy. A large meta-analysis of 19 studies was published in 2001. As with most meta-analyses, trials included differed in size, design, schedules and agents used to treat. However, the conclusions drawn suggested a survival advantage, reduction in the incidence of local recurrence and a significant reduction in the incidence of distant metastases. Of note is that in the combined arms of all trials, acute toxicity was increased.
Relapsed disease The 5-year survival for patients with recurrent disease is less than 5%. Occasionally, if a recurrence is central and there is no evidence of distant spread, an exenterative procedure may be considered. This should be carefully planned by a multidisciplinary team, including colorectal and urological surgeons, since it may be necessary to remove the bladder (anterior exenteration), rectum (posterior exenteration) or both bladder and rectum (total exenteration). Input from both a psychiatrist and clinical psychologist is also vital in determining which patients are less likely to cope with the procedure and also in providing psychological support before and after. Patients who have undergone these procedures, particularly total exenteration, have been shown to be at a higher risk of suicide. Cisplatin may have a role in palliating symptoms in relapsed cases, although response rates may only be 30%. Since nearly all patients relapsing will have been exposed to radiotherapy, chemotherapy is less likely to be effective due to radiation-induced ischaemia. Re-irradiation rarely has a role in treating relapse. It was previously thought that further exposure to radiotherapy was possible if a significant time period had passed since the first exposure. Salvage percentages of between 10% and 25% were described. In reality, those cases where a ‘success’ was seen were likely to have received an inadequate dose at the outset. Nowa-
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days, with more modern sophisticated radiotherapy techniques, this situation is unlikely to occur. Reirradiation has been shown to result in major complications in at least 50% of cases.
Follow-up The strategy for following-up patients treated for cervical cancer will vary from centre to centre. This reflects the lack of evidence to back up any one strategy. Certainly, the use of vault smears is questionable since the sensitivity and specificity has been shown to be poor, particularly following radiotherapy. In reality, the follow-up will vary depending on local service provision and the wishes of the patient. Any follow-up should be based on history and clinical examination. Imaging should only be performed if there is clinical suspicion of recurrence.
R.W. Todd, M. Shafi
developed world, the same cannot be said of the developing world. Improved treatments, particularly in relation to chemoradiotherapy, have also led to improved survival in the developed world. More work is needed to develop and identify those strategies that will allow a similar reduction to occur in the developing world.
Practice points
*
*
*
*
The future *
The future will almost certainly see developments in the use of vaccines for both prevention and treatment of cervical cancer. The results of a randomized double-blind study looking at vaccination against HPV 16 in over 2300 young women were published in 2002. After a median of 17 months follow-up, the vaccine was shown to have an efficacy of 100% when looking at prevention of persistent genital HPV 16 infection. Clearly, these results are exciting and further work is needed. The main questions still to be answered are who to vaccinate, when, how often, which viruses to vaccinate against and what will be the effect on the incidence of cervical cancer and precancer? Work is also ongoing looking at therapeutic vaccines directed against HPV proteins, particularly the E6 and E7 proteins which are expressed by transformed cells. This could be of value in treating either CIN or cancer. Initial trials have yielded disappointing results and more work is needed. Finally, trials are ongoing to investigate the role of chemoradiotherapy, particularly in relation to studying different cytotoxic agents and treatment regimens.
Conclusions Cervical cancer continues to represent a major global health challenge. While screening for CIN has led to a fall in the incidence of the disease in the
Accurate staging of cervical cancer is critical in planning appropriate treatment. Staging is clinical and additional information may be obtained through the use of appropriate imaging. Early-stage disease is usually dealt with surgically. Fertility-sparing surgery may be possible in some cases. Combined chemoradiotherapy is more effective than either modality alone in the treatment of advanced disease. The prognosis for relapsed disease is poor, with a 5-year survival of approximately 5%.
Further reading Bernardini M, Barrett J, Seaward G, Covens A. Pregnancy outcomes in patients after radical trachelectomy. Am J Obstet Gynecol 2003;189:1378–82. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358:781–6. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217–26. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645–51. Landoni, F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib–IIa cervical cancer. Lancet 1997;350:535–40. Shepherd JH, Mould T, Oram DH. Radical trachelectomy in earlystage carcinoma of the cervix: outcome as judged by recurrence and fertility rates. Br J Obstetr Gynaecol 2001;108:882–5. Stanley M. Genital human papillomavirus infectionsFcurrent and prospective therapies. J Natl Cancer Inst Monogr 2003;31:117–24 [Chapter 17]. Van Geene P, Tidy JA. Prognostic factors in cervical cancer. In: Luesley DM, Barrasso R, editors. Cancer and Pre-cancer of the Cervix. Lippincott-Raven Publishers, Cambridge, UK, 1998. p. 275–95.